Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.C1(C)C=CC=CC=1.C(O)C.O.B([O-])([O-])O[C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH3:54])=[N:51][C:50]=2[CH:55]=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:54][C:52]1[O:53][C:49]2[CH:48]=[CH:47][C:46]([C:2]3[CH:3]=[CH:4][C:5]4[S:11](=[O:12])(=[O:13])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]5[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]6[CH2:26][CH2:27][O:28][CH2:29][CH2:30]6)=[CH:19][CH:18]=5)=[O:15])=[CH:7][C:6]=4[CH:32]=3)=[CH:55][C:50]=2[N:51]=1
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: Cc1nc2cc(OB([O-])[O-])ccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2cc(-c3ccc4c(c3)C=C(C(=O)Nc3ccc(CN(C)C5CCOCC5)cc3)CCS4(=O)=O)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.6 %

Procedure:
To 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.35 g) was added toluene/ethanol/water (10/1/1,16.3 ml) and then were added 2-methyl-1,3-benzoxazol-5-yl borate (0.14 g) and potassium carbonate (0.23 g), and the mixture was stirred at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (31 mg), and the mixture was refluxed for 14 hours, cooled to room temperature, poured into water. The mixture was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. Under reduced pressure, the solvent was removed, and the residue was purified with silica gel column chromatography (ethyl acetate/ethanol=4/1) and recrystallized from ethanol to give 7-(2-methyl-1,3-benzoxazol-5-yl)-N-[4-([N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 135) (110 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([O:23][CH2:24][C:25]#[N:26])[C@@H:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.N#N.B.S(C)C>C1COCC1>[NH2:26][CH2:25][CH2:24][O:23][C@@H:9]([C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCC#N)c2cc(F)cc(Cl)c2)C1
Agent: B
Agent: N#N
Solvent: CSC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cc(F)cc(Cl)c2)C1
Yield: 26.4 %

Procedure:
A solution of (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(cyanomethoxy)methyl)piperidine-1-carboxylate (90 g) in anhydrous THF (1.3 L), under protection of N2, was heated to reflux followed by the dropwise addition of 10 M H3B.SMe2 in THF (70 mL, 0.7 mol). The mixture was stirred at reflux overnight. The reaction was quenched with MeOH (500 mL) and the solvent removed in vacuo, the residue was purified by column chromatography to give (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chloro-5-fluorophenyl)methyl)piperidine-1-carboxylate (24 g, 0.062 mol).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][N:9]=1>ClC1C=CC=CC=1>[N:1]1([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[S:10][N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: Clc1nsc2ccccc12
Reactant: C1CNCCN1
Solvent: Clc1ccccc1
Product: c1ccc2c(N3CCNCC3)nsc2c1
Temperature: 120 °C
Reaction time: 20 h
Yield: 47.3 %

Procedure:
304.2 g (3.53 mol) of piperazine, 7.5 g of chlorobenzene, 39.8 g (0.235 mol) of 3-chloro-1,2-benzisothiazole were placed in a four-neck 1000 ml flask equipped with a stirrer, a thermometer, a dropping funnel and a condenser, which was heated to stir at about 120° C. for 20 hours. After excess piperazine was removed with water, the reaction mixture was made acidic with hydrochloric acid, extracted into an aqueous layer, which was made alkaline with aqueous sodium hydroxide to obtain 24.4 g (m.p. 89° to 90 ° C.) of 3-(1-piperazinyl)-1,2-benzisothiazole as crystals. Yield from 3-chloro-1,2-benzisothiazole was 47.4%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)[N:3]=1
Reactant: COCc1cc(Cl)nc(-c2cccc(C)c2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COCc1cc(Nc2cc(OC)ccc2C)nc(-c2cccc(C)c2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-(methoxymethyl)-2-(3-methylphenyl)pyrimidine (50 mg, 0.201 mmol) and 5-methoxy-2-methylaniline (28 mg, 0.201 mmol) similar to Example 13. 1H NMR (CDCl3): 8.20–8.16 (m, 2H), 7.35 (t, J=7.5 Hz, 1H), 7.28 (s, 1H), 7.18 (s, 1H), 7.17 (d, J=8.1 Hz, 1H), 6.73 (dd, J=2.7, 8.4 Hz, 1H), 6.61 (s, 1H), 6.57 (s, 1H), 4.49 (s, 2H), 3.82 (s, 3H), 3.47 (s, 3H), 2.44 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:13]2[C:7]([CH2:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]=[CH:12]2)=[N:6][N:5]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:26])C=1>>[CH2:1]([S:3]([C:4]1[N:13]2[C:7]([CH2:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[CH:11]=[CH:12]2)=[N:6][N:5]=1)=[O:26])[CH3:2]
Reactant: CCSc1nnc2n1C=Cc1ccccc1C2
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CCS(=O)c1nnc2n1C=Cc1ccccc1C2

Procedure:
By a procedure similar to that described in Example 17, 3-ethylthio-11H-s-triazolo[3,4-b][3]benzazepine was reacted with m-chloroperbenzoic acid to obtain 3-ethylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from ethyl acetate), m.p. 98°-99° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[N:25]=[CH:24]3)[C@H:9]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH2:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([C:30]2[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=2)[N:25]=[CH:24]3)[C@@H:9]([NH:10][C:47](=[O:48])[CH2:46][O:45][CH3:44])[CH2:11][O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)Cl
Reactant: N[C@@H](COCc1ccccc1)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)N[C@@H](COCc1ccccc1)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-[(phenylmethoxy)methyl]benzeneethanamine is synthesized in analogy to the sequence previously described in example 1: commercially available Boc-Ser(Bn)-OH is transformed into its Weinreb-amide. Reduction to the aldehyde with LiAl4, reaction with 3-fluorophenylgrignard, cleavage of the tert.-butyloxycarbonyl protecting group, liberation of the amine from the hydrochloride and etherification with 1-(4-fluorophenyl)-5-iodo-1H-indazole gives the desired amine. This amine (123.3 mg, 0.25 mmol) is dissolved in 10 mL of dichloromethane. Triethylamine (0.084 mL, 0.61 mmol) and 0.028 mL (0.3 mmol) 2-methoxyacetylchloride are added. The reaction mixture is stirred overnight at r.t., then diluted with dichloromethane, washed with water and brine and dried over Na2SO4. After filtration the solvent is evaporated and the residue purified by chromatography (silicagel, eluents: ethyl acetate/hexane). 79.1 mg (55.9%) of the title compound as a mixture of stereoisomers are isolated.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[C:14]([O:26][CH3:27])=[CH:15][C:16]3[N:22]([CH3:23])[C:21](=[O:24])[O:20][CH2:19][CH2:18][C:17]=3[CH:25]=2)[N:3]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)[CH:33]=[CH:32][C:31]=1[NH2:42]>>[CH3:27][O:26][C:14]1[C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:42][C:31]3[CH:32]=[CH:33][C:34]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:35][C:30]=3[O:29][CH3:28])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:25][C:17]2[CH2:18][CH2:19][O:20][C:21](=[O:24])[N:22]([CH3:23])[C:16]=2[CH:15]=1
Reactant: COc1cc2c(cc1Nc1ncc(C(F)(F)F)c(Cl)n1)CCOC(=O)N2C
Reactant: COc1cc(N2CCOCC2)ccc1N
Product: COc1cc2c(cc1Nc1ncc(C(F)(F)F)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCOC(=O)N2C
Yield: 9 %

Procedure:
In an analogous manner to Example 1513, the product was prepared from 2-(4-Chloro-5-trifluoromethyl-pyrimidin-2-ylamino)-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 2-Methoxy-4-morpholin-4-yl-phenylamine. Product isolated as a white solid (8.0 mg, 9%). mp: 232-234° C., MS (ESI+): 575 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.31 (s, 1H), 8.22 (s, 1H), 7.95 (m, 1H), 7.70 (s, 1H), 7.25 (s, 1H), 6.69 (s, 1H), 6.54 (s, 1H), 6.49 (d, J=8 Hz, 1H), 4.44 (t, J=6 Hz, 2H), 3.92 (s, 4H), 3.90 (s, 6H), 3.40 (s, 3H), 3.16 (t, J=5 Hz, 4H), 2.78 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([OH:12])=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][O:22][CH3:23].O>CC(C)=O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][CH2:20][CH2:21][O:22][CH3:23])[N:3]=1
Reactant: COCCBr
Reactant: Oc1cccc2nc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COCCOc1cccc2nc(Cl)ccc12
Temperature: 50 °C
Reaction time: 18 h
Yield: 32.4 %

Procedure:
2-Chloro-quinolin-5-ol (CAS 124467-35-2) (0.3 g, 1.56 mmol) was dissolved in acetone (10 mL) and potassium carbonate (0.368 g, 2.75 mmol) was added. After addition of 2-bromethylmethylether (0.25 ml, 2.7 mmol) the reaction mixture was stirred for 18 h at 50° C. Then water was added and the mixture was extracted with ethyl acetate (3×). The combined organic phases were dried, filtered and concentrated. The residue was subjected to column chromatography (silica gel, heptane/ethyl acetate 9:1/4:1) to yield 2-chloro-5-(2-methoxy-ethoxy)-quinoline as a colourless oil (0.12 g, 30%). MS: m/e=238.8 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:16]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[C:11]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:10]=2[O:33][CH3:34])=[O:7])=[CH:4][C:3]=1[F:37].O.[F:39][C:40]([F:44])([F:43])[CH:41]=O.C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O.O.CCOC(C)=O>[CH2:22]([O:21][C:16]1[C:15]([C:13]2[CH:12]=[C:11]([C:29]([CH3:31])([CH3:32])[CH3:30])[C:10]([O:33][CH3:34])=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:35]=[CH:36][C:2]([NH:1][CH2:41][C:40]([F:44])([F:43])[F:39])=[C:3]([F:37])[CH:4]=3)[CH:14]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=CC(F)(F)F
Reactant: COc1c(NC(=O)c2ccc(N)c(F)c2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1c(NC(=O)c2ccc(NCC(F)(F)F)c(F)c2)cc(-c2cccnc2OCc2ccccc2)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 38.1 %

Procedure:
step 3—To a solution of 318 (201 mg, 0.402 mmol) in TFA (4 mL) at RT was added trifluoroacetaldehyde hydrate (98 mg, 0.845 mmol) and H2O (2 drops). The reaction mixture was stirred at RT for 5 min, and then sodium cyanoborohydride (33 mg, 0.523 mmol) was added. Gas evolution was briefly observed. The reaction mixture was stirred at RT for 4.5 h, then diluted with H2O and EtOAc and carefully poured into sat'd NaHCO3. The layers were separated, and the organic phase was subsequently twice washed sequentially with sat'd. NaHCO3, H2O and brine. The organic layer was dried (MgSO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography, eluting with an EtOAc/hexane gradient (0% to 30% EtOAc) to afford 89 mg (38%) of N-[5-(2-benzyloxy-pyridin-3-yl)-3-tert-butyl-2-methoxy-phenyl]-3-fluoro-4-(2,2,2-trifluoro-ethylamino)-benzamide (320) as a foamy, light yellow solid.
Reaction SMILES: [O:1]1CCOCC1.[CH3:7][O:8][CH2:9][C:10]1([C:15]#[N:16])[CH2:13][C:12](=C)[CH2:11]1.I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[CH3:7][O:8][CH2:9][C:10]1([C:15]#[N:16])[CH2:13][C:12](=[O:1])[CH2:11]1
Reactant: C=C1CC(C#N)(COC)C1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: COCC1(C#N)CC(=O)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of water (2 mL, 0.1 mol) and 1,4-dioxane (7 mL, 0.08 mol), 1-(methoxymethyl)-3-methylenecyclobutanecarbonitrile (0.294 g, 0.00214 mol), and 0.2 M of osmium tetraoxide in water (0.04 mL) was stirred for 5 min, during which time the mixture became brown. While the temperature was maintained at room temperature, sodium periodate (0.963 g, 0.00450 mol) was added in portions over a period of 30 min. The mixture was stirred overnight. The mixture was extracted with EtOAc and the combined organic layers were dried over MgSO4. After removal of the solvents, the crude product was used directly in next step (298 mg, 99.92%). 1H NMR (400 MHz, CDCl3): 3.70 (2H, s), 3.68 (3H, s), 3.58 (2H, m), 3.38 (2H, m) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH:3]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][CH:5]=1>[Ni].CO>[N:13]1([CH:3]([C:4]2[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=2)[CH:2]([CH3:18])[CH3:1])[CH:17]=[CH:16][N:15]=[CH:14]1
Reactant: CC(C)C(c1ccc([N+](=O)[O-])cc1)n1ccnc1
Agent: [Ni]
Solvent: CO
Product: CC(C)C(c1ccc(N)cc1)n1ccnc1
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of 12 parts of intermediate 40, namely 1-[2-methyl-1-(4-nitrophenyl)propyl]-1H-imidazole, and 79 parts of methanol was hydrogenated for 1 hour at room temperature and 2.105Pa with 3 parts of Raney nickel. The catalyst was filtered off and the filtrate was evaporated, yielding 12 parts (100%) of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (interm. 41).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1)([O-:13])=[O:12]>>[N+:11]([C:14]1[CH:19]=[CH:18][C:17]2[NH:20][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[NH:21][C:16]=2[CH:15]=1)([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: O=C(O)c1cccnc1Cl
Product: O=C1Nc2ccc([N+](=O)[O-])cc2Nc2ncccc21
Temperature: 170 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
A mixture of 2-chloronicotinic acid (15.7 g, 0.1 mol) and 4-nitrophenylene diamine (15.3 g, 0.1 mol) was heated in sulfonane (100 ml) at 170° C. for 5 hrs. The reaction mixture was then cooled and left standing overnight. The solid material was filtered and taken up in boiling ethanol. The solid was filtered again an dried giving 21 g (82% theory) of 6,11-dihydro-9-nitro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one suitable for use in the next reaction.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:14][C:15]3[C:20]([CH:21]=2)=[C:19]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17][CH:16]=3)=[O:12])[CH2:6][CH2:5]1.[NH:27]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]([NH2:34])[CH2:28]1>>[NH2:34][CH:29]1[CH2:30][CH2:31][CH2:32][CH2:33][N:27]([CH2:2][CH2:3][N:4]2[CH2:5][CH2:6][CH:7]([NH:10][C:11]([C:13]3[NH:14][C:15]4[C:20]([CH:21]=3)=[C:19]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH:18]=[CH:17][CH:16]=4)=[O:12])[CH2:8][CH2:9]2)[CH2:28]1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCO)CC3)cc12
Reactant: NC1CCCCNC1
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCC(N)C4)CC3)cc12

Procedure:
This compound is synthesized analogously to example 150 from 4-isobutoxy-1H-indole-2-carboxylic acid [1-(2-hydroxy-ethyl)piperidin-4-yl]-amide, 190 and azepan-3-ylamine.
Reaction SMILES: [CH2:1]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([NH2:24])=O)[CH2:18][CH2:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:24][CH2:22][CH:19]1[CH2:20][CH2:21][N:16]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18]1
Reactant: CCCCCCCCCCCCCCCN1CCC(C(N)=O)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCCCCCCCCCCCN1CCC(CN)CC1
Yield: 104.3 %

Procedure:
Prepared from 1-pentadecylpiperidine-4-carboxamide (4.3 g, 12.7 mmol) and LAH (0.97 g, 21.2 mmol) according to general procedure used for Example 8 (Step B) to give 4.3 g of title compound as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>[I-].[K+].CC(=O)CC>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[C:6]([C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C(C)(C)C)c1
Reactant: CCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCOc1ccc(C(=O)OC)cc1C(C)(C)C
Yield: 105.2 %

Procedure:
A mixture of 12.0 g of 3-(1,1-dimethylethyl)-4-hydroxybenzoic acid methyl ester, 11.15 g of 1-bromodecane, 9.95 g of potassium carbonate, 0.797 g of potassium iodide and 100 ml of 2-butanone is heated at reflux temperature for 40 hours. The reaction is cooled, filtered and the filtrate concentrated in vacuo. The residue is purified by chromatography (silica gel: 0-3% ethyl acetate/hexane) to give 18.49 g of the desired product as a light yellow oil.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[CH:10]=1.[N:22]1[N:23]([C:27]2[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=2[C:29](O)=[O:30])[N:24]=[CH:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:20][N:19]([CH3:21])[C:11]1[CH:10]=[C:9]([N:2]2[CH2:3][CH:4]3[CH:5]([CH2:6][N:7]([C:29]([C:28]4[CH:32]=[CH:33][CH:34]=[CH:35][C:27]=4[N:23]4[N:24]=[CH:25][CH:26]=[N:22]4)=[O:30])[CH2:8]3)[CH2:1]2)[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: CN(C)c1cc(N2CC3CNCC3C2)nc(C(F)(F)F)n1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1cc(N2CC3CN(C(=O)c4ccccc4-n4nccn4)CC3C2)nc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A mixture of [6-(hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-2-trifluoromethyl-pyrimidin-4-yl]-dimethyl-amine (50 mg, 0.17 mmol), 2-[1,2,3]triazol-2-yl-benzoic acid (34.5 mg, 0.18 mmol), HATU (94.6 mg, 0.25 mmol) and DIPEA (0.09 mL, 0.50 mmol) in DMF (4.0 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (60.0 mL) and washed with water (2×100 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (Basic system) to yield pure title compound (34.0 mg, 43.4%). MS (ESI) mass calcd. for C22H23F3N8O, 472.47; m/z found 473.2 [M+H]+. 1H NMR (CDCl3): 7.98 (d, J=8.1, 1H), 7.70-7.69 (m, 2H), 7.56-7.49 (m, 1H), 7.45-7.37 (m, 2H), 5.20-5.10 (m, 1H), 3.90-3.66 (m, 4H), 3.60-3.28 (m, 4H), 3.08 (s, 6H), 3.02-2.89 (m, 2H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C(O)=O)(=O)C.[CH3:22][O:23][C:24]([NH:26]C1C=CC(OC)=C(O)C=1)=[O:25]>>[CH3:22][O:23][C:24]([NH:26][C:7]1[CH:11]=[CH:12][C:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:5]([OH:4])[CH:6]=1)=[O:25]
Reactant: CC(=O)Oc1cc(C(=O)O)ccc1OCc1ccccc1
Reactant: COC(=O)Nc1ccc(OC)c(O)c1
Product: COC(=O)Nc1ccc(OCc2ccccc2)c(O)c1

Procedure:
3-Acetoxy-4-benzyloxybenzoic acid (14.4 g) was treated in the same manner as in the preparation of N-methoxycarbonyl-3-hydroxy-4-methoxyaniline in Experimental Example 4 to obtain N-methoxycarbonyl-4-benzyloxy-3-hydroxyaniline (11.8 g).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:37]([CH3:38])[C:36]4[CH:39]=[CH:40][C:41]([CH3:43])=[CH:42][C:35]=4[N:34]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(-c3nc4cc(C)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2ccc(-c3nc4cc(C)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(1,5-dimethyl-benzimidazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=2[CH:11]=[C:10]([F:19])[CH:9]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:18][CH2:17][CH:14]1[CH2:13][C:12]2[CH:11]=[C:10]([F:19])[CH:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:16]=2[O:15]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cc(F)cc(-c3ccccc3Cl)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cc(F)cc(-c3ccccc3Cl)c2O1)OCc1ccccc1

Procedure:
Treatment of (±)-1-[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.92 g, 10.5 mmol) with diisopropylethylamine (1.70 g, 13.1 mmol) and benzyl chloroformate (1.97 g, 11.6 mmol) generally according to the procedure described for Intermediate 12 provided 3.02 (70%) of (±)-benzyl[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf=0.76 (silica, ethyl acetate:hexanes 1:9); Anal. calcd. for C23H19ClFNO3.0.5H2O: C, 65.64; H, 4.79; N, 3.33. Found: C, 65.28; H, 4.73; N, 3.18. Chiral HPLC separation of (±)-benzyl[7-(2-chlorophenyl)-5-fluoro-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate (Chiralcel OJ, hexane:ethanol 1:1) provided two fractions. Fraction 1 (Rt=9.322 min, Chiralcel OJ, hexane:ethanol 1:1); Fraction 2 (Rt=13.646 min, Chiralcel OJ, hexane:ethanol 1:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.S(Cl)([Cl:17])=O.CN(C=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(Br)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2cc(Br)ccc2c1
Temperature: 60 °C

Procedure:
A suspension of 6-bromo-2-naphthoic acid (100 g), thionyl chloride (37.7 mL) and DMF (0.5 mL) in THF (1000 mL) was stirred with heating at 60° C. for 90 min. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The obtained solid was dissolved in toluene and the solvent was evaporated to give a pale-yellow powder of 6-bromo-2-naphthoyl chloride.