Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[OH:60])=[N:46][C:47]=1[CH2:48][CH3:49]>>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:42]1[N:43]=[C:44]([CH2:61][CH3:62])[C:45]([NH:50][C@@H:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH2:53][C@@H:52]2[O:60][CH2:2][CH3:3])=[N:46][C:47]=1[CH2:48][CH3:49]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(OC)cc2OC)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2OC)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but substituting (1R,2S)-1-{[5-(2,4-dimethoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a white solid, m.p. 120–121° C. (uncorrected). IR (diffuse reflectance) 2965, 2935, 1615, 1566, 1480, 1390, 1305, 1256, 1215, 1209, 1183, 1165, 1040, 825, 747 cm−1; OAMS supporting ions at: ESI+ 448.1; MS (EI) m/z 447 (M+); HRMS (FAB) calcd for C27H33N3O3+H1 448.2600, found 448.2600. Anal. Calcd for C27H33N3O3: C, 72.46; H, 7.43; N, 9.39. Found: C, 72.46; H, 7.59; N, 9.39.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:13].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(O)C.ClCCl>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][N:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)=[CH:16][CH:17]=1
Reactant: O=C(CCCCCCCCCCBr)Nc1ccc(O)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCCCCCCN1CCN(c2ccccc2)CC1)Nc1ccc(O)cc1

Procedure:
A solution of 66.8 g (0.187 mol) of 11-bromo-N-(4-hydroxyphenyl)undecanamide, 30.3 g (0.187 mol) of 1-phenylpiperazine and 27.0 ml (19.6 g, 0.194 mol) of triethylamine in 600 ml of ethanol was heated under reflux overnight and then cooled. The resulting solid was shaken with sodium bicarbonate solution and dichloromethane and the suspension was filtered. The solid was recrystallized from 95% ethanol to give the end product as colorless crystals, mp 160.5°-162.5°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]([O:10]C)=O.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([CH2:17][C:18]#[N:19])=[CH:15][CH:14]=1>C1(C)C(C)=CC=CC=1>[C:18]([CH2:17][C:16]1[CH:20]=[CH:21][C:13]([NH:12][C:8](=[O:10])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:14][CH:15]=1)#[N:19]
Reactant: N#CCc1ccc(N)cc1
Reactant: COC(=O)Cc1ccccn1
Solvent: Cc1ccccc1C
Product: N#CCc1ccc(NC(=O)Cc2ccccn2)cc1
Yield: 66.4 %

Procedure:
A reaction mixture of 5.12 g of methyl 2-pyridylacetate, 5.14 g of 4-aminobenzyl cyanide and 50 ml of xylene was heated to reflux for 24 hours. An appropriate amount of the solvent was evaporated, diethyl ether was added to the residue, and the resulting crystals were taken by filtration to give 5.65 g of 4′-cyanomethyl-2-(2-pyridyl)acetanilide.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].C(=O)(O)[O-].[Na+].O.[Cl:11][C:12]1[N:17]=[C:16]([C:18]2[C:19](F)=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=2)[C:15]2[N:26]([CH2:38][C@H:39]3[CH2:44][CH2:43][C@H:42]([CH3:45])[CH2:41][CH2:40]3)[C:27]([N:29]3[CH2:34][CH2:33][O:32][C@@H:31]4[CH2:35][CH2:36][CH2:37][C@@H:30]34)=[N:28][C:14]=2[CH:13]=1>CCO>[Cl:24][C:22]1[CH:23]=[C:18]([C:16]2[C:15]3[N:26]([CH2:38][C@H:39]4[CH2:44][CH2:43][C@H:42]([CH3:45])[CH2:41][CH2:40]4)[C:27]([N:29]4[CH2:34][CH2:33][O:32][C@@H:31]5[CH2:35][CH2:36][CH2:37][C@@H:30]45)=[N:28][C:14]=3[CH:13]=[C:12]([Cl:11])[N:17]=2)[C:19]([N:3]([CH3:4])[CH3:2])=[N:20][CH:21]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cc(Cl)cnc4F)c32)CC1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN(C)c1ncc(Cl)cc1-c1nc(Cl)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Temperature: 90 °C

Procedure:
To a solution of dimethylamine hydrochloride (580 mg, 7.25 mmol) and sodium bicarbonate (812 mg, 9.67 mmol) in EtOH:water (4 mL:2 mL) was added 6-chloro-4-(5-chloro-2-fluoropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic) (125 mg, 0.24 mmol). The reaction was heated to 90° C. for 5 hours. The reaction was then concentrated and diluted with EtOAc. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue on a silica gel column (0 to 45% EtOAc/hexanes) afforded 5-chloro-3-{6-chloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-4-yl}-N,N-dimethylpyridin-2-amine (racemic). MS ES calc'd. for C28H36Cl2N6O [M+H]+ 543. found 543.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH2:28])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37](Cl)([CH3:40])(=[O:39])=[O:38]>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][S:37]([CH3:40])(=[O:39])=[O:38])=[CH:23][C:22]=3[F:29])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(N)cc3F)CC2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(NS(C)(=O)=O)cc3F)CC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 34-1 (49 mg, 0.12 mmol) and triethylamine (17 μL, 0.12 mmol) in 2 mL of DCM, was added mesyl chloride (10 μL, 0.13 mmol). After 2 h, a second equivalent of triethylamine (17 μL, 0.12 mmol) and mesyl chloride (10 μL, 0.13 mmol) was added. After 1 h, the mixture was washed with brine, concentrated and purified on preparative HPLC to give 44-1: LC-MS 489.1 (MH), tR=7.31 (Method 2). EC50: 170 nM.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1.OC1C=CC=C2C=1[N+](=CCCS([O-])(=O)=O)CC=C2>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH2:8][N+:9]2=[CH:13][CH2:12][CH2:18][S:15]([O-:17])(=[O:16])=[O:14])=[CH:4][CH:3]=1
Reactant: Oc1ccc2cccnc2c1
Reactant: O=S1(=O)CCCO1
Agent: O=S(=O)([O-])CCC=[N+]1CC=Cc2cccc(O)c21
Product: O=S(=O)([O-])CCC=[N+]1CC=Cc2ccc(O)cc21

Procedure:
This compound is prepared from 7-hydroxyquinoline and 1,3-propanesultone as published (GB 1,122,704) for 3-(8-hydroxyquinolinio-1-yl)propanesulfonate.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:6][CH2:5]2.[CH3:19][C:20](OC(C)=O)=[O:21]>N1C=CC=CC=1>[C:20]([O:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=[O:15])[CH2:6][CH2:5]2)(=[O:21])[CH3:19]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)O)O2
Temperature: 40 °C
Reaction time: 8 h

Procedure:
6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (5.0 g, 19.99 mmol) was dissolved in pyridine (18 mL) and Ac2O added (10 mL) in one portion. The exothermic reaction warmed to 40° C., was let cool to room temperature and stirred overnight. The crude reaction mixture was quenched with 100 mL H2O, stirred for 1 h followed by additional 100 mL H2O and 1 h of stirring. A fine white precipitate of 6-acetoxy-2,5,7,8-tetramethylchroman-2-carboxylic acid was formed and collected by filtration (4.544 g).
Reaction SMILES: [Cl:1][CH:2]([Cl:31])[C:3]([NH:5][C@H:6]([CH2:29][F:30])[C@@H:7]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[S:19][C:18]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[OH:8])=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:21][CH2:20][C:18]1[S:19][C:15]([C:12]2[CH:11]=[CH:10][C:9]([C@@H:7]([OH:8])[C@H:6]([NH:5][C:3](=[O:4])[CH:2]([Cl:31])[Cl:1])[CH2:29][F:30])=[CH:14][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.1 %

Procedure:
To a solution of tert-butyl ((5-(4-((1R,2S)-2-(2,2-dichloroacetamido)-3-fluoro-1-hydroxypropyl)phenyl)thiophen-2-yl)methyl)carbamate (140 mg, 0.238 mmol) in CH2Cl2 (10 mL) is added trifluoroacetic acid (1.0 mL) and the reaction mixture stirred at room temperature for 2 hours. The solvent is removed under reduced pressure and the residue washed with diethyl ether, then dissolved in 10% methanol in CH2Cl2 and evaporated to dryness. Washed with n-pentane and dried under vacuum to give the title compound (56 mg): 1HNMR (400 MHz, DMSO-d6) δ: 4.19-4.21 (m, 1H), 4.24-4.26 (m, 2H), 4.29-4.31 (m, 0.5H), 4.39-4.43 (m, 0.5H), 4.55-4.59 (m, 0.5H), 4.67-4.70 (m, 0.5H), 4.87 (bs, 1H), 5.90 (bs, 1H) 6.50 (s, 1H), 7.20 (d, J=3.64 Hz, 1H), 7.39 (d, J=8.24 Hz, 2H), 7.43 (d, J=3.68 Hz, 1H), 7.57 (d, J=8.16 Hz, 2H), 8.20 (bs, 3H), 8.59-8.63 (m, 1H). m/z (Cl) 388 [M−H].
Reaction SMILES: CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:32][C:33]1[CH:34]=[C:35]2[C:39](=[C:40]([C:42]([OH:44])=O)[CH:41]=1)[NH:38][CH:37]=[CH:36]2.[C:45]([C:49]1[CH:68]=[CH:67][C:52]([CH2:53][NH:54][CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)=[C:51]([Cl:69])[CH:50]=1)([CH3:48])([CH3:47])[CH3:46]>CN(C=O)C.O>[C:45]([C:49]1[CH:68]=[CH:67][C:52]([CH2:53][N:54]([CH2:55][CH2:56][C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([C:63]([F:66])([F:65])[F:64])[CH:58]=2)[C:42]([C:40]2[CH:41]=[C:33]([Cl:32])[CH:34]=[C:35]3[C:39]=2[NH:38][CH:37]=[CH:36]3)=[O:44])=[C:51]([Cl:69])[CH:50]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cc(Cl)cc3cc[nH]c23)c(Cl)c1
Temperature: 25 °C
Yield: 83 %

Procedure:
91 mg (0.9 mmol) of N-methyl morpholine and then 170 mg (0.45 mmol) of HBTU were added to 59 mg (0.30 mol) of 5-chloro-1H-indol-7-carboxylic acid and 122 mg (0.33 mmol) of (4-tert-butyl-2-chloro-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine dissolved in 3 ml DMF at rt under nitrogen. The reaction mixture was stirred at rt over night. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layers were washed once with 1N aqueous HCl solution, once with saturated aqueous NaHCO3 solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 150 mg (91%) product as a yellow viscous oil. MS (ISP) 547.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10]([OH:16])[CH2:11][CH2:12][CH2:13][C:14]#[CH:15]>C(N(CC)CC)C.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:16][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[C:15][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1ccccc1Br
Reactant: C#CCCCCO
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=Cc1ccccc1C#CCCCCO
Temperature: 25 °C

Procedure:
To a solution of 2-bromobenzaldehyde (5.0 g, 27.0 mmol) and 5-hexyn-1-ol (3.18 g, 32.0 mmol) in triethyl amine (100 mL) was added bis(triphenylphosphine)palladium (II) dichloride (0.28 g, 0.4 mmol) and cuprous iodide (51 mg, 0.27 mmol). After heating the resulting mixture to reflux under an argon atmosphere for 1 hour, the reaction mixture was allowed to cool to room temperature and filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel chromatography eluting with 2:1 diethyl ether/hexanes to afford a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C@@H:13]([NH2:17])[CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1.C([O-])([O-])=O.[K+].[K+].[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[S:38][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:36][CH:35]=1.O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][C@@H:13]([NH:17][S:39]([C:37]2[S:38][C:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=3)=[CH:35][CH:36]=2)(=[O:40])=[O:41])[CH:14]([CH3:15])[CH3:16])[CH2:10][CH2:11]1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: CC(C)[C@H](N)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)[C@@H](CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1)NS(=O)(=O)c1ccc(-c2ccccn2)s1
Reaction time: 1 h
Yield: 27.5 %

Procedure:
The product of Example 7, Step (c) (0.050 g) was dissolved in acetone (1 ml). K2CO3 [0.033 g dissolved in H2O (0.5 ml)] was then added, followed by 5-pyridin-2-yl-thiophene-2-sulfonyl chloride (0.041 g) and the reaction left to stir for 1 hr. Water was then added and the product extracted with ethyl acetate. The combined organic extracts dried, filtered and concentrated. Purification by flash silica column chromatography with 30% EtOAc/68% Hexane/2% TEA as eluent, and then reverse phase HPLC [(50% MeCN/NH4OAcaq (0.1%)] gave the title compound as a solid (0.023 g).
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24]N)=[CH:20][CH:19]=2)=[O:14])=[CH:8][CH:7]=1)(=[O:4])[CH3:3].C(O[CH:29](OCC)[CH2:30][CH2:31][C:32]#[N:33])C.[OH-].[Na+].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C(O)C.CC(=O)OCC.C(O)(=O)C>[C:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:15][CH2:16][CH2:17][C:18]2[CH:23]=[C:22]3[C:21](=[CH:20][CH:19]=2)[NH:24][CH:29]=[C:30]3[CH2:31][C:32]#[N:33])=[O:14])=[CH:8][CH:7]=1)(=[O:4])[CH3:3]
Reactant: CCOC(CCC#N)OCC
Reactant: CC(=O)Nc1ccc(CC(=O)NCCc2ccc(NN)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(CC(=O)NCCc2ccc3[nH]cc(CC#N)c3c2)cc1
Yield: 5.8 %

Procedure:
The compound of Example 29 Section (c) (1.5 g) was suspended in aqueous 25% acetic acid (10 ml) and 3-cyanopropanal diethyl acetal (0.237 g) was added. The mixture was heated at 80° for 2.5 h. The cooled reaction mixture was poured into NaOH solution (2N, 15 ml) and EA (15 ml) cooled in an ice-bath. K2CO3 (2 g) was added portionwise and the layers were separated. The aqueous layer was washed with EA (25 ml) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo to give a yellow oil. The oil was dissolved in CH2Cl2 /ethanol/aqueous NH3 (200:8:1) and flash chromatographed using the same solvent system to give the title compound (33 mg) as a white solid, m.p. 187.5°-189°.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6]([CH2:13][CH3:14])[C:7](=[O:12])[CH2:8][C:9](=O)[CH3:10])=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(OCC)C>[CH2:13]([C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[C:9]([CH3:10])=[CH:8][C:7]=1[OH:12])[CH3:14]
Reactant: CCC(C(=O)CC(C)=O)c1ccsc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCc1c(O)cc(C)c2sccc12

Procedure:
5-Thiophen-3-yl-heptane-2,4-dione (410 mg, 2 mmol) was dissolved in 15 ml benzene, and p-toluene sulfonic acid monohydrate (408 mg, 2 mmol) was added. The reaction mixture was heated to reflux for 30 min, cooled, diluted with diethy ether, washed with saturated sodium bicarbonate, water, brine, and dried over magnesium sulfate. Concentration in vacuo 370 mg of 4-Ethyl-7-methyl-benzo[b]thiophen-5-ol, 98%, as a white solid.
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.C(OC([NH:25][C@H:26]1[C@@H:29]([CH3:30])[N:28]([S:31]([O-:34])(=[O:33])=[O:32])[C:27]1=[O:35])=O)(C)(C)C>C(O)=O>[NH2:25][C@H:26]1[C@@H:29]([CH3:30])[N:28]([S:31]([OH:34])(=[O:32])=[O:33])[C:27]1=[O:35]
Reactant: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1S(=O)(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O=CO
Product: C[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.4 %

Procedure:
(3S-cis)-3-t-Butoxycarbonylamino-4-methyl-2-oxo-1-azetidinesulfonic acid, tetrabutyl ammonium salt (10.76 g) is dissolved in 50 ml of 95-97% formic acid and stirred for 4 hours under nitrogen. A small amount of product from a previous reaction is added as seed and the mixture is stirred for one more hour. The mixture is stored in the freezer for about 16 hours and the frozen mixture is warmed to room temperature and stirred for an additional hour. The solid formed is filtered and washed with methylene chloride to yield 982 mg of the title compound. The filtrate is diluted with 1 liter of methylene chloride and kept at -20° C. for 4 hours. The precipitate that forms is recrystallized from water-methanol-acetone to give an additional 167 mg of title compound.
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:32])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:31])([F:30])[F:29])[CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:32])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([C:28]([F:29])([F:30])[F:31])[CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccc2c(c1)CCCN2

Procedure:
A nitrogen flushed mixture of 4-chloro-3-trifluoromethyl-phenyl-carbamic acid 1-benzyl-1, 2, 3, 4-tetrahydro-quinolin-6-yl ester (0.23 g. ½ mmol) and 5% Pd—C (0.02 g.) in absolute ethanol (20 ml) was shaken in a par apparatus at room temperature (38° C.) under 50 psi pressure of hydrogen for 5 hours. Pd—C was then discarded through filtration. The reaction mixture was concentrated under reduced pressure and the residue was washed dichloromethane (2×3 ml) to give 2e; yield: 0.16 g. (86.4%), m.p.: 150° C., C17H14ClF3N2O2; 1H NMR δ ppm (DMSO-d6): 1.89-1.95 (m, 2H.), 2.76 (t, 2H), 3.28 (t, 2H), 6.44-6.49 (m, 1H), 6.72-6.75 (m, 2H), 7.37-8.0 (m, 2H),10.14 (bs, 1H); IR vmax (KBr) (cm−1): 661, 698, 769, 796, 819, 892, 944, 1023, 1072, 1147, 1217, 1290, 1347, 1384, 1424, 1450, 1506, 1599, 1707, 1740, 2364, 2489, 2837, 2950, 3359, 3773, 3888.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\Cl)/[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[K+]>O1CCOCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Cl/C(=C\c1ccc(Br)cc1)c1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Clc1ccc(C#Cc2ccc(Br)cc2)cc1
Yield: 94.1 %

Procedure:
To a 100 mL flask containing a solution of 1-bromo-4-[(Z) -2-chloro-2-(4-chloro-phenyl) vinyl] benzene (VId) (7.89 g; 24.05 mmol) in 1,4-dioxane (40 mL; 5 vols) and MeOH (12 mL; 1.5 vols), KOH (2.699 g; 48.10 mmol) was added in one portion. Protocol and work-up was then similar with those described above. Title compound (m=6.598 g) was obtained in a 94% yield. Melting point: 179° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][CH:29]([CH:32]([C:34]4[NH:38][C:37]5[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=5[N:35]=4)[OH:33])[CH2:28][CH2:27]3)OCC[O:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C.Cl.C(=O)(O)[O-].[Na+]>ClCCl.CO>[NH:35]1[C:36]2[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=2[N:38]=[C:34]1[C:32]([CH:29]1[CH2:30][CH2:31][N:26]([CH2:25][CH2:24][CH2:23][C:18]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[O:19])[CH2:27][CH2:28]1)=[O:33]
Reactant: OC(c1nc2ccccc2[nH]1)C1CCN(CCCC2(c3ccc(F)cc3)OCCO2)CC1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCN1CCC(C(=O)c2nc3ccccc3[nH]2)CC1)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of oxalyl chloride (0.51 ml, 0.74 g, 5.8 mmol) in dichloromethane (13 ml) at -78° C. under argon was added dimethylsulfoxide (0.91 g, 12 mmol) in dichloromethane (2.5 ml) at such a rate as to keep the temperature below -50° C. After stirring 20 minutes at -78° C., α-[1-[3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl]-4-piperidinyl]-lH-benzimidazole-2-methanol (2.3 g, 5.2 mmol) was added in dichloromethane (20 ml), dropwise, via syringe. After an additional 20 minutes of stirring at -78° C., triethylamine (3.0 ml, 22 mmol) was added, the cooling bath was removed, and the solution was allowed to stir for 1 hour. Water was added, the layers separated, and the aqueous layer extracted with dichloromethane. The combined organic layers were dried (MgSO4), and filtered through a pad of silica (eluting with acetone). The eluent was concentrated to give a white foam. The foam was dissolved in methanol (50 ml), treated with 10% hydrochloric acid, and stirred for 3 hours. The solution was neutralized with 5% sodium bicarbonate, concentrated, and extracted twice with dichloromethane. The combined organic layers were dried (MgSO4), concentrated, and the resulting solid recrystallized from ethyl acetate to afford 4-[4-(lH-benzimidazol-2-yl-carbonyl)-1-piperidinyl]-1-(4-fluorophenyl)-1-butanone as an off-white solid m.p. 155-156° C.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25]>ClCCl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:22]([Cl:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 10.2 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.04 g, 3.03 mmol) in 25 mL of dichloromethane and 3,4-dichloroaniline (0.982 g, 6.06 mmol) in 8 mL of pyridine. The crude product was recrystallized from ethyl acetate-hexanes to yield 0.184 g of the title compound, mp 230°-233° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([C:12](OCC)=[O:13])=[CH:7]2.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[C:8]([CH2:12][OH:13])=[CH:7]2
Reactant: CCOC(=O)c1cc2cccc(Br)c2n1C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(CO)cc2cccc(Br)c21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a tetrahydrofuran (40 mL) solution of ethyl 7-bromo-1-methyl-1H-indole-2-carboxylate (1.99 g), lithium tetrahydroborate (463 mg) was added at 0° C., followed by stirring at room temperature for 5 hours. To the reaction mixture, an aqueous saturated ammonium chloride solution was added, followed by extraction with ethyl acetate. The organic layer was washed in turn with water and saturated saline, dried over anhydrous sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-70:30) to obtain the titled compound having the following physical properties (880 mg).