Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[C:39]([F:42])([F:41])[F:40].CCN(C(C)C)C(C)C>C1COCC1.C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([F:31])=[C:33]([C:39]([F:42])([F:40])[F:41])[CH:34]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Reactant: Nc1ccc(F)c(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3ccc(F)c(C(F)(F)F)c3)c3c(c2[nH]1)CC(C)(C)O3
Yield: 5.6 %

Procedure:
The title compound was prepared by following the procedure as described for Example-108 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.150 g, 0.403 mmol), thionyl chloride (2.0 mL), 4-fluoro-3-(trifluoromethyl)aniline (0.108 g, 0.604 mmol), benzene (4 mL), THF (6.0 mL) and DIPEA (4 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.012 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 2.24 (s, 3H), 3.10 (s, 2H), 7.30-7.54 (m, 5H), 7.82 (m, 1H), 8.36 (m, 1H), 9.08 (s, 1H), 9.92 (s, 1H), 10.96 (s, 1H); MS [M+H]+: 533.25.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)=[O:22])[CH2:17][CH2:16]1.Cl.[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:29][N:30]([CH3:34])[CH2:31][CH2:32][N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=2)[C:5]([N:15]2[CH2:16][CH2:17][N:18]([C:21]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[O:22])[CH2:19][CH2:20]2)=[C:6]([C:13]#[N:14])[C:7]1=[O:12]
Reactant: CN(C)CCCl
Reactant: Cc1ccc2[nH]c(=O)c(C#N)c(N3CCN(C(=O)c4cccs4)CC3)c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3cccs3)CC1)c(C#N)c(=O)n2CCN(C)C
Temperature: 0 °C
Yield: 22.1 %

Procedure:
A solution of Compound 107 (800 mg, 2.11 mmol), 2-dimethylamino ethyl chloride hydrochloride (1.52 g, 10.55 mmol), and potassium carbonate (2.91 g, 21.10 mmol) in DMF was heated overnight at 90° C. The solution was cooled and poured into ice water. The solids formed were filtered, washed by water, and dried. The crude product was purified by flash chromatography eluting with 0–10% methanol in ethylacetate gradient to yield 210 mg (24%) of pale yellow solids. M.P. 132° C. 1H NMR (DMSO-d6): δ 2.24 (s, 6H), 2.40 (s, 3H), 2.44 (m, 2H), 3.63 (m, 4H), 3.97 (m, 4H), 4.29 (m, 2H), 7.17 (dd, J=3.4, 4.8 Hz, 1H), 7.49 (m, 2H), 7.57 (m, 1H), 7.69 (s, 1H), 7.80 (d, J=5.2 Hz, 1H). EIMS m/z 450 (M+1). Anal. (C24H27N5O2S) C, H, N.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O.O>O1CCOCC1>[C:18]([O:17][C:15]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:13])[N:12]=2)[CH2:6][CH2:5]1)=[O:14])([CH3:21])([CH3:20])[CH3:19]
Reactant: Oc1cccc(N2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(O)n2)CC1
Temperature: 75 °C

Procedure:
To a stirring solution of 6-piperazin-1-yl-pyridin-2-ol (0.6 g, 3.30 mmol—Pavia, M. R., Taylor, C. P., Hershenson, F. M., Lobbestael, S. J. J. Med. Chem. 1987, 30(7), 1210) in 1,4-dioxane (15 ml) was added t-BOC2O (0.80 g, 3.68 mmol) and H2O (3 ml). The reaction mixture was heated at 75° C. for 8 h and cooled to RT. The heterogenous mixture was filtered and concentrated. Purification by flash silica gel chromatography afforded the title compound as a red solid, 0.90 g (97%). MS (ESI) 280.4 (M+H+).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][CH:41]([CH:44]([OH:47])[CH2:45][OH:46])[CH2:40][CH2:39]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:38]3[CH2:43][CH2:42][CH:41]([CH:44]([OH:47])[CH2:45][OH:46])[CH2:40][CH2:39]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCC(O)C1CCNCC1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(C(O)CO)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-piperidin-4-yl-ethane-1,2-diol (prepared from 4-vinyl-pyridine using procedure reported by Aaron, H. S. et al. J. Org. Chem. 1965, 30, 1331-1333) to give the title compound as a mixture of diastereomers. HR-MS (ES, m/z) calculated for C35H44Cl2N5O4 [(M+H)+] 668.2765, observed 668.2767.
Reaction SMILES: [CH:1](=[CH:8][C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH3:20])[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>C(O)C.O>[C:2]1([CH:1]=[CH:8][C:9](=[O:11])[CH:10]=[CH:20][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=CC(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 72.5 %

Procedure:
A mixture of 146.0 g (1.0 mole) of benzalacetone and 122.0 g (1.02 mole) 4-tolualdehyde (Compound II-A) was dissolved in 750 ml ethanol, and the solution was diluted with 200 ml water. With stirring, at room temperature, all at once, 100 ml of 10% NaOH solution were added. After 1.5 hours the thick, cream precipitate was filtered off, resuspended in 1 liter 20% ethanol in water, refiltered, sucked dry and recrystallized from ethanol/ethyl acetate to give 180 g of 1-phenyl-5-(4-tolyl)-1,4-pentadiene-3-one (Compound IV-A). The product structure was confirmed by field desorption mass spectrometry (FDMS) and infrared (IR) spectrometry.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[H-].[Na+].[CH2:17]([O:19][C:20]([C:22]1[C:26]([Cl:27])=[C:25]([Cl:28])[N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]=1[CH2:34]Br)=[O:21])[CH3:18]>CN(C=O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([Cl:27])=[C:25]([Cl:28])[N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:23]=1[CH2:34][N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:14])=[O:21])[CH3:18]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1c(Cl)c(Cl)n(CCC(C)C)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Cl)c(Cl)n1CCC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.9 %

Procedure:
To a solution of tert-butoxycarbonylamino-acetic acid ethyl ester (10.4 g, 51.3 mmol) in 90 mL of N,N′-dimethylformamide at 0° C. was added sodium hydride (60% dispersion in mineral oil, 2.35 g, 58.7 mmol). The ice bath was then removed, and the reaction mixture was stirred at ambient temperature for 10 min. After the reaction mixture was cooled at 0° C., the crude 4,5-dichloro-2-bromomethyl-1-(3-methyl-butyl)-1H-pyrrole-3-carboxylic acid ethyl ester (18.1 g, 48.9 mmol) in 20 mL of N,N′-dimethylformamide was added. The ice bath was removed, and the reaction mixture was stirred at ambient temperature for 1 hour. Saturated ammonium chloride aqueous solution (200 mL) and ethyl acetate (350 mL) were added to quench the reaction. The organic layer was washed with water and saturated sodium chloride aqueous solution, dried, filtered, and concentrated to afford 24.1 g of the crude 2-[(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-methyl]-4,5-dichloro-1-(3-methyl-butyl)-1H-pyrrole-3-carboxylic acid ethyl ester as a black oil.
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32]([NH:6][C@@H:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoic acid as in Example 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=9.75 min. MS (ESI−): mass calcd. for C22H15Br2FN4O5S2, 658.32; m/z found, 655/657/659 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.76 (s, 1H), 8.46-8.41 (m, 1H), 8.32-8.27 (m, 1H), 8.16-8.09 (m, 1H), 7.93-7.82 (m, 2H), 7.66-7.60 (m, 1H), 7.53-7.47 (m, 1H), 7.41-7.34 (m, 1H), 7.24-7.11 (m, 2H), 4.95-4.86 (m, 1H), 3.39-3.31 (m, 1H), 3.21-3.12 (m, 1H).
Reaction SMILES: F[C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([N:14]([CH3:25])[C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:26]([NH2:28])=[O:27])=[O:7])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN1C(=O)CCC1>[CH3:25][N:14]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)[C:12]1[S:13][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:29]=[CH:30][C:2]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:3][CH:4]=2)=[C:10]([C:26]([NH2:28])=[O:27])[N:11]=1
Reactant: CN(c1ccc2ncccc2c1)c1nc(C(N)=O)c(NC(=O)c2ccc(F)cc2)s1
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(C(=O)Nc3sc(N(C)c4ccc5ncccc5c4)nc3C(N)=O)cc2)CC1
Temperature: 150 °C
Yield: 54 %

Procedure:
A mixture of 5-(4-fluorobenzamido)-2-[methyl(quinolin-6-yl)amino]thiazole-4-carboxamide (100 mg, 0.24 mmol) and 1-methyl-piperazine (110 mg, 1.10 mmol) in NMP (3 mL) was heated at 150° C. for 1.5 hrs. The reaction mixture was diluted with ice-water (5 mL), and the resulting solids were collected by filtration and washed successively with water and ether to give 0.065 g (54% yield) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:17][CH2:9][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(Cl)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)nc1Cl
Temperature: 80 °C
Yield: 97.9 %

Procedure:
To a solution of 2,3-dichloro-6-methylpyridine (2 g, 12.3 mmol) in carbon tetrachloride (40 mL) was added NBS (2.64 g, 14.8 mmol) followed by AIBN (40 mg, 0.24 mmol). The reaction heated to 80° C. under nitrogen for 3.5 hours. The reaction was cooled and concentrated in vacuo. The residue was sonicated in heptanes and filtered. The filtrate was eluted through a pad of silica using 10% TBME in heptanes to afford the title compound (2.90 g). The crude material was taken on directly to the next step.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH:28]1[C:33]([OH:35])=[O:34]>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[N:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH:28]2[C:33]([OH:35])=[O:34])=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nncs2)=NC1c1ccc(F)cc1F
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nncs2)=NC1c1ccc(F)cc1F
Yield: 40.5 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-difluorophenyl)-2-(1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.66 g, 1.5 mmol) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.5 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.3 g, 41%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Ni]>[NH2:14][C:12]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:10][C:8]2[N:9]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6][C:7]=2[CH:13]=1
Reactant: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2[N+](=O)[O-])CC1
Agent: [Ni]
Solvent: CCO
Product: CN1CCN(c2cc3nc(C(C)(C)C)sc3cc2N)CC1

Procedure:
A solution of 86 g of the above nitro compound in 150 ml of ethanol is hydrogenated in presence of 30 g of Raney nickel at 45°. The solution is filtered to give 6-amino-2-tert-butyl-5-(4-methylpiperazin-1-yl)benzothiazole, melting at 130° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17]O)[N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][C@@H:14]([CH2:17][N:31]3[C:27](=[O:37])[C:28]4[C:29](=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:30]3=[O:32])[N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:12][C:11]=2[S:10][C:9]=1[NH2:26])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1C[C@@H](CO)N(C(=O)OC(C)(C)C)C2
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1C[C@@H](CN1C(=O)c3ccccc3C1=O)N(C(=O)OC(C)(C)C)C2
Temperature: 0 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
To a mixture of the above 2-amino-5-(S)-hydroxymethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (2.00 g, 5.20 mmol), phthalimide (0.92 g, 6.24 mmol) and triphenylphosphine (1.64 g, 6.24 mmol) in dry tetrahydrofuran (30 ml) cooled to 0° C. under a nitrogen atmosphere was added diethyl azodicarboxylate (DEAD) (0.98 ml, 6.24 mmol). The reaction mixture was allowed to stir overnight, slowly warming to room temperature. Next day the reaction mixture was again cooled to 0° C. and phthalimide (0.46 g, 3.12 mmol), triphenylphosphine (0.82 g, 3.12 mmol) and diethyl azodicarboxylate (DEAD) (0.49 ml, 3.12 mmol) was added in sequence and the reaction mixture was allowed to stir overnight, slowly warming to room temperature. The volatiles were evaporated in vacuo and the resultant solid dissolved in dichloromethane (20 ml). The residue was subjected to flash column chromatography using a mixture of ethyl acetate/hexane (1:2) as eluent. Fractions were collected affording after evaporation in vacuo 1.0 g of the desired compound contaminated with phthalimide. Recrystallization from ethanol gave 0.23 g (9%) of pure 2-amino-5-(S)-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:18]([CH2:19][CH3:20])[CH2:16][CH3:17])(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: CCNCC
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)S(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Yield: 82.9 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and diethylamine (0.40 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N,N-diethyl-2 (trifluoromethyl)benzenesulfonamide (0.46 g, 83%) was provided after purification. MS (ESI) m/z 360. HPLC purity 100.0% at 210-370 nm, 10.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1B(O)O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:26]4[S:25][CH:29]=[CH:28][CH:27]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: OB(O)c1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccs4)cc32)N=C1N
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 4.5 %

Procedure:
A mixture of 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (21 mg, 0.05 mmol), thiophen-2-ylboronic acid (14 mg, 0.1 mmol), Cs2CO3 solution (2 M, 0.5 mL) and Pd(PPh3)2Cl2 (10 mg) in 1,4-dioxane (1 mL) was stirred in a microwave test tube under Ar at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 2′-amino-1′-methyl-2-phenyl-6-(thiophen-2-yl)spiro[chroman-4,4′-imidazol]-5′-(1′H)-one (0.87 mg, 4%). 1H-NMR (MeOD): 2.45-2.54 (M, 1H), 2.60-2.63 (m, 1H), 3.32 (s, 3H), 5.88 (d, 1H), 7.06-7.14 (m, 2H), 7.33-7.39 (m, 2H), 7.41-7.50 (m, 3H), 7.51-7.64 (m, 4H).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:15]1[S:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][N:19]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.Cl>CS(C)=O.[I-].[K+].O>[CH3:23][O:22][C:20]([C:17]1[S:16][C:15]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[N:19][CH:18]=1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1cnc(Br)s1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Agent: Cl
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
1,1-Dimethylethyl 1-piperazinecarboxylate (1.86 g, 10 mmol), methyl 2-bromo-5-thiazolecarboxylate (2.0 g, 9.0 mmol), diazabicycloundecene (1.5 mL, 10 mmol) and a catalytic amount of potassium iodide (2 mg) were dissolved in 10 mL of dry dimethylsulfoxide and stirred at ambient temperature for 1 h to give a precipitate. An additional 10 mL of dimethylsulfoxide was added, the mixture was heated briefly to dissolve the solids, and the mixture was stirred at ambient temperature for 40 minutes and then at 50° C. for 2 h. The warm solution was added dropwise with stirring to 200 mL of cold water containing 10 mL of 1 N aqueous hydrochloric acid, and the resulting precipitate was filtered, dissolved in ether, dried over MgSO4 and concentrated under reduced pressure to give 2.62 g of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3](=[O:30])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[S:22][C:21]=3[CH:28]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:29].[BH4-].[Na+]>C1COCC1>[CH2:13]([C:12]([C:17]1[CH:18]=[CH:19][C:20]2[CH:24]=[C:23]([C:25]([OH:27])=[O:26])[S:22][C:21]=2[CH:28]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:30])[C:2]([CH3:31])([CH3:32])[CH3:1])=[C:7]([CH3:29])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)sc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2cc(C(=O)O)sc2c1
Reaction time: 4 h
Yield: 87.6 %

Procedure:
A solution of 6-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzo[b]thiophene-2-carboxylic acid (102 mg, 0.226 mmol) in THF (5.0 mL) at RT is treated with NaBH4 (17 mg, 0.451 mmol). The resulting mixture is stirred for 4 h. The reaction is quenched with HCl (1.0 N, 1.0 mL) and extracted with EtOAc (2×20 mL). The organic layer is dried over Na2SO4 and concentrated to afford the title compound (90 mg, 88%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[C:6]([F:10])[C:5]([Br:11])=[CH:4][CH:3]=1.[NH2:12][C:13](N)=[O:14]>>[Br:11][C:5]1[C:6]([F:10])=[C:7]2[C:2](=[CH:3][CH:4]=1)[N:1]=[C:13]([OH:14])[N:12]=[CH:8]2
Reactant: Nc1ccc(Br)c(F)c1C=O
Reactant: NC(N)=O
Product: Oc1ncc2c(F)c(Br)ccc2n1
Temperature: 180 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
A mixture of 6-amino-3-bromo-2-fluorobenzaldehyde (3.0 g, 13.76 mmol) and urea (12.40 g, 206.40 mmol) was heated to 180° C. and stirred for 2 hours. The reaction mixture was cooled to room temperature. The resulting precipitate was collected, washed with water (3×100 mL) and co-evaporated with toluene three times to completely remove the moisture trapped. The title compound (3.3 g, 99%) was obtained as a yellow solid. MS (ES+) C8H4BrFN2O requires: 242, found: 243, 245 [M+H]+.
Reaction SMILES: C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.CC(C)([O-])C.[Na+].Cl[C:31]1[CH:36]=[CH:35][N:34]=[C:33]2[S:37][C:38]([CH2:40][CH2:41][CH3:42])=[N:39][C:32]=12.[NH2:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[CH:46][C:45]=1[S:51][C:52]1[CH:57]=[CH:56][C:55]([NH:58][C:59](=[O:61])[CH3:60])=[CH:54][CH:53]=1.NC1C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:50][C:48]1[CH:47]=[CH:46][C:45]([S:51][C:52]2[CH:53]=[CH:54][C:55]([NH:58][C:59](=[O:61])[CH3:60])=[CH:56][CH:57]=2)=[C:44]([NH:43][C:31]2[CH:36]=[CH:35][N:34]=[C:33]3[S:37][C:38]([CH2:40][CH2:41][CH3:42])=[N:39][C:32]=23)[CH:49]=1
Reactant: CCCc1nc2c(Cl)ccnc2s1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Solvent: Cc1ccccc1
Solvent: Nc1ccccc1
Product: CCCc1nc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3)ccnc2s1
Temperature: 100 °C
Yield: 12.1 %

Procedure:
A dry nitrogen-purged flask was charged with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (38.6 mg, 0.1128 mmol), tris(dibenzylideneacetone)-dipalladium (25.8 mg, 0.0282 mmol), and sodium tert-butoxide (83.8 mg, 0.8463 mmol). A solution of the product of Example 5G (120 mg, 0.5642 mmol) in anhydrous toluene (5 mL) was added via syringe, followed by the product from Example 7b (130 mg, 0.4773 mmol). The reaction was heated in a preheated 100° C. oil bath for 2.5 hours, cooled to room temperature, treated with additional 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phospha-bicyclo[3.3.3]undecane (38.6 mg), tris(dibenzylideneacetone)dipalladium (25.8 mg) and starting aniline (130 mg), and heated at 100° C. for an additional 18 hours. The reaction was cooled to room temperature and the solvent removed by rotary evaporation in vacuo. Purification by silica gel flash chromatography with a gradient of 40% to 60% ethyl acetate/methylene chloride gave the desired title compound as a tan foam (26 mg, 10%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.01 (t, J=7.35 Hz, 3H) 1.73-1.91 (m, 2H) 2.01 (s, 3H) 2.34 (s, 3H) 3.07 (t, J=7.54 Hz, 2H) 6.78 (d, J=5.52 Hz, 1H) 6.97-7.09 (m, 1H) 7.16-7.30 (m, 3H) 7.36 (s, 1H) 7.51 (d, J=8.82 Hz, 2H) 8.15 (d, J=5.52 Hz, 1H) 8.53 (s, 1H) 9.99 (s, 1H); MS (DCI/NH3) m/z 449 (M+H)+.