Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][C:16]([C:20]([NH:22][C:23]4[CH:28]=[CH:27][C:26]([CH2:29][N:30]([CH:32]5[CH2:37][CH2:36][C:35]6(OCC[O:38]6)[CH2:34][CH2:33]5)[CH3:31])=[CH:25][CH:24]=4)=[O:21])=[CH:15][C:14]=3[CH:42]=2)=[CH:6][CH:5]=1)[CH3:2].Cl.C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:19][CH2:18][CH2:17][C:16]([C:20]([NH:22][C:23]4[CH:24]=[CH:25][C:26]([CH2:29][N:30]([CH3:31])[CH:32]5[CH2:37][CH2:36][C:35](=[O:38])[CH2:34][CH2:33]5)=[CH:27][CH:28]=4)=[O:21])=[CH:15][C:14]=3[CH:42]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC5(CC4)OCCO5)cc2)CCO3)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCC(=O)CC4)cc2)CCO3)cc1
Reaction time: 22 h
Yield: 74.1 %

Procedure:
To a solution of 7-(4-ethoxyphenyl)-N-[4-[N-(4,4-ethylenedioxycyclohexyl)-N-methylaminomethyl]phenyl]-2,3-dihydro-1-benzoxepine-4-carboxamide (151.5 mg) in THF (10 ml) was added at room temperature 3N hydrochloric acid (2 ml), and the mixture was stirred for 22 hours. To the mixture was added saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the mixture was concentrated to give colorless solid, which was recrystallized from ethyl acetate/diisopropylether to give colorless crystals of 7-(4-ethoxyphenyl)-N-[4[N-methyl-N-(4-oxocyclohexyl)aminomethyl]phenyl]-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 288) (103.5 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>C1COCC1.C(N(CC)CC)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[CH:7]=[C:6]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(I)ccn1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-iodo-pyridine (10.0 g, 41.8 mmol) was dissolved in 200 mL dry THF and 17.5 mL triethyl amine. This mixture was evacuated and backfilled with argon several times to remove oxygen from the solution. Triphenylphosphine (329 mg, 1.25 mmol) and bis(triphenylphosphine)palladium(II)chloride (1.47 g, 2.09 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Copper(I)iodide (239 mg, 1.25 mmol) and trimethylsilylacetylene (6.28 g, 6.39 mmol) were added. The reaction mixture was stirred at room temperature overnight. The solvent was evaporated. The residue was taken up in 500 mL water and extracted three times with ethyl acetate (500 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/ethyl acetate 80:20). The desired product was obtained as a light brown semi solid (10 g, >100%). This material was used without any further purification for the next step.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]([C:31]1[CH:39]=[C:38]2[C:34]([CH:35]=[CH:36][NH:37]2)=[CH:33][CH:32]=1)=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:29][C:31]3[CH:39]=[C:38]4[C:34]([CH:35]=[CH:36][NH:37]4)=[CH:33][CH:32]=3)[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1ccc2cc[nH]c2c1
Product: FC(F)(F)c1cccc2c(-c3cccc(NCc4ccc5cc[nH]c5c4)c3)c(Cc3ccccc3)cnc12

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 6-formylindole to the procedure of step 1, Example 66. MS (ESI) m/z 508.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][OH:8])=[N:5][CH:4]=[N:3]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1)(=[O:19])=[O:18]
Reactant: Cn1ncnc1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1ncnc1COS(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1-methyl-1H-1,2,4-triazol-5-yl)methanol (53 mg, 0.47 mmol) in 2 mL of dichloromethane was added triethylamine (0.13 mL, 0.94 mmol), followed by methanesulfonyl chloride (0.044 mL, 0.56 mmol). The mixture was stirred at room temperature for 3 hours, then partitioned between EtOAc and water. The organic layer was washed with saturated NaHCO3 solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title product. ESI+MS: 192.2 [M+H]+.
Reaction SMILES: C(N(CCCC)CCCC)CCC.[C:14]([O:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=1[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][C:36]([O:39]C)=[CH:35][CH:34]=1)=[O:32])(=O)[CH2:15][CH2:16][CH2:17][CH3:18].Cl>C1(C)C(C)=CC=CC=1>[CH2:15]([C:14]1[O:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:22]=2[C:30]=1[C:31](=[O:32])[C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCC(=O)Oc1ccc([N+](=O)[O-])cc1CC(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Product: CCCCc1oc2ccc([N+](=O)[O-])cc2c1C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 ml of dry xylene, 2.1 ml (8.9 mmol) of tri-n-butylamine and 10 g of the recovered molecular sieve from example 3 were heated under reflux using a Dean-Stark condenser. Then 2.20 g (5.92 mmol) of 2-(2-pentanoyloxy-5-nitrophenyl)-1-(4-methoxyphenyl)-ethanone (example 2) dissolved in 5 ml of dry xylene were added to the reaction mixture. After 8 h LC-MS analysis indicated the complete consumption of the starting material. The reaction mixture was cooled to room temperature and the molecular sievel was filtered off. After evaporation of the solvent, 2.1 ml (8.9 mmol) of tri-n-butylamine were added followed by the addition of 17.8 mmol of gaseous HCl. The resulting mixture was heated at 200° C. for 4 h until LC-MS analysis indicated the complete consumption of the 2-n-butyl-3-(4-methoxybenzoyl)-5-nitrobenzofuran. The reaction mixture was cooled to room temperature and 20 ml of water and 50 ml MTBE were added. The organic phase was washed once with 25 ml of 1M aqueous HCl and 20 ml of water dried over MgSO4 and concentrated to dryness. Flash chromatography of the residue provided the pure title compound which crystallized directly to yield 1.30 g (65%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:6]([OH:13])=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:4]=1.[CH:18]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)([CH3:20])[CH3:19]>O1CCCC1>[C:9]([C:7]1[CH:8]=[C:3]([CH2:2][NH:28][C:25]2[CH:24]=[CH:23][C:22]([NH:21][CH:18]([CH3:20])[CH3:19])=[CH:27][CH:26]=2)[CH:4]=[C:5]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:6]=1[OH:13])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Reactant: CC(C)Nc1ccc(N)cc1
Solvent: C1CCOC1
Product: CC(C)Nc1ccc(NCc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
4-Bromomethyl-2,6-di-tert-butyl-phenol (2.42 g, 0.008 mole) was dissolved in 50 mL of dry tetrahydrofuran. In a separate conical flask N-Isopropyl-benzene-1,4-diamine (2.40 g, 0.016 mole) was dissolved in 25 mL of tetrahydrofuran and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 4-Bromomethyl-2,6di-tert-butyl-phenol was kept in oil-bath at 85° C. Solution in the flask was continuously stirred with the help of magnetic stirrer. N-Isopropyl-benzene-1,4-diamine solution was added drop-by-drop, from funnel to the flask in acidic medium for a span of 4-5 hours till all the solution was poured out. The reaction was terminated after that and the final reaction mixture was allowed to attain room temperature. The product was purified using silica gel column chromatography. Product was identified by 1H-NMR. The yield of 2,6di-tert-butyl4-[(4isopropylamino-phenylamino)methyl]-phenol is 2.025 g (68%).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].Cl.[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH:29]([C:33]([OH:35])=[O:34])[CH2:28]2)=[C:4]1[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Reactant: O=C(O)C1CNCCO1
Agent: Cl
Product: COC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 36.8 %

Procedure:
Methyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.15 g, 2.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.5 g, 3 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.47 g, 37%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1>O.C(#N)C>[I:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([NH2:19])(=[O:17])=[O:18])=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Fc1cc(I)ccn1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: O
Solvent: CC#N
Product: NS(=O)(=O)c1ccc(Nc2cc(I)ccn2)cc1
Temperature: 150 °C

Procedure:
A mixture of 2-fluoro-4-iodopyridine (1.0 g, 4.48 mmol) and 4-aminobenzenesulfonamide (772 mg, 4.48 mmol) was heated with an oil bath for 3 hours at 150° C. The title compound A4 was obtained from the residue by preparative HPLC (water/ACN gradient). Yield: 135 mg (8%). MS (ES) C11H10IN3O2S requires: 375. found: 376 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[NH:8]2)=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.I[CH3:22]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[N:8]2[CH3:22])=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[N:3]=1
Reactant: CI
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Product: Cn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
2-(2-Chloro-6-morpholino-9H-purin-8-yl)propan-2-ol (100 mg) was treated with iodomethane via General Procedure C to give crude intermediate 2-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)propan-2-ol which was treated with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A and purified via reverse phase HPLC to give 44 mg of 130 as a white solid. MS (Q1) 371.2 (M)+.
Reaction SMILES: [CH2:1]([CH:3]([CH2:12][CH3:13])[CH2:4][CH:5](C(O)=O)[C:6]([OH:8])=[O:7])[CH3:2]>C(Cl)Cl.CO>[CH2:1]([CH:3]([CH2:12][CH3:13])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCC(CC)CC(C(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CO
Product: CCC(CC)CCC(=O)O
Temperature: 25 °C
Yield: 0 %

Procedure:
2-(2-Ethyl-butyl)-malonic acid (3.55 g, 18.8 mmol) was heated at 195° C. for 2 h. After this time, the solution was cooled to 25° C. and diluted with a 90/10 methylene chloride/methanol solution. The organics were then washed with a saturated aqueous sodium chloride solution, concentrated in vacuo and azeotroped with acetonitrile (2×50 mL) to afford 4-ethyl-hexanoic acid (1.24 mg, 45%) as yellow oil, which was used without further purification; EI+-HRMS m/e calcd for C8H16O2 [M−H]+ 143.1072, found 143.1074. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.81 (t, J=7.2 Hz, 6H) 1.02-1.35 (m, 5H) 1.32-1.59 (m, 2H) 2.16 (t, J=7.8 Hz, 2H) 11.98 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:37])([F:19])[F:36])[CH:22]=3)=[O:34])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)o2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(C(F)(F)F)c2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C(F)(F)F)c3)n2)o1

Procedure:
Following general procedure A followed by L, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-trifluoromethyl-phenyl)-2-methyl-oxazole-4-carboxylic acid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][NH:24][CH2:25][CH2:26][OH:27]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:24]([CH3:23])[CH2:25][CH2:26][OH:27])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CNCCO
Product: CN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 2-(methylamino)ethanol were converted to yield 2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-methyl-amino]-ethanol, MS: 436 (MH+, 1Br).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]3=[N:9][C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([C:31]4[N:35]=[C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)[NH:33][N:32]=4)[CH2:27][CH2:26]3)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46]>CC(C)=O>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46].[C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][C:14]([C:16]#[N:17])=[CH:15][C:10]3=[N:9][C:8]=2[C:18]2[CH:19]=[CH:20][C:21]([CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([C:31]4[NH:35][C:34]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=5)=[N:33][N:32]=4)[CH2:29][CH2:30]3)=[CH:22][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccn2c(-c3ccccc3)c(-c3ccc(CN4CCC(c5n[nH]c(-c6ccccn6)n5)CC4)cc3)nc2c1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CC(C)=O
Product: N#Cc1ccn2c(-c3ccccc3)c(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)nc2c1

Procedure:
To 3.0 g 3-phenyl-2-(4-{[4-(5-pyridin-2-yl-1,2,4-triazol-3-yl)piperidin-1-yl]methyl}phenyl)imidazo[1,2-a]pyridine-7-carbonitrile (prepared as described under example 29) in 50 ml acetone is added a solution of 0.714 g fumaric acid in. The reaction mixture is stirred at ambient temperature for 3d. The desired compound is collected by filtration and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=O)[CH2:14]Br)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[NH2:19][C:20]([NH2:22])=[S:21]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:19]=[C:20]([NH2:22])[S:21][CH:14]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: NC(N)=S
Reactant: COc1ccc(Cn2cc(C(=O)CBr)cn2)cc1
Solvent: CC(C)=O
Product: COc1ccc(Cn2cc(-c3csc(N)n3)cn2)cc1
Yield: 83.9 %

Procedure:
According to Scheme 6, Step 1: A solution of 1-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-bromoethanone (9.70 mmol, 3.00 g) and of thiourea (9.70 mmol, 739 mg) in acetone (20 mL) was stirred under reflux for 1 hour. After filtration and evaporation of the filtrate, the white solid was partitioned between EtOAc and a saturated solution of Na2CO3. The aqueous phase was extracted with EtOAc. The organic phase was dried over Na2SO4, was filtered and was concentrated to yield 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-amine (8.14 mmol, 2.33 g) as an orange foam.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].[C:11](=[O:14])([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:14][CH2:11][CH2:3][CH2:2][CH2:9][CH3:8])[CH:5]=[O:6]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCOc1ccc(C=O)cc1O
Reaction time: 8 h
Yield: 48.6 %

Procedure:
n-Bromopentane (0.90 mL, 7.25 mmol, 1 eq) was added dropwise to a stirred solution of 3,4-dihydroxybenzaldehyde (1 g, 7.25 mmol, 1 eq) and cesium carbonate (7.07 g, 21.7 mmol, 3 eq) in N,N-dimethylformamide. The reaction mixture was stirred overnight and concentrated in vacuo. The residue was dissolved in ethyl acetate (50 mL), and the organic solution washed with water (2×50 mL), and brine (50 mL), then dried over magnesium sulfate and evaporated. Chromatography on silica with dichloromethane:petroleum ether (4:1) as eluent gave the product as a brown oil (367 mg, 24%). 1H NMR (CDCl3) δ 9.79 (s, 1H, O═C—H), 6.21 (s, 1H, OH), 4.08 (t, 2H, OCH2), 1.81 (m, 2H, OCH2CH2), 1.40 (m, 4H, CH2CH2CH3), 0.89 (t, 3H, CH3).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[S:14]([NH2:17])(=[O:16])=[O:15].ClS([N:22]=[C:23]=[O:24])(=O)=O.O>C(Cl)Cl>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:4][C:3]([S:14]([NH2:17])(=[O:15])=[O:16])=[C:2]([NH:1][C:23]([NH2:22])=[O:24])[CH:6]=2)=[CH:8][CH:9]=1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Nc1cc(-c2ccc(F)cc2)sc1S(N)(=O)=O
Solvent: ClCCl
Solvent: O
Product: NC(=O)Nc1cc(-c2ccc(F)cc2)sc1S(N)(=O)=O
Yield: 38.4 %

Procedure:
To the mixture of 3c (30 mg, 0.11 mol) in CH2Cl2 (10 mL) was added chlorosulfonyl isocyanate (14 μL, 0.165 mmol). The resultant mixture was stirred at room temperature for 3 h, then mixed with water (0.5 mL). Separation using a reverse phase HPLC afforded 3d (20 mg, 58%) as a white solid: MS (ES) 316 (M+H)+; 1H NMR (400 MHz, CD3OD) δ8.02 (s, 1 H), 7.69 (m, 2 H), 7.20 (m, 2 H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([Cl:17])[CH:16]=1)[C:11]([OH:13])=O.[C:18]([O:22][C:23]([N:25]1[CH2:35][CH2:34][C:28]2[N:29]=[C:30]([NH2:33])[N:31]=[CH:32][C:27]=2[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].[OH-].[Na+]>CN(C=O)C.C(Cl)Cl>[C:18]([O:22][C:23]([N:25]1[CH2:35][CH2:34][C:28]2[N:29]=[C:30]([NH:33][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:17])[CH:16]=[C:8]([Cl:7])[CH:9]=3)[N:31]=[CH:32][C:27]=2[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N)ncc2C1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nc(NC(=O)c3cc(Cl)cc(Cl)c3)ncc2C1
Reaction time: 1 h
Yield: 56.5 %

Procedure:
Oxalyl chloride 1184 μl (13.8 mmol) and two drops of DMF were added to a solution of 3,5-dichlorobenzoic acid 527 mg (2.76 mmol) in CH2Cl2 and stirring was performed for 1 h at RT under nitrogen as inert gas. After removal of the solvent, the 3,5-dichlorobenzoyl chloride was dissolved in pyridine (30 ml). 2-Amino-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 599 mg (2.39 mmol) was added to this solution at 0° C. and stirring was performed for 2 h at 0° C. and then for 2 h at RT under nitrogen as inert gas. After the addition of aqueous 1 M NaOH (40 ml) and stirring for 20 minutes, CH2Cl2 (50 ml) was added and the aqueous phase extracted with CH2Cl2 (3×20 ml). The combined organic phases were dried over Na2SO4. After filtration and removal of the solvent, purification was performed by means of column chromatography and the product 2-(3,5-dichloro-benzoylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylic acid tert-butyl ester 573 mg (1.35 mmol, 57% of theoretical) was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([C:37](O)=[O:38])([CH3:36])[CH3:35])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][C:34]([CH3:36])([CH3:35])[C:37]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:38])=[C:6]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][CH:10]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=3[CH3:22])[C:9]32[C:30]2[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=2)[NH:24][C:23]3=[O:32])[CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Br)ccc2OC(C)(C)C(=O)O)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cc(Br)ccc2OC(C)(C)C(=O)NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 45.1 %

Procedure:
A solution of racemic (2′S,3S,4′R)-4′-[5-bromo-2-(1-hydroxycarbonyl-1-methyl-ethoxy)-phenyl]-6-chloro-2′-(5-fluoro-2-methyl-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (20 mg, 0.032 mmol) and CDI (11 mg, 0.064 mmol) in DMF (0.2 mL) was heated at 60° C. for 30 min, then cooled to room temperature. To this solution was added a mixture of methanesulfonamide (19 mg, 0.2 mmol) and NaH (8 mg, 60%, 0.2 mmol) in DMF (0.2 mL). The resulting mixture was stirred at room temperature for 10 min, purified by prep-HPLC to give the title compound as a white solid (10 mg).
Reaction SMILES: COC1[C:8]2[C@H:9]3[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][C@@H:10]3[CH2:21][CH2:22][O:23][C:7]=2[CH:6]=[CH:5][CH:4]=1.Br.N1C=CC=CC=1.[C:31]([O:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])(OC(C)(C)C)=O>O>[C:42]([O:41][C:39]([O:38][C:31]1[C:8]2[C@H:9]3[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])[CH2:11][C@@H:10]3[CH2:21][CH2:22][O:23][C:7]=2[CH:6]=[CH:5][CH:4]=1)=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1cccc2c1[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1CCO2
Agent: Br
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)Oc1cccc2c1[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1CCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Example 272E (2.0 g, 6.3 mmol) and pyridine-HBr (8.0 g, 50 mmol) was heated at 135° C. for 72 hours. The mixture was cooled to room temperature, water was added, and saturated NaHCO3(aqueous) was added to adjust the pH value to 7. Di-tert-butyl dicarbonate (3.0 g, 13.8 mmol) was added, and the mixture was stirred for 16 hours. The reaction mixture was extracted with ethyl acetate, dried, and concentrated. The mixture was purified by silica gel column chromatography eluting with hexanes and ethyl acetate (5:1) to give a mixture of Example 374A and tert-butyl trans-10-[(tert-butoxycarbonyl)oxy]-1,3,3a,4,5,10b-hexahydro-2H-[1]benzoxepino[4,5-c]pyrrole-2-carboxylate side product. The mixture was dissolved in methanol (10 mL) and sodium methoxide (25%, 1.5 mL) was added. The mixture was heated at 50° C. for 1 hour, 1 N HCl(aq) was added to adjust pH value to 2, and the mixture was extracted with ethyl acetate. The crude material was triturated in acetone, precipitates were collected to afford the titled compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[C:8]([N:12]=[C:13]=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([NH:12][C:13]([N:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Piperidin-4-ol (1 g) was dissolved in dichloromethane, and tert-butyl isocyanate was added thereto. Then, triethylamine was added thereto at room temperature, and the reaction mixture was stirred for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to remove the solvent, crystallized in the presence of ether 50 mL, and filtered to obtain the title compound (1.8 g) as a white solid.