Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([O:22]C)[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>Br>[CH:1]1([CH2:6][CH2:7][CH2:8][N:9]2[C@@H:17]3[C@@H:12]([C:13]4[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[C:14]=4[CH2:15][CH2:16]3)[CH2:11][CH2:10]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCC1CCCC1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCC1CCCC1
Temperature: 0 °C
Yield: 73.9 %

Procedure:
4.40 g (0.014 mol) of rac-cis-3-(3-cyclopentyl-propyl)-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole were dissolved in 0.16 l of 48% aqueous HBr and boiled under reflux for 17 hours. The mixture was poured on to ~200 g of ice and treated with 180 ml of 28% aqueous NaOH solution. The mixture was extracted three times with CH2Cl2, whereupon the organic phase was washed with water, dried with MgSO4, filtered and concentrated. By chromatography of the residue over silica gel with n-hexane/ethyl acetate 1:1 there were obtained 3.1 g (74%) of rac-cis-3-(3-cyclopentyl-propyl)-2,3,3a,4,5,9b-hexahydro-1H-benzo[e]indol-6-ol as an oily material.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:15][C@@H:14]([O:16]CC=C)[CH2:13][N:12]2[CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:9][C:8](=[O:33])[NH:7]1.C(O[C@H]1C[C@H]([C@H]2OC(=O)N[C@H]2CC2C=C(F)C=C(F)C=2)N(C(C2C=CC=CC=2)C2C=CC=CC=2)C1)(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](O)CN2C(C2C=CC=CC=2)C2C=CC=CC=2)OC(=O)N1.C(O)(=O)C>C1COCC1.C(OCC)(=O)C.CCCCCC>[F:37][C:35]1[CH:34]=[C:4]([CH:3]=[C:2]([F:1])[CH:36]=1)[CH2:5][C@H:6]1[C@@H:10]([C@H:11]2[CH2:15][C@H:14]([OH:16])[CH2:13][N:12]2[CH:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:33])[NH:7]1
Reactant: C=CCO[C@@H]1C[C@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)N(C(c2ccccc2)c2ccccc2)C1
Agent: CC(=O)O[C@H]1C[C@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)N(C(c2ccccc2)c2ccccc2)C1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 81 %

Procedure:
Step K (1): (3S,5R)-5-((4S,5S)-4-(3,5-difluorobenzyl)-2-oxooxazolidin-5-yl)-1-benzhydrylpyrrolidin-3-yl acetate. To a solution of triphenylphosphine (510 mg, 1.94 mmol) in THF (20 mL) at 0° C. was added DEAD (0.36 mL, 1.94 mmol) and the mixture was allowed to come to rt for 5 min and was again cooled to 0° C. A solution of (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-1-benzhydryl-4-hydroxypyrrolidin-2-yl)oxazolidin-2-one (Preparation J, 750 mg, 1.62 mmol) in THF (20 mL) was added and the mixture was allowed to come to rt for 5 min and was again cooled to 0° C. Acetic acid (0.093 mL, 1.62 mmol) was added and the mixture was warmed to rt and stirred for 30 min. pH 7 buffer was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with sat. aqueous NaCl, dried (MgSO4), and concentrated in vacuo. Flash chromatography (silica gel, 5-100% ethyl acetate/hexane) gave 661 mg (81% yield) of the title compound as a clear, very slightly yellow oil: 1H NMR (CDCl3, 500 MHz) δ 1.31-1.34 (1H, m), 2.08-2.16 (1H, m), 2.39 (3H, m), 2.80 (1H, brd s), 3.26 (1H, brd s), 3.60 (2H, brd s), 4.11 (1H, m), 4.27-4.33 (1H, m), 4.91 (2H, m), 5.28 (1H, m), 6.40 (2H, brd s), 6.51 (2H, m), 6.69 (1H, m), 7.22 (1H, m), 7.28-7.49 (8H, m). HPLC retention time: 1.50 min (method A). MS (ESI) (M+H)+ 507.17.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][CH2:21][NH2:22])=[CH:12]1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]2[C:12]3[NH:11][C:19]4[C:14]([C:13]=3[CH2:20][CH2:21][NH:22]2)=[CH:15][CH:16]=[CH:17][CH:18]=4)=[CH:5][CH:4]=1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: COc1ccc(C=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 0.5 M solution of 4-methoxybenzaldehyde in dichloromethane (800 μl) was added a 0.25 M solution of 2-(1H-indol-3-yl)ethanamine in dichloromethane (800 μl) followed by trifluoracetic acid (20 μl). The mixture was sealed and shaken at room temperature for 24 hours. The mixture was evaporated to dryness resuspended in toluene (1 ml) vortexed and re-evaporated to dryness. To the residue was added methanol (1.5 ml) and dichloromethane (1 ml). After vortexing the solution was filtered through a pre-washed (methanol, 5 ml) SCX cartridge (Bakerbond JT7090-07, aromatic sulfonic acid). 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, was eluted from the cartridge with 0.5 M aqueous ammonia in methanol (5 ml). Evaporation to dryness gave 1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole that was used directly for the next step.
Reaction SMILES: [C:1]([C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Cl:28]C1C=CC=CC=1>>[C:1]([C:3]1[C:8]([CH2:9][Cl:28])=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: Clc1ccccc1
Reactant: Cc1cccnc1C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: N#Cc1ncccc1CCl

Procedure:
The 2-cyano-3-chloromethylpyridine was prepared by chlorination of 2-cyano-3-methylpyridine in chlorobenzene with benzoylperoxide by gradual addition of SO2Cl2 at 80° C. 2-Cyano-3-chloromethylpyridine was obtained in 60-65% conversion. The main impurities are 2-cyano-3-dichloromethylpyridine and unreacted 2-cyano-3-methylpyridine, which do not cause problems in the process of this Preparation.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH:24]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:25]1[CH:26]=[C:27]([C:31]2[CH:32]=[C:33]([CH:41]([CH3:43])[CH3:42])[CH:34]=[C:35]3[C:40]=2[N:39]=[CH:38][CH:37]=[CH:36]3)[CH:28]=[CH:29][CH:30]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.[Cl-].[NH4+].C(OCC)(=O)C>[CH2:11]([O:10][C:8](=[O:9])[CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[CH:24]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[C:33]([CH:41]([CH3:43])[CH3:42])[CH:34]=[C:35]3[C:40]=2[N:39]=[CH:38][CH:37]=[CH:36]3)[CH:26]=1)[CH3:12]
Reactant: CCOC(=O)Cc1ccncc1
Reactant: CC(C)c1cc(-c2cccc(C(Cl)c3ccc(Cl)cc3)c2)c2ncccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C(c1ccncc1)C(c1ccc(Cl)cc1)c1cccc(-c2cc(C(C)C)cc3cccnc23)c1
Temperature: 21 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-pyridinylacetate (1.28 g, 7.74 mmol) in THF/HMPA (3:1, 5 mL) at −10° C. was added NaHMDS (1M, 7.8 mL, 7.8 mmol) dropwise. After 60 min., the crude chloride from Step 2 above was added and the resulting reaction mixture was stirred for 18 h at 21° C., and then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O, brine), dried (MgSO4), filtered and concentrated.
Reaction SMILES: [OH:1][N:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[N:13][N:14]([CH:16]4[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]4)[CH:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([F:40])([F:39])[F:38].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH:19]1[CH2:20][CH2:21][CH:16]([N:14]2[CH:15]=[C:11]([C:8]3[CH:9]=[C:10]4[N:2]([O:1][CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=5[C:37]([F:40])([F:39])[F:38])[CH:3]=[CH:4][C:5]4=[N:6][CH:7]=3)[CH:12]=[N:13]2)[CH2:17][CH2:18]1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc4ccn(O)c4c3)cn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccccc1COn1ccc2ncc(-c3cnn(C4CCNCC4)c3)cc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
tert-butyl 4-[4-(1-hydroxy-1H-pyrrolo[3,2-b]pyridin-6-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (30 mg, 0.078 mmol, 1.0 eq), 1-(bromomethyl)-2-(trifluoromethyl)benzene (0.066 mmol), and K2CO3 (30 mg) in 1.5 ml of DMF were shaken at r.t. for 30 min and then filtered and evaporated. The resulting crude product was dissolved in 1.5 ml of methanol and 0.5 ml of 4.0 M HCl/dioxane was dropped in. The reaction was shaken at room temperature for 0.5-1 h. The solvent was evaporated and the residue was dissolved in 2 ml of DCM. To this solution were added 20 mg of NaHCO3, 10 mg of Na2CO3, and drops of water. After stirred for 10 min, the organic solution was separated and purified with preparation HPLC to give the final product.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH:18]=[CH:17][C:16]([OH:23])=[CH:15][C:14]=1[CH:13]=[C:12]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=O)(=O)C.[CH3:37][NH:38][CH2:39][CH2:40][CH2:41][CH3:42]>>[CH2:39]([N:38]([CH3:37])[C:34](=[O:36])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:12]1[C@@H:11]2[C@@H:20]([C:19]3[CH:18]=[CH:17][C:16]([OH:23])=[CH:15][C:14]=3[CH:13]=1)[CH2:21][CH2:22][C@@:6]1([CH3:7])[C@H:8]2[CH2:9][CH2:10][C@@H:5]1[OH:4])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCNC
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C(CCCCCCCCCCC(=O)O)=Cc4cc(O)ccc4[C@H]3CC[C@]12C
Product: CCCCN(C)C(=O)CCCCCCCCCCC1=Cc2cc(O)ccc2[C@H]2CC[C@]3(C)[C@@H](O)CC[C@H]3[C@H]12

Procedure:
The process described in the first two paragraphs of Example 1 was repeated except that 11-(17β-acetoxy-3-hydroxyoestra-1,3,5(10),6-tetraen-7-yl)undecanoic acid and N-methyl-N-butylamine were used as starting materials. There was thus obtained as an oil N-n-butyl-N-methyl-11-(3,17β-dihydroxyoestra-1,3,5(10),6-tetraen-7-yl)undecanamide, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:14]([N+:15]([O-])=O)=[CH:13][CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:18]O>[Pd]>[OH:1][CH2:2][CH2:3][N:4]1[C:5]2[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=[CH:13][C:14]=2[N:15]=[CH:18]1
Reactant: CO
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1NCCO
Agent: [Pd]
Product: COC(=O)c1cccc2ncn(CCO)c12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Suspension of methyl 2-[(2-hydroxyethyl)amino]-3-nitrobenzoate (3.06 g, 12.7 mmol) in methanol (130 mL) was hydrogenated at atmospheric pressure over 10% palladium on activated charcoal for 10 min. The mixture was filtered through a pad of Celite and the solvent was removed in vacuum. The residue was dissolved in formic acid (60 mL) and heated at 100° C. for 45 min and then kept at ambient temperature overnight. Excess of the formic acid was removed under reduced pressure. The residue was dissolved in methanol (100 mL) and treated with concentrated ammonia in methanol (20 mL) for 50 min followed by evaporation of the volatiles. Purification by column chromatography on silica using dichloromethane in methanol 95:5 afforded methyl 1-(2-hydroxyethyl)-1H-benzimidazole-7-carboxylate, 2.31 g (83%). %). MS (ESI) m/z 221 [M+H]. 1H NMR (400 MHz, CD3OD) δ ppm 3.78 (t, J=5.05 Hz, 2H), 3.96 (s, 3H), 4.70 (t, J=5.05 Hz, 2H), 7.33 (t, J=7.83 Hz, 1H), 7.84-7.91 (m, 2H), 8.20 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14](OC)=O)[C:8]=2[N:7]=[C:6]1[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25].[Al]([NH2:34])(C)C>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:14]#[N:34])[C:8]=2[N:7]=[C:6]1[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25]
Reactant: COC(=O)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reactant: C[Al](C)N
Solvent: Cc1ccccc1C
Product: N#Cc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Yield: 61 %

Procedure:
To methyl 1-(2,6-difluorobenyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (Example 102) (1.02 g, 2.46 mmol) suspended in xylene (60 mL) was added freshly prepared 1.0 M AlMe2NH2 (20 mL). After 3 h at reflux, the reaction was concentrated. The residue was redissolved in CH2Cl2 and washed with NaHSO4 (10% soln), NaHCO3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol/CH2Cl2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- benzimidazole-4-carbonitrile (1.72 g, 4.51 mmol, 61% yield). M.p. 156-157° C.; 1H NMR (200 MHz, CD2Cl2): δ7.76 (dd, J=1.0, 8.6 Hz, 1H, H5), 7.63 (dd, J=1.0, 7.6 Hz, 1H, H7), 7.58 (m, 1H, H4′), 7.37 (dd, J=7.6, 8.6 Hz, 1H, H6), 7.28 (m, 1H, H4″), 7.11 (m, 2H, H3′,5′), 6.83 (m, 2H, H3″,5″), 5.40 (s, 2H, CH2PhF2).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:11][S:12][CH:13]1[N:16]([CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[C:15](=[O:31])[CH:14]1[CH:32]([O:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=1)=[O:36])[CH3:33].[C:48](Cl)(=[O:53])[C:49]([CH3:52])([CH3:51])[CH3:50]>O1CCCC1.C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:50][C:49]([CH3:52])([CH3:51])[C:48](=[O:53])[CH:17]([N:16]1[CH:13]([S:12][CH3:11])[CH:14]([CH:32]([O:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[CH3:33])[C:15]1=[O:31])[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=1)=[O:19]
Reactant: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)C(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CSC1C(C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)C(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
1.1 ml of 1M lithium bis(trimethylsilyl)amide are added over the course of 5 minutes to a stirred mixture of 275 mg (0.515 mmol) of p-nitrobenzyl 2-[4-methylthio-3-(1-(p-nitrobenzyloxycarbonyloxy)-ethyl)-2-oxoazetidinyl]-acetate and 67 μl (0.55 mmol) of pivaloyl chloride in 6.7 ml of dry tetrahydrofuran at -70° C., and the reaction mixture is stirred at -70° C. for a further 30 minutes and then diluted with 40 ml of toluene and washed with 30 ml of 2N HCl, then twice with 40 ml of NaCl solution in each case. The organic phase is dried over MgSO4 and filtered, and the solvent is removed in vacuo. The residue is chromatographed over 10 g of silica gel using toluene:ethyl acetate (9:1), to give 268 g of a white, non-crystalline solid. IR spectrum in CH2Cl2 : 2930, 2850, 1775, 1760, 1720, 1610, 1535, 1350 cm-1 .
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][C:4]([O:6]CC)=O.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[ClH:1].[C:9]1([C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([OH:6])[CH2:3][NH2:2])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)CN
Agent: Cl
Product: NCC(O)(c1ccccc1)c1ccccc1

Procedure:
Treatment of ethyl glycinate hydrochloride (4.5 g) with phenylmagnesium bromide (from 0.39 mole each of bromobenzene and magnesium), as discussed by A. McKenzie and G. O. Wills J. Chem. Soc. 1925, 127, 283 (and references cited therein), affords the title compound (mp 191°-193° C.).
Reaction SMILES: C([O:5][C:6]([C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[N:12]=1)=[O:7])(C)(C)C.[ClH:18]>C(Cl)Cl.O1CCOCC1>[F:17][C:13]1[N:12]=[C:11]([C@@H:9]2[CH2:10][C@H:8]2[C:6]([OH:7])=[O:5])[CH:16]=[CH:15][CH:14]=1.[ClH:18]
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@H]1c1cccc(F)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(O)[C@@H]1C[C@H]1c1cccc(F)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarboxylic acid t-butyl ester (165 mg, 0.7 mmol) in DCM (3 mL) was added HCl in dioxane (4 M, 10 mL). The resulting mixture was stirred at rt for 3 h. The mixture was then concentrated to give the desired product as HCl salt (120 mg, 79%). MS (M−H 181).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[C:28](Cl)[N:27]=[C:26]([NH2:31])[N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1.CCCCCC.CCOC(C)=O>CO.[Pd]>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[C:20]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH2:31])[N:25]=4)[CH:21]=[CH:22][C:13]2=3)=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1nc(Cl)cc(Oc2ccc3c(c2)CCCCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1nccc(Oc2ccc3c(c2)CCCCN3C(=O)Nc2cccc(C(F)(F)F)c2)n1

Procedure:
Hydrogenation of 0.26 g (0.54 mMol) 7-(2-amino-6-chloro-pyrimidin-4-yloxy)-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide in 15 ml methanol in the presence of 70 mg Pd/C (Engelhard 4505), filtration and column chromatography (SiO2; hexane/EtOAc 3:2→2:3) of the filtrate gives the title compound: m.p.: 207° C.; MS: [M+1]+=444/480; Anal.: C,H,N,F.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[CH2:14]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH4+].[Cl-]>C1COCC1>[CH2:14]([N:21]1[CH2:26][CH2:25][C:24]([OH:27])([C:2]2[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:23][CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1cccnc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccnc1C1(O)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 50.2 %

Procedure:
Following the procedure of N. I. Carruthers et al. (J. Med. Chem. 2005, 48, 1857-1872), to a −78° C. solution of 2-bromo-3-methylpyridine (10.0 g, 7.1 mL, 57.1 mmol) in THF (150 mL) was added drop wise a solution of n-BuLi (2.5 M in hexanes, 25.1 mL, 62.8 mmol) over 10 min. After 1.5 h a solution of N-benzyl-4-piperidone (10.8 g, 57.1 mmol) in THF (20 mL) was added drop wise over 15 min and the mixture was allowed to slowly warm to room temperature overnight. After 18 h sat. NH4Cl solution (40 mL) was added and the mixture was concentrated. The resulting residue was diluted with 1N NaHCO3 (100 ml) and extracted with EtOAc. The combined organic phase washed with brine, dried (MgSO4), and concentrated. Flash chromatography afforded the alcohol (8.1 g), an orange viscous oil, in 50% yield.
Reaction SMILES: O1C2C=CC=CC=2N=C1.[C:10]([C:13]1[CH:32]=[CH:31][CH:30]=[CH:29][C:14]=1[C:15]([NH:17][N:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)[CH3:19])=O)([OH:12])=[O:11].C(O)(=O)C.C(C1C=CC=CC=1C=O)(O)=O>O>[C:10]([C:13]1[CH:32]=[CH:31][CH:30]=[CH:29][C:14]=1[CH:15]=[N:17][N:18]([C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)[CH3:19])([OH:12])=[O:11]
Reactant: CN(NC(=O)c1ccccc1C(=O)O)c1nc2ccccc2o1
Agent: O=Cc1ccccc1C(=O)O
Agent: c1ccc2ocnc2c1
Solvent: O
Solvent: CC(=O)O
Product: CN(N=Cc1ccccc1C(=O)O)c1nc2ccccc2o1
Reaction time: 16 h

Procedure:
To a stirred suspension of 1.6 g. of the benzoxazole intermediate product of Example 1 in 50 ml. of glacial acetic acid is added 1.5 g. of 2-carboxybenzaldehyde. After a few minutes the mixture becomes homogeneous, then quickly thickens as a new precipitate forms. Stirring is continued for 16 hours, water is added, and the solid is filtered, washed with water and dried to give 2.5 g. of product, m.p. 253°-5°.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]3)[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]([C:31](O)=[O:32])=[N:27][N:28]([CH3:30])[CH:29]=2)=[CH:21][CH:20]=1>>[F:1][C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][N:13]3[C:31]([C:26]3[C:25]([C:22]4[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=4)=[CH:29][N:28]([CH3:30])[N:27]=3)=[O:32])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc(-c2ccc(F)cc2)c(C(=O)O)n1
Reactant: Fc1cccc2oc(CC3CCCCN3)cc12
Product: Cn1cc(-c2ccc(F)cc2)c(C(=O)N2CCCCC2Cc2cc3c(F)cccc3o2)n1

Procedure:
The title compound (45 mg) was prepared from (RS)-2-(4-fluoro-benzofuran-2-ylmethyl)-piperidine, D76 (157 mg) and 4-(4-fluoro-phenyl)-1-methyl-1H-pyrazole-3-carboxylic acid (160 mg) according to a procedure similar to that described for Example 4.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[F:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:12]2[N:11]=[CH:10][N:9]=[C:8]3[NH:7][N:6]=[C:5]([O:4][CH2:3][CH2:2][N:34]4[CH2:35][CH2:36][CH:31]([F:30])[CH2:32][CH2:33]4)[C:13]=23)[CH:20]=[CH:19][C:18]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Reactant: FC1CCNCC1
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCC(F)CC5)c34)cc2Cl)cn1
Yield: 43 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (prepared as described in Example 16) and 4-fluoropiperidine to give the title compound in 43% yield; NMR Spectrum: 1.66-1.70 (m, 2H), 1.80-1.87 (m, 2H), 2.41-2.44 (m, 2H), 2.45 (s, 3H), 2.64-2.68 (m, 2H), 2.83 (t, 2H), 4.44 (t, 2H), 4.65 (dm, 1H), 7.20 (d, 1H), 7.25 (br s, 2H), 7.73 (d, 1H), 8.11 (s, 1H), 8.21 (s, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 498 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH:18]1[C:30]2[CH:29]([CH2:31][O:32][C:33]([N:35]=[C:36]=[S:37])=[O:34])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][NH:17][C:36](=[S:37])[NH:35][C:33]([O:32][CH2:31][CH:29]3[C:28]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:22]4[C:30]3=[CH:18][CH:19]=[CH:20][CH:21]=4)=[O:34])[CH2:14][CH2:15]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Solvent: C1CCOC1
Product: O=C(NC(=S)NCC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving {1-[(3,4-dichlorophenyl)methyl]-4-piperidyl}methylamine (1325 mg, 4.84 mmol) in tetrahydrofuran (20 ml), FmocNCS (9-fluorenylmethoxycarbonyl isothiocyanate) (1498 mg, 5.32 mmol) was added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=85/15) to obtain N-{[({1-[(3,4-dichlorophenyl)methyl](4-piperidyl)}methyl)amino]thioxomethyl}(fluoren-9-ylmethoxy)carboxamide. The compound was identified by LC-MS.