Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4]1.[CH3:10][C:11]1([CH3:39])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21](O)=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[C:32](=[O:37])[C:31]2=[O:38])[CH:25]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[CH3:10][C:11]1([CH3:39])[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:21]([NH:9][S:6]([CH:3]3[CH2:5][CH2:4]3)(=[O:8])=[O:7])=[O:22])[CH:18]=2)[NH:13][CH:12]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[C:32](=[O:37])[C:31]2=[O:38])[CH:25]=1
Reactant: CN1CCN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)C(=O)C1=O
Reactant: NS(=O)(=O)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2cccc(C3Nc4ccc(C(=O)NS(=O)(=O)C5CC5)cc4CC3(C)C)c2)C(=O)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 20 %

Procedure:
To a suspension of 60% sodium hydride (192 mg, 4.8 mmol) in N,N-dimethylformamide (2.5 mL) was added cyclopropanesulfonamide (593 mg, 4.9 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 3,3-dimethyl-2-[3-(4-methyl-2,3-dioxo-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (200 mg, 0.5 mmol) and 1,1′-carbonyldiimidazole (200 mg, 1.2 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of cyclopropanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded cyclopropanesulfonic acid {3,3-dimethyl-2-[3-(4-methyl-2,3-dioxo-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carbonyl}-amide (51 mg, 20%) as a white solid: LC/MS m/e calcd for C26H30N4O5S (M+H)+: 511.62, observed: 511.2.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:16])([CH3:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[CH2:17][CH2:18][C:19](=[O:21])[CH3:20].[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>N1C=CC=CC=1>[C:22]([O:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([CH3:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH:5]=[CH:4][C:3]=1[CH2:17][CH2:18][C:19](=[O:21])[CH3:20])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(O)c1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCC(C)(C)c1ccc(CCC(C)=O)c(OC(C)=O)c1

Procedure:
A solution of 2.0 g. of 4-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-2-butanone in 15 ml. of pyridine is treated at 10° C. with 10 ml. acetic anhydride and the mixture stirred for 18 hours under nitrogen. It is then poured onto ice/water and acidified with dilute hydrochloric acid. The acidified mixture is extracted with ethyl acetate (2×100 ml.), the extracts combined, washed with brine and dried (MgSO4). Evaporation under reduced pressure affords the title product as an oil.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([NH2:30])[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([NH:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:31])([F:32])[F:22])[CH:25]=4)=[O:18])=[CH:13][CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
To a solution of (4-adamantan-1-yl-phenoxy)-acetic acid (50 mg, 0.17 mmol), 3-trifluoromethyl-phenylamine (42 mg, 0.26 mmol) and DIPEA (33.85 mg, 0.26 mmol) in DMF (2 mL) was added EDC (50.2 mg, 0.26 mmol) and HOBt (35.39 mg, 0.26 mmol) at room temperature. The reaction mix was stirred at room temperature until completion and then poured into water (100 mL). The resulting solid was extracted with ethyl acetate, washed with brine, aqueous sodium bicarbonate and water, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash chromatography on silica gel (EtOAc: hexanes=1:9 to 2:8) to afford of 2-(4-adamantan-1-yl-phenoxy)-N-(3-trifluoromethyl-phenyl)acetamide as a colorless solid (0.061 g, 81% yield).
Reaction SMILES: [CH2:1]([C@:3]12[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@@H:8]1[CH2:7][C@:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)([OH:18])[C@:5]([CH3:26])([OH:25])[CH2:4]2)[CH3:2].Cl[CH2:28][C:29]#[N:30]>>[CH2:1]([C@@:3]12[CH2:4][C@:5]([OH:25])([CH3:26])[C@:6]([OH:18])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:7][C@H:8]1[CH2:9][CH2:10][C:11]1[CH:12]=[C:13]([O:17][CH2:28][C:29]#[N:30])[CH:14]=[CH:15][C:16]2=1)[CH3:2]
Reactant: N#CCCl
Reactant: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccn3)C[C@H]1CCc1cc(O)ccc12
Product: CC[C@@]12C[C@@](C)(O)[C@](O)(c3ccccn3)C[C@H]1CCc1cc(OCC#N)ccc12

Procedure:
The title compound was prepared from the compound of Example 102 according to the procedure of Example 57, running the reaction at room temperature overnight and using chloroacetonitrile as the alkylating agent. Mass spectrum (m/e) 393 (M++1).
Reaction SMILES: [N:1]([CH2:4][CH2:5]CO)=[N+:2]=[N-:3].S(Cl)(C)(=O)=O.[CH3:13][S:14]([O:17][CH2:18]CN=[N+]=[N-])(=[O:16])=[O:15]>>[CH3:13][S:14]([O:17][CH2:18][CH:4]([N:1]=[N+:2]=[N-:3])[CH3:5])(=[O:16])=[O:15]
Reactant: [N-]=[N+]=NCCCO
Reactant: CS(=O)(=O)OCCN=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Product: CC(COS(C)(=O)=O)N=[N+]=[N-]

Procedure:
Reaction of 3-azidopropanol (1.00 g, 9.90 mmol) and mesyl chloride (1.14 mL, 14.85 mmol) within 3 h as described for synthesis of 156a gave compound 156b (1.18 g) as a crude colorless oil.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][N:14]1[C:19]2=[CH:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:18]2[C:17](=[O:31])[N:16]([CH3:32])[C:15]1=[O:33].C([O:37][B:38](OC(C)C)[O:39]C(C)C)(C)C>C1COCC1>[CH3:13][N:14]1[C:19]2=[CH:20][N:21]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:30])[CH3:29])[C:22]([B:38]([OH:39])[OH:37])=[C:18]2[C:17](=[O:31])[N:16]([CH3:32])[C:15]1=[O:33]
Reactant: Cn1c(=O)c2cn(COCC[Si](C)(C)C)cc2n(C)c1=O
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(B(O)O)n(COCC[Si](C)(C)C)cc2n(C)c1=O
Temperature: -5 °C
Reaction time: 0.5 h

Procedure:
Butyl lithium (1.26M, 28.4 mL, 35.8 mmol) was added dropwise to a solution of diisopropylamine (3.63 g, 35.8 mmol) in THF (20 mL) at −78° C., keeping the internal temperature below −40° C. Once the addition was complete, the contents of the flask were allowed to warm to −5° C., then were re-cooled to −78° C. The resulting mixture was cannulated over a period of about 30 minutes into a suspension of 1,3-dimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (step 1) (6.93 g, 22.4 mmol) in THF (75 mL) at −78° C. The mixture was stirred at −78° C. for 30 minutes, then triisopropylborate (8.3 mL, 35.8 mmol) was added dropwise. The solution was stirred at −78° C. for 1.5 hours, then was quenched by carefully adding sat ammonium chloride (200 mL).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6]>N1CC=CCC1>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:30]5[CH2:2][CH:3]=[CH:4][CH2:28][CH2:29]5)[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Agent: C1=CCNCC1
Product: Cc1ccc(NC(=O)c2ccnc(N3CC=CCC3)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) in 1,2,3,6-tetrahydropyridine (1 ml) was heated at 120° C. for 18 h in a sealed tube. The reaction was concentrated under vacuum, the residue chromatographed on an SPE (C18) eluting with a water/acetonitrile gradient, to give after evaporation of the solvents under vacuum N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(1,2,3,6-tetrahydropyrid-1-yl)isonicotinamide. NMR; δH [2H6]—DMSO 10.31,(1H, s), 8.62,(1H, t), 8.25,(1H, d), 7.93,(2H, d), 7.72,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.18,(1H, s), 7.04,(1H, d), 5.90,(1H, m), 5.83,(1H, m), 3.99,(2H, m), 3.75,(2H, t), 3.16,(2H, t), 2.21,(5H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.44 min, MH+467.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[O:13]=[C:14]1[CH2:19][C:18](=O)[CH2:17][N:16]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:15]1>C(O)(=O)C>[Br:12][C:3]1[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][C:18]1[CH2:17][N:16]([C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:15][C:14](=[O:13])[CH:19]=1
Reactant: O=C1CC(=O)CN(C(=O)OCc2ccccc2)C1
Reactant: COC(=O)c1cccc(N)c1Br
Solvent: CC(=O)O
Product: COC(=O)c1cccc(NC2=CC(=O)CN(C(=O)OCc3ccccc3)C2)c1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
Methyl 3-amino-2-bromobenzoate (0.25 g, 1.1 mmol) and benzyl 3,5-dioxopiperidine-1-carboxylate (0.13 g, 0.55 mmol) were dissolved in 10 mL of acetic acid at 25° C., under nitrogen. The mixture was stirred for 8 hours at 70° C. The resultant solid was purified by chromatography column on silica gel (elution with hexane/ethyl acetate) to afford 0.13 g (51%) of benzyl 3-((2-bromo-3-(methoxycarbonyl)phenyl)amino)-5-oxo-5,6-dihydropyridine-1(2H)-carboxylate as a tan foam. 1H NMR (CDCl3-d1) δ 7.53-7.58 (m, 3H), 7.42-7.48 (m, 5H), 5.56 (s, 1H), 5.16 (s, 2H), 4.46 (s, 2H), 4.13 (s, 2H), 3.93 (s, 3H). MS (ESI) m/e [M+1]+ 459.0.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[CH2:15][CH2:16][O:17]C1CCCCO1)=O)(C)(C)C.[ClH:24]>C(O)C>[ClH:24].[ClH:24].[C@H:12]12[CH2:14][C@H:9]([NH:8][CH2:13]1)[CH2:10][N:11]2[CH2:15][CH2:16][OH:17]
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2CCOC1CCCCO1
Agent: Cl
Solvent: CCO
Product: OCCN1C[C@@H]2C[C@H]1CN2

Procedure:
A mixture of 5-[2-(tetrahydro-pyran-2-yloxy)ethyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.80 mmol, 2.4 mmol) and aqueous hydrochloric acid (2 mL, 2N) in ethanol (10 mL) was stirred under reflux for one hour and then evaporated under reduced pressure to yield crude (1S,4S)-2-(2,5-Diazabicyclo[2.2.1]hept-2-yl)ethanol, dihydrochloride (0.51 g) as a dark oil which was used in the next step without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]1[C:7]([O:9]C(C)(C)C)=[O:8].[ClH:14]>O>[ClH:14].[ClH:14].[NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)[C@@H]1CNCCN1
Agent: Cl
Solvent: O
Product: O=C(O)[C@@H]1CNCCN1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The crude tert-butyl (S)-piperazine-2-carboxylate from Example 7 was stirred in 2.9 g of water and 2.1 g (18.4 mmol) of 32 percent hydrochloric acid for 20 minutes at 100° C. The mixture was cooled to 0° C. and stirred for a further 1 hour. The hydrochloride which had precipitated out was filtered off and washed with 10 ml of dichloromethane. The yield of the title compound was 0.24 g (41 percent, based on tert-butyl pyrazinecarboxylate). The ee value was 77.6 percent.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH2:11]([N:23]=[C:24]=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:11]([NH:23][C:24]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=c1[nH]sc2ccccc12
Reactant: CCCCCCCCCCCCN=C=O
Product: CCCCCCCCCCCCNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6g (78% yield) was synthesized from benzo[d]isothiazol-3-one and dodecyl isocyanate as a white solid. mp 66-67° C.; IR(CHCl3) 3279, 1709, 1660, 1536 cm−1; 1H-NMR (CDCl3) δ0.87 (t, J=6.8 Hz, 3H), 1.20-1.39 (m, 18H), 1.59-1.66 (m, 2H), 3.40-3.46 (m, 2H), 7.42 (t, J=7.6 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 8.87 (br s, 1H); ESIMS m/e 363 (M++1).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:12][C:13]3[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=3[Cl:21])[CH2:9][CH2:10][NH:11][C:5]2=[N:4][CH:3]=1.[NH:22]([C:24](=[O:36])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[NH2:23]>>[Cl:21][C:14]1[C:15]([F:20])=[CH:16][CH:17]=[C:18]([F:19])[C:13]=1[CH2:12][N:8]1[CH2:9][CH2:10][NH:11][C:5]2[N:4]=[CH:3][C:2]([C:30]3[CH:29]=[CH:28][C:27]([CH2:26][CH2:25][C:24]([NH:22][NH2:23])=[O:36])=[CH:32][CH:31]=3)=[N:7][C:6]1=2
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(Br)nc32)c1Cl
Reactant: NNC(=O)CCc1ccc(B(O)O)cc1
Product: NNC(=O)CCc1ccc(-c2cnc3c(n2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cc1

Procedure:
The entitled compound was prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazine and 4-(3-Hydrazino-3-oxopropyl)benzeneboronic acid using Suzuki coupling conditions as described in Example 1.
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][S:15]([C:17]2[NH:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]=2)=[O:16])[C:9]=1[CH3:26].CCN(CC)CC.C([O-])(O)=O.[Na+].[C:39]1([CH3:64])[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH2:49][O:50][C:51](=[O:63])[C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[C:54]([S:59](Cl)(=[O:61])=[O:60])[CH:53]=2)(=[O:47])=[O:46])=[CH:41][CH:40]=1>C(Cl)Cl.O>[C:39]1([CH3:64])[CH:44]=[CH:43][C:42]([S:45]([CH2:48][CH2:49][O:50][C:51](=[O:63])[C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[C:54]([S:59]([N:21]3[C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=[C:17]3[S:15]([CH2:14][C:10]3[C:9]([CH3:26])=[C:8]([O:7][CH2:6][CH2:5][CH2:4][O:3][CH3:2])[CH:13]=[CH:12][N:11]=3)=[O:16])(=[O:61])=[O:60])[CH:53]=2)(=[O:47])=[O:46])=[CH:41][CH:40]=1
Reactant: COCCCOc1ccnc(CS(=O)c2nc3ccccc3[nH]2)c1C
Reactant: Cc1ccc(S(=O)(=O)CCOC(=O)c2ccc(C)c(S(=O)(=O)Cl)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3n2S(=O)(=O)c2cc(C(=O)OCCS(=O)(=O)c3ccc(C)cc3)ccc2C)c1C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
To a solution of 2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-1H-benzimidazole sodium salt (RABEPRAZOLE sodium salt, 1.0 g, 2.62 mmol), 5 mL of Et3N, and about 1 g of NaHCO3 in CH2Cl2 (15 mL) was added the sulfonyl chloride (Intermediate 49, 1.30 g, 3.15 mmol, 1.2 eq) in CH2Cl2 (5 mL) at room temperature, and then the mixture was stirred for 0.5 h. Thereafter water was added, the mixture was extracted with CH2Cl2, and the organic layers were dried, and concentrated. The residual oil was purified by column chromatography (CH2Cl2 to 1% MeOH in CH2Cl2) to yield 1.6 g (80%) of 3-{2-[4-(3-methoxy-propoxy)-3-methyl-pyridin-2-yl-methanesulfinyl]-benzimidazole-1-sulfonyl}-4-methylbenzoic acid 2-(toluene-4-sulfonyl)ethyl ester (Intermediate 53) as an off-white foam.
Reaction SMILES: BrC[CH2:3][C:4]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>>[Cl:14][C:11]1[CH:12]=[CH:13][C:4]([CH2:3][O:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[F:15])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Cl)ccc1CCBr
Reactant: Oc1ccccc1F
Product: COC(=O)c1cc(Cl)ccc1COc1ccccc1F

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 1 from methyl 2-(bromoethyl)-5-chlorobenzoate and 2-fluorophenol: 1H-NMR (CDCl3) δ 8.02 (1H, d, J=2.4 Hz), 7.80-7.77 (1H, m), 7.57-7.53 (1H, m), 7.15-6.89 (4H, m), 5.52 (2H, s), 3.92 (3H, s).
Reaction SMILES: [Li]CCCC.CN(C)CCN(C)C.[CH2:14]([C:17]1[C:30]2[CH2:29][C:28]3[C:23](=[C:24]([CH2:40][CH2:41][CH3:42])[C:25]([CH2:37][CH2:38][CH3:39])=[C:26]([CH2:34][CH2:35][CH3:36])[C:27]=3[CH2:31][CH2:32][CH3:33])[CH2:22][C:21]=2[C:20]([CH2:43][CH2:44][CH3:45])=[C:19]([CH2:46][CH2:47][CH3:48])[C:18]=1[CH2:49][CH2:50][CH3:51])[CH2:15][CH3:16].CI>CCCCCC>[CH2:43]([C:20]1[C:21]2[C:30](=[CH:29][C:28]3[C:23]([CH:22]=2)=[C:24]([CH2:40][CH2:41][CH3:42])[C:25]([CH2:37][CH2:38][CH3:39])=[C:26]([CH2:34][CH2:35][CH3:36])[C:27]=3[CH2:31][CH2:32][CH3:33])[C:17]([CH2:14][CH2:15][CH3:16])=[C:18]([CH2:49][CH2:50][CH3:51])[C:19]=1[CH2:46][CH2:47][CH3:48])[CH2:44][CH3:45]
Reactant: CCCc1c(CCC)c(CCC)c2c(c1CCC)Cc1c(CCC)c(CCC)c(CCC)c(CCC)c1C2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Product: CCCc1c(CCC)c(CCC)c2cc3c(CCC)c(CCC)c(CCC)c(CCC)c3cc2c1CCC
Temperature: 50 °C
Yield: 98 %

Procedure:
After 2.2 equivalents of n-BuLi and 2.2 equivalents of tetramethylethylenediamine were added to the hexane solution of 9,10-dihydro-1,2,3,4,5,6,7,8-octapropylanthracene at room temperature, the mixture was heated at 50° C. for 3 hours. The reaction solution was cooled to room temperature and 1.1 equivalent of methyl iodide was added thereto. Stirring for an hour produced the title compound in the NMR yield of 98%. The compound was treated with 3N hydrochloric acid, and washed with saturated sodium hydrogencarbonate aqueous solution and brine. The organic phase was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the pure title compound in the yield of 96%. In this case, purification by column chromatography, etc. was unnecessary.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[NH2:10][C:11]1[CH:16]=[C:15](Cl)[N:14]=[C:13]([C:18](=[N:24][O:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:12]=1.Cl>CN(C)C=O.O>[NH2:10][C:11]1[CH:16]=[C:15]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:14]=[C:13]([C:18](=[N:24][O:25][CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:12]=1
Reactant: CCOC(=O)C(=NOC)c1nc(N)cc(Cl)n1
Reactant: Sc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC)c1nc(N)cc(Sc2ccccc2)n1
Reaction time: 0.33 h
Yield: 17.9 %

Procedure:
To a solution of thiophenol (2.55 g) in N,N-dimethylformamide (20 ml) was added 50% sodium hydride (1.1 g) under cooling in an ice bath and the mixture was stirred for 20 minutes at 0° C. to 5° C. To the mixture was added ethyl 2-(4-amino-6-chloropyrimidin-2-yl)-2-methoxyiminoacetate (2.0 g) and the mixture was stirred for 6 hours at ambient temperature. The resultant mixture was poured into cold water, adjusted to pH 7 with diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was subjected to column chromatography on silica gel (50 g) using a mixture of chloroform and ethyl acetate (3:1 by valume) as an eluent. The fractions containing the object product were collected and evaporated to give ethyl 2-(4-amino-6-phenylthiopyrimidin-2-yl)-2-methoxyiminoacetate (syn isomer) (460 mg), mp 154°-156° C.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:60][C:61]1([CH2:65]O)[CH2:64][O:63][CH2:62]1>O1CCCC1>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:60][C:61]3([CH3:65])[CH2:64][O:63][CH2:62]3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CC1(CO)COC1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCc1cc2c(=O)n(CC3(C)COC3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 55.9 %

Procedure:
A mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.3 g), tributylphosphine (1.6 mL), (3-methyloxetan-3-yl)methanol (0.29 g) and tetrahydrofuran (30 mL) was stirred at room temperature for 3 hr. The reaction mixture was extracted with water and ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.68 g, 56%).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:15])[CH3:14])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18].N1C=CC=CC=1>C(Cl)Cl>[C:13]([NH:12][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH:2]([O:1][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:3][CH2:4]2)(=[O:15])[CH3:14]
Reactant: CC(=O)Nc1cccc2c1CC(O)CC2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cccc2c1CC(OS(C)(=O)=O)CC2
Yield: 51 %

Procedure:
A solution of N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-acetamide (5 g, 24 mmol), methylsulfonylchloride (6.9 g, 60 mmol) and pyridine (4.7 g, 60 mmol) in methylene chloride (100 mL) was heated at reflux for 8 h. The mixture was then cooled and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated. The resulting solid was washed with diethyl ether and dried (3.8 g, 51% yield) without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34].[Cl-].[NH4+]>ClCCl>[CH3:32][S:33]([O:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:3]2[CH:4]=[CH:5][C:6]3[N:7]([CH2:11][CH:12]4[CH2:14][CH2:13]4)[N:8]=[N:9][C:10]=3[C:2]=2[Cl:1])=[CH:20][CH:19]=1)(=[O:35])=[O:34]
Reactant: OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc(-c2ccc3c(nnn3CC3CC3)c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
{4-[4-Chloro-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]phenyl}methanol (0.71, 2.3 mmol) was dissolved in dichloromethane (7 mL) and treated with N,N-diisopropylethylamine (0.79 mL, 4.5 mmol). The mixture was cooled to 0° C. and treated with methanesulfonyl chloride (0.21 mL, 2.7 mmol) and after 1 hour, the mixture was treated with additional methanesulfonyl chloride (50 uL). After stirring for an additional 30 minutes, the mixture was poured into ammonium chloride (50 mL, aqueous saturated) and extracted with dichloromethane (2×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo, providing the titled compound.