Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[C:32]([O-])([O-:34])=[O:33].[K+].[K+].Br[CH2:39][CH2:40][CH2:41][N+:42]([CH3:45])([CH3:44])[CH3:43].[Br-]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([O:20][CH2:39][CH2:40][CH2:41][N+:42]([CH3:45])([CH3:44])[CH3:43])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH2:6][C@@H:5]1[CH3:31])(=[O:3])[CH3:2].[CH:32]([O-:34])=[O:33]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Reactant: C[N+](C)(C)CCCBr
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)OCCC[N+](C)(C)C)cc3)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Product: O=C[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
4-{(2S,4R)-1-Acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}benzoic acid (for a preparation see Intermediate 18) (150 mg, 0.345 mmol) was dissolved in DMF (3 mL) and K2CO3 (47.7 mg, 0.345 mmol) then 3-bromo-N,N,N-trimethyl-1-propanaminium, bromide (90 mg, 0.345 mmol) were added. The resulting mixture was stirred at room temperature overnight, whereupon the reaction mixture was concentrated in vacuo and purified by MDAP (formate) to give 3-{[(4-{(2S,4R)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl}phenyl)carbonyl]oxy}-N,N,N-trimethyl-1-propanaminium, formate (41 mg, 0.064 mmol, 19% yield) as a yellow oil. LCMS (Formate, 2 min), Rt=0.86 min, MH+=534.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.I[C:26]1[CH:27]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:30][CH:31]=1.N>>[F:33][C:32]([F:35])([F:34])[C:28]1[CH:27]=[C:26]([N:10]2[C:9](=[O:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=3)[CH:12]=[N:11]2)[CH:31]=[CH:30][CH:29]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: CS(=O)(=O)c1ccc(-c2cn[nH]c(=O)c2-c2ccc(Cl)cc2)cc1
Agent: N
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(C(F)(F)F)c3)c(=O)c2-c2ccc(Cl)cc2)cc1

Procedure:
The title compound was prepared according to Example 93, starting with 4-(4-chlorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-3(2H)-pyridazinone and substituting 3-iodobenzotrifluoride in place of 4-bromothioanisole (yield: 210 mg, 59.5%). mp 103-105° C. 1H NMR (300 MHz, CDCl3) δ 3.08 (s, 3H), 7.18 (d, J=9 Hz, 2H), 7.28 (d, J=9 Hz, 2H), 7.41 (d, J=9 Hz, 2H), 7.65 (m, 2H), 7.95 (m, 3H), 8.04 (m, 2H). MS (DCI/NH3) m/z 505 (M+H)+, 525 (M+NH4)+. Anal. calc. for C24H16ClF3N2O3S: C, 57.14; H, 5.56. Found: C, 56.61; H, 3.28; N, 5.38.
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][CH2:30][C:31]1[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][C:31]4[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ClCc1cccnc1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1N(Cc2cccnc2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 227° C. and MS: m/e=461.3 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 3-chloromethyl-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([OH:15])=[C:13]([CH:16]=O)[CH:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26]>>[ClH:1].[C:25]([NH:29][CH2:16][C:13]1[C:14]([OH:15])=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:10]=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH:12]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=Cc1cc(-c2ccc(Cl)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Reactant: CC(C)(C)N
Product: CC(C)(C)NCc1cc(-c2ccc(Cl)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Product: Cl

Procedure:
5′-((tert-Butylamino)methyl)-3″,4,4″-trichloro-[1,1′:3′,1″-terphenyl]-4′-ol hydrochloride was prepared from 3,4,4″-trichloro-6′-hydroxy-[1,1′:3′,1″-terphenyl]-5′-carbaldehyde and tert-butylamine using the same procedure described in Example 5.
Reaction SMILES: Cl.[OH:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].[H-].[Na+].[C:10]([N:12]=[C:13](SC)[S:14][CH3:15])#[N:11]>CN(C)C=O>[NH2:11][C:10]1[N:12]=[C:13]([S:14][CH3:15])[N:5]=[C:4]([CH:3]([OH:2])[CH3:7])[N:6]=1
Reactant: CSC(=NC#N)SC
Reactant: CC(O)C(=N)N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nc(N)nc(C(C)O)n1
Temperature: 65 °C
Reaction time: 18 h
Yield: 4 %

Procedure:
Under a nitrogen atmosphere 2-hydroxypropanimidamide hydrochloride (4.97 g) was suspended in dry N,N-dimethylformamide (25 mL) and sodium hydride (1.66 g, 60 wt % in mineral oil) was added in one portion. When gas evolution ceased the white suspension was heated to 65° C. After 1 h dimethyl cyanocarbonimidodithioate (6.24 g) was added and the mixture was stirred at 65° C. for 18 hours. The reaction mixture was concentrated and triturated with water (200 mL). The resulting precipitate was filtered off, washed with water and the aqueous layer was extracted with 5% methanol in dichloromethane (3×100 mL). The combined organic extracts were dried (sodium sulfate) and concentrated before being purified by flash chromatography eluting with 10% methanol in dichloromethane to give the title compound (300 mg) as a yellow oil that solidified on standing.
Reaction SMILES: CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[C:59]([OH:63])(C)([CH3:61])[CH3:60].O.[Br:65][C:66]1C(C=C)=[C:74]([CH3:78])[CH:73]=[C:72]2[C:67]=1[CH:68]=[CH:69][CH:70]=[N:71]2>C(OCC)(=O)C>[Br:65][C:66]1[C:60]([C@H:59]([OH:63])[CH2:61][OH:22])=[C:74]([CH3:78])[CH:73]=[C:72]2[C:67]=1[CH:68]=[CH:69][CH:70]=[N:71]2
Reactant: C=Cc1c(C)cc2ncccc2c1Br
Reactant: CC(C)(C)O
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2ncccc2c(Br)c1[C@H](O)CO
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
AD-mix-α (0.7 g) was added to a mixed solvent of t-butanol and water (2.5 mL/2.5 mL) and stirred at 25° C. for 5 min, cooled to 0° C. The mixture was transferred to another flask containing 5-bromo-7-methyl-6-vinylquinoline (120 mg) and stirred at 0° C. for 48 hours. The mixture was diluted with ethyl acetate, washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc) to provide (S)-1-(5-bromo-7-methylquinolin-6-yl)ethane-1,2-diol (118 mg). LCMS-ESI+ (m/z): 282.1, 284.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:12]([NH2:17])[CH2:13][CH:14]([CH3:16])[CH3:15]>CN1CCCC1=O>[N:7]1[C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[NH:4][C:3]=1[CH2:2][NH:17][CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: ClCc1nc2ccccc2[nH]1
Reactant: CC(C)CCN
Solvent: CN1CCCC1=O
Product: CC(C)CCNCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of 5.0 9 (30.0 mmole) of 2-(chloromethyl)benzimidazole in 25 mL of anhydrous 1-methyl-2-pyrrolidinone is treated at 0° C. with 17.4 mL (150 mmole) of isoamylamine. The reaction mixture is allowed to warm to room temperature and stir for 16 hr. The reaction mixture is poured into 800 mL of ice/water, and the tan solid filtered and dried to afford 6.08 g (93%) of (benzimidazol-2-ylmethyl)(3-methylbutyl)amine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[C@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6])[CH3:2].ClCCl.Cl[CH2:15]/[CH:16]=[CH:17]\[CH2:18]Cl.CCCCCC>CCCCCC.C(OCC)(=O)C>[CH3:8][CH:7]([CH3:9])[C@H:5]([N:6]1[CH2:18][CH:17]=[CH:16][CH2:15]1)[C:4]([O:3][CH2:1][CH3:2])=[O:10]
Reactant: CCOC(=O)[C@@H](N)C(C)C
Reactant: ClC/C=C\CCl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](C(C)C)N1CC=CC1
Yield: 52 %

Procedure:
From L-valine ethyl ester (1.0 g, 6.9 mmol), dichloromethane (1 ml) and cis-1,4-dichloro-2-butene (250 mg, 2.0 mmol). Flash chromatography: silica gel, gradient neat hexane to hexane:ethyl acetate (1:2) afforded the product (205 mg, 52%) as yellow oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]=[C:5]=[O:6].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Br:7][C:8]1[CH:9]=[C:10]([N:11]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:12]=[CH:13][CH:14]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C=NCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1NCCN1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-Chloro-2-isocyanatoethane (1.18 mL, 13.8 mmol) was added dropwise to a solution of 3-bromoaniline (1.5 mL, 13.8 mmol) in DMF (30 mL) at 0° C. then stirred at room temperature for 16 hr, then 70° C. for 2 hr. The solution was cooled to room temperature and 1-chloro-2-isocyanatoethane (0.40 mL, 4.69 mmol) was added. After stirring at room temperature for 2 hr, the solution was diluted with DMF (120 mL), cooled to 0° C. and NaH (660 mg, 60% dispersion in mineral oil, 16.5 mmol) added in portions. The mixture was stirred at room temperature for 64 hr, then diluted with EtOAc. After washing with H2O three times then brine the solution was dried over Na2SO4, concentrated in vacuo and the residue purified by silica gel chromatography (EtOAc/hexanes) to give 1-(3-bromophenyl)-2-imidazolidinone as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.56-3.62 (m, 2H), 3.88-3.92 (m, 2H), 5.20 (br s, 1H), 7.15-7.20 (m, 2H), 7.49-7.51 (m, 1H), 7.71 (s, 1H).
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][CH:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[CH:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1.[O:35]1[CH2:39][CH2:38][CH:37]([C:40](O)=[O:41])[CH2:36]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.O>[CH3:3][C:4]1[N:8]([CH:9]2[CH2:15][C@H:14]3[N:16]([CH2:17][CH2:18][C:19]4([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[CH2:20][CH2:21][N:22]([C:40]([CH:37]5[CH2:38][CH2:39][O:35][CH2:36]5)=[O:41])[CH2:23][CH2:24]4)[C@H:11]([CH2:12][CH2:13]3)[CH2:10]2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2ccccc2)CCNCC1
Reactant: O=C(O)C1CCOC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2ccccc2)CCN(C(=O)C2CCOC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
A mixture of 2-methyl-1-{8-[2-(4-phenyl piperidin-4-yl)ethyl]-8-azabicyclo[3.2.1]oct-3-yl}-1H-benzimidazole dihydrochloride (75 mg, 0.16 mmol), tetrahydro-3-furoic acid (18 mg, 0.16 mmol) and triethylamine (48 mg, 0.48 mmol) in dimethylformamide (0.5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (68 mg, 0.18 mmol) and the resulting mixture was stirred at rt for 1 h. The reaction mixture was diluted with water and extracted with dichloromethane. The residue from the dichloromethane layer was purified by chromatography on silica gel eluting with 1:20 methanol:dichloromethane to give 2-methyl-1-((1R,5S)-8-{2-[4-phenyl-1-(tetrahydrofuran-3-ylcarbonyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-1H-benzimidazole as a clear oil (0.019 g, 23%). 1H NMR (400 MHz, DMSO-d6) δ 7.46 (m, 1H), 7.36 (m, 5H), 7.21 (m, 1H), 7.09 (m, 2H), 4.49 (m, 1H), 3.58-3.87 (m, 7H), 3.12-3.35 (m, 6H), 2.28-2.39 (m, 2H), 1.89-2.12 (m, 5H), 1.58-1.86 (m, 10H), 1.53-1.60 (m, 2H). HRMS C33H42N4O2 m/z 527.3386 (M+H)Cal., 527.3397 (M+H)Obs..
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([CH3:20])[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]>>[CH3:20][C:18]1[CH:17]=[C:12]([CH:11]=[C:10]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[CH:19]=1)[C:13]([O:15][CH3:16])=[O:14]
Reactant: OB(O)c1cccs1
Reactant: COC(=O)c1cc(C)cc(Br)c1
Product: COC(=O)c1cc(C)cc(-c2ccsc2)c1

Procedure:
Following the general procedure of EXAMPLE 766 and making non-critical variations but using 2-thiopheneboronic acid and methyl 3-bromo-5-methylbenzoate, methyl 3-methyl-5-(3-thienyl)benzoate is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1([NH:16][S:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[K+].[C:43]([Si:47]([O:50][CH2:51][CH2:52][CH2:53]I)([CH3:49])[CH3:48])([CH3:46])([CH3:45])[CH3:44].CCCCCC>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([C:11]1([N:16]([CH2:53][CH2:52][CH2:51][O:50][Si:47]([C:43]([CH3:44])([CH3:46])[CH3:45])([CH3:48])[CH3:49])[S:17]([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[CH:24][CH:25]=2)(=[O:18])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)C1(NS(=O)(=O)c2ccc(-c3ccc(F)cc3)cc2)CCCC1
Reactant: CC(C)(C)[Si](C)(C)OCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCCCN(C1(C(=O)OCc2ccccc2)CCCC1)S(=O)(=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 86.2 %

Procedure:
To a solution of 1-(4'-fluorobiphenyl-4-sulfonylamino)cyclopentanecarboxylic acid benzyl ester (23.0 grams, 50.7 mmol) in dry N,N-dimethylformamide (500 ml) at room temperature was added potassium hexamethyldisilazide (12.2 grams, 61.1 mmole) and, after 45 minutes, tert-butyl-(3-iodopropoxy)dimethylsilane (18.3 grams, 60.9 mmol). The resulting mixture was stirred at room temperature for 16 hours. Additional potassium hexamethyidisilazide (3.0 grams, 15 mmole) and tert-butyl-(3-iodopropoxy)-dimethylsilane (4.5 grams, 15 mmol) were then added. Stirring at room temperature was continued for a further 5 hours. The mixture was quenched by addition of saturated ammonium chloride solution. The N,N-dimethylformamide was removed by evaporation under vacuum. The residue was taken up in diethyl ether and washed successively with water, dilute aqueous hydrochloric acid solution and brine. After drying over magnesium sulfate, the diethyl ether was evaporated to afford a yellow oil. To this was added hexane and methylene chloride to induce crystallization of the starting material which was recovered by filtration. Evaporation of solvents from the filtrate afforded crude 1-[[3-(tert-butyl-dimethylsilanyloxy)propyl]-(4'-fluorobiphenyl-4-sulfonyl)amino]-cyclopentanecarboxylic acid benzyl ester as an amber oil (27.35 grams).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])[C:6]([Br:9])=[CH:7][CH:8]=1.CN(/[CH:24]=[N:25]/[C:26]1[N:27]=[CH:28][NH:29][C:30]=1[C:31](OCC)=[O:32])C.C1(O)C=CC=CC=1>C(Cl)Cl>[Br:9][C:6]1[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([Cl:19])[CH:18]=2)[C:14]#[N:15])=[C:4]([F:20])[C:3]([CH2:2][N:1]2[C:31](=[O:32])[C:30]3[NH:29][CH:28]=[N:27][C:26]=3[N:25]=[CH:24]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1[nH]cnc1/N=C/N(C)C
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(CN)c2F)c1
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cn3cnc4nc[nH]c4c3=O)c2F)c1

Procedure:
The title compound was prepared in a manner similar to that described herein using 3-{[3-(aminomethyl)-6-bromo-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.15 g, 0.422 mmol), ethyl 4-{[(1E)-(dimethylamino)methylidene]amino}-1H-imidazole-5-carboxylate (0.098 g, 0.464 mmol) and phenol (0.052 g, 0.548 mmol) in DCM (2 mL) to give 0.070 (34%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (s, 1H), 8.17 (s, 1H), 7.82 (s, 1H), 7.59 (d, 1H), 7.52 (s, 1H), 7.46 (s, 1H), 7.15 (t, 1H), 5.28 (s, 2H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C:10]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[C:10]3[C:15]4[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=4[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: Clc1nc(NCc2ccc(Cl)c(Cl)c2)c2c3c(sc2n1)CCCC3
Product: Clc1ccc(CNc2nc(-n3cncn3)nc3sc4c(c23)CCCC4)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-5,6,7,8-tetrahydro-4-(3,4-dichlorobenzylamino)-[1]-benzothieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[NH2:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=2)=[O:18])=[C:15]([O:30][CH3:31])[CH:14]=1.Br.C([O-])(O)=O.[Na+]>CC(O)C.O>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:12][C:13]2[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)=[O:18])=[C:15]([O:30][CH3:31])[CH:14]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ccnc12
Reactant: COc1cc(N)ccc1C(=O)NCc1ccc(C)nc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: COc1cc(Nc2ncc(Br)n3ccnc23)ccc1C(=O)NCc1ccc(C)nc1
Yield: 41.7 %

Procedure:
5,8-dibromoimidazo[1,2-a]pyrazine (285 mg, 1.03 mmol) and 4-amino-2-methoxy-N-[(6-methylpyridin-3-yl)methyl]benzamide (280 mg, 1.03 mmol) are stirred in iPrOH (5 mL) and HBr (48% aq., 380 μL) is added. The mixture is heated at reflux for 24 hours. The cooled suspension is poured into NaHCO3 (sat. aq., 25 mL) and water (25 mL) and extracted with CHCl3 (3×40 mL). The extracts are dried over MgSO4 and evaporated. The residue is purified by column chromatography, eluting with 10%-20% DCM/MeOH to afford the title compound as a pale yellow solid (200 mg, 0.43 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: Brc1nccs1
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2nccs2)cc1
Temperature: 95 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
To a stirred solution of (4-fluorophenyl)boronic acid (10 g, 60.9 mmol) in toluene (70 mL) and ethanol (200 mL) was added 2-bromothiazole (12.7 g, 91.4 mmol), followed by Pd(PPh3)4 (3.5 g, 3.04 mmol). The reaction mixture was purged with argon for 20 min, Na2CO3 solution (2M, 100 mL, 19.39 g) added, and the reaction mixture stirred at 95° C. for 5 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (2×100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layer was washed with ice-cold water (2×100 mL) followed by brine solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to obtained crude product. The crude product was purified by column chromatography (100-200 mesh silica gel) using 10% ethyl acetate in hexane to obtain 2-(4-fluorophenyl)thiazole as white solid (9.0 g, 82% yield). 1H NMR (400 MHz, DMSO): 7.98 (dd, 2H, J=6.8 & 14.0 Hz), 7.88 (d, 1H, J=4.8 Hz), 7.91 (d, 1H, J=2.8 Hz), 7.88 (d, 1H, J=4.8 Hz), 7.31 (t, 2H, J=8.8 & 17.2 Hz).
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]1[C:10](=[O:11])[CH:9]=[CH:8]O[C:6]=1[CH3:12])[CH3:3]>C(O)C>[CH2:2]([O:4][C:5]1[C:10](=[O:11])[CH:9]=[CH:8][NH:1][C:6]=1[CH3:12])[CH3:3]
Reactant: N
Reactant: CCOc1c(C)occc1=O
Solvent: CCO
Product: CCOc1c(C)[nH]ccc1=O
Temperature: 25 °C
Yield: 95 %

Procedure:
Ammonia (28% aq. 20 mL) was added to a solution of 3-ethoxy-2-methyl-4H-pyran-4-one (8.5 g, 55 mmol, obtained from Example 4(a)) in ethanol (20 mL) and the mixture was stirred under reflux for 24 h. The reaction mixture was cooled to r.t. and the solution was evaporated in vacuo. The pH was adjusted to pH 1 with 2M HCl, and the aqueous phase was extracted with ethyl acetate. The pH of the water phase was then adjusted to pH 10 with 2M sodium hydroxide. The aqueous phase was extracted with ethyl acetate (3×100 mL) and then saturated with NaCl (s) and extracted with CHCl3. The organic phase was dried (Na2SO4) and evaporated to give the title product (8.0 g, 95%). The crude product was used in the next step without further purification.
Reaction SMILES: O=[C:2]([C:9]1SC=[CH:12][CH:13]=1)[CH2:3][C:4]([O:6][CH2:7]C)=O.S1C=CC=C1C1C=CN=C(N)N=1.C[C:27]1([CH3:35])[O:32][C:31](=[O:33])[CH2:30][C:29](=[O:34])O1.COC1C=C(C=CC=1)C(O)=O>>[O:34]=[C:29]([C:13]1[CH:9]=[CH:2][CH:3]=[C:4]([O:6][CH3:7])[CH:12]=1)[CH2:30][C:31]([O:32][CH2:27][CH3:35])=[O:33]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCOC(=O)CC(=O)c1cccs1
Agent: COc1cccc(C(=O)O)c1
Agent: Nc1nccc(-c2cccs2)n1
Product: CCOC(=O)CC(=O)c1cccc(OC)c1

Procedure:
This material is prepared by a method analogous to that described for preparation of ethyl 3-oxo-3-(2-thienyl)propanoate in preparation of 1D, starting from 2,2-dimethyl-1,3-dioxane-4,6-dione and 3-methoxybenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[OH:15])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:16]I.[OH-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)COc1ccc(O)c(Cl)c1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
Ethyl 4-hydroxyphenoxyacetate (1.5 g, 7.6 mmol) was reacted with SO2Cl2 (1.5 mL) to give ethyl 3-chloro-4hydroxyphenoxyacetate (700 mg, ~80% pure) as a white powder. To a solution of ethyl 3-chloro-4-hydroxyphenoxyacetate (700 mg, 3.0 mmol) and MeI(0.28 mL, 4.5 mmol) in DMF(5 mL) at 0° C. was added 10M aq.NaOH(0.320 mL, 3.2 mmol). The mixture was stirred at r.t. for 12 h, then diluted with H2O and extracted with EtOAc to give ethyl 3-chloro-4-methoxyphenoxy-acetate (700 mg).