Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH2:12])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:19][O:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH:23]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[O:20][CH3:19])[CH:6]=[C:5]2[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccccc1C=O
Reactant: Nc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccccc1CNc1cc(-c2ccccc2)c2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Chloro-4-phenyl-quinolin-2-ylamine (CAS 51478-40-1, 750 mg, 2.94 mmol) was dissolved in 40 mL dichloromethane. 2-Methoxybenzaldehyde (481 mg, 3.54 mmol) and acetic acid (354 mg, 5.9 mmol) were added. The reaction mixture was stirred at room temperature for 2 h. Sodium triacetoxy borohydride (1.39 g, 6.59 mmol) was added and stirring was continued overnight. The reaction mixture was quenched by addition of 100 mL sat. sodiumbicarbonate solution. The mixture was extracted three times with dichloromethane (100 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The residue purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100:0->80:20 gradient). (6-Chloro-4-phenyl-quinolin-2-yl)-(2-methoxy-benzyl)-amine was obtained as an off-white solid (595 mg, 54%), MS: m/e=375.1 (M+H+).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].F[C:8]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:9]=1[CH:10]=O>CS(C)=O>[CH3:6][O:5][C:1]([C:2]1[S:3][C:12]2[CH:13]=[C:14]([O:16][CH3:17])[CH:15]=[CH:8][C:9]=2[CH:10]=1)=[O:4]
Reactant: COC(=O)CS
Reactant: COc1ccc(C=O)c(F)c1
Solvent: CS(C)=O
Product: COC(=O)c1cc2ccc(OC)cc2s1
Yield: 65.6 %

Procedure:
To a solution of methyl thioglycolate (1.29 mL, 14 mmol, 1.1 eq.) in 22 mL of DMSO was added Nail 50% (0.972 g, 20 mmol, 1.56 eq.) and the mixture was stirred for 5 Min., before 2-fluoro-4-methoxybenzaldehyde (2.00 g, 13 mmol) was added (strongly exothermic). When the internal temperature had reached again 25° C., the reaction mixture was poured onto crashed ice and the precipitate filtered off, washed with water, and dried to obtain 1.896 g of the title compound as light yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:15]=[C:14]2[CH:16]=[CH:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]2=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].IC.[CH3:28][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:9][C:10]1[N:15]=[C:14]2[CH:16]=[CH:17][N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:13]2=[CH:12][CH:11]=1)[CH3:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(ccn2C(=O)OC(C)(C)C)n1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(Cc1ccc2c(ccn2C(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a stirred solution of tert-butyl 5-[(tert-butoxycarbonylamino)methyl]-pyrrolo-[3,2-b]pyridine-1-carboxylate (360.0 mg, 1.036 mmol) and iodomethane (0.065 mL, 1.036 mmol) in anhydrous THF (6.3 mL) cooled to −40° C. was added dropwise lithium bis(trimethylsilyl)amide in THF (1.24 mL, 1.24 mmol, 1M). The reaction mixture was warmed to 0° C. and stirred at 0° C. for 1 h. The reaction was quenched with water and then diluted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by SiO2 chromatography eluting with a mixture of EtOAc containing 1% TEA and heptane to afford 130.0 mg (37.3%) of tert-butyl 5-((tert-butoxycarbonyl(methyl)amino)methyl)-1H-pyrrolo[3,2-b]pyridine-1-carboxylate as a foam: 1H NMR (400 MHz, CDCl3) δ 8.33 (d, J=7.6 Hz, 1H), 7.82 (d, J=3.5 Hz, 1H), 7.27-7.10 (m, 1H), 6.73 (d, J=3.7 Hz, 1H), 4.64 (s, 2H), 3.02-2.82 (m, 3H), 1.68 (s, 9H), 1.56-1.41 (m, 9H); MS (ESI) m/z: 362.3 [M+1]+
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[NH:21][C:22]([C:24]2[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:23])=[CH:6][CH:5]=1.[CH:35](=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C.CO>[CH2:35]([NH:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][C:12]=2[NH:21][C:22]([C:24]2[CH:32]=[C:31]([Cl:33])[C:30]([Cl:34])=[CH:29][C:25]=2[C:26]([OH:28])=[O:27])=[O:23])=[CH:8][CH:9]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=Cc1ccccc1
Reactant: NCc1ccc(Nc2ccc(C(F)(F)F)cc2NC(=O)c2cc(Cl)c(Cl)cc2C(=O)O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1cc(Cl)c(Cl)cc1C(=O)Nc1cc(C(F)(F)F)ccc1Nc1ccc(CNCc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
In a small round bottom flask equipped with a stirbar, 2-({[2-{[4-(aminomethyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid hydrochloride (0.2 mmol, 107 mg) is combined with benzaldehyde (0.96 mmol, 102 mg) and diluted with 1 mL acetic acid and 4 mL methanol. After 15 minutes, sodium cyanoborohydride (3.5 mmol, 0.24 mL) is added portionwise. After 20 hours, the reaction is stopped. The reaction mixture is made basic with 5N NaOH and extracted three times with ethyl acetate. The organics are combined and washed with brine then dried over MgSO4. After concentration the crude oil is purified by column chromatography (100% EtOAc) to give a white solid in low yield. 1H NMR (400 MHz, DMSO-d6): □ 10.39 (s, 1H), 7.98 (m, 1H), 7.80 (s, 1H), 7.66 (s, 1H), 7.43, (m, 14H), 4.12 (m, 4H). ESI+ for C29H22Cl2F3N3O3 m/z 588 M+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[N+:10]([O-])([OH:12])=[O:11]>ClC1C=CC=CC=1>[N+:10]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([O-:12])=[O:11]
Reactant: Brc1ccccc1
Reactant: O=[N+]([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Product: O=[N+]([O-])c1ccc(Br)cc1

Procedure:
The bromobenzene may then be converted to phenols by a reaction with a sodium hydroxide solution, similar to the hydrolysis of chlorobenzene, with NaOH under pressure. In addition, bromobenzene may be reacted with nitric acid to form p-nitro-bromobenzene, which can then be converted after several other chemical processing steps to p-methoxyphenol. Other chemicals may be produced using bromobenzene as a raw starting material.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)(=O)C.[N:17]#[C:18]Br.[OH-].[Na+]>C(O)C.O>[C:18]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH2:8][CH2:9]1)#[N:17]
Reactant: N#CBr
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: N#CN1CCc2ccc([N+](=O)[O-])cc21
Temperature: 4 °C
Reaction time: 21 h
Yield: 83.9 %

Procedure:
To a cooled (4° C.) and stirred solution of 6-nitroindoline (3.04 g) in a mixture of glacial acetic acid (22 ml), water (11 ml) and absolute ethanol (23 ml) was added solid cyanogen bromide (2.93 g) followed by 1N aqueous sodium hydroxide solution (25 ml) over 3 minutes. The mixture was then allowed to warm to room temperature, stirred for a further 21 hours and the solid formed was collected by filtration, washed with water and dried over phosphorous pentoxide to give the title compound (2.94 g) as a solid; δH (250 MHz, DMSO-d6) 7.90 (1H, dd, J=8.1 and 2.2 Hz), 7.55-7.50 (2H, m), 4.23 (2H, t, J=8.4 Hz), 3.30 (2H, t, J=8.4 Hz); m/z (CI) 189 (M-).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]([C:13]1[CH:14]=[C:15]([CH3:39])[C:16]2[O:22][C:21]3[C:23]([Cl:35])=[CH:24][C:25]([N:27]([C:31](=[O:34])[CH2:32]Cl)[CH2:28][CH2:29]Cl)=[CH:26][C:20]=3[CH2:19][S:18](=[O:37])(=[O:36])[C:17]=2[CH:38]=1)=[O:12]>CN(C=O)C>[CH3:9][O:10][C:11]([C:13]1[CH:14]=[C:15]([CH3:39])[C:16]2[O:22][C:21]3[C:23]([Cl:35])=[CH:24][C:25]([N:27]4[CH2:28][CH2:29][N:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:32][C:31]4=[O:34])=[CH:26][C:20]=3[CH2:19][S:18](=[O:36])(=[O:37])[C:17]=2[CH:38]=1)=[O:12]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCCl)C(=O)CCl)cc(Cl)c1O2
Reactant: NCc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4ccccc4)CC3=O)cc(Cl)c1O2
Temperature: 80 °C
Reaction time: 5 h

Procedure:
Benzylamine (0.17 mL, 1.581 mmol) was added to a solution of Example 57k (0.4 g, 0.79 mmol) in DMF (5 mL) and stirred at 80° C. for 5 h. The reaction mixture was concentrated, treated with water and extracted with chloroform. The organic layer was washed with water, brine, dried and concentrated to obtain the crude title compound which was purified using flash chromatography (silica gel, 1% methanol/chloroform). Yield: 125 g, (29.2%); 1H NMR (DMSO-d6): δ 2.68 (s, 3H, CH3), 2.8 (t, 2H, CH2), 3.2 (s, 2H, CH2), 3.63 (s, 2H, CH2), 3.7 (t, 2H, CH2), 3.88 (s, 3H, OCH3), 5.31 (s, 2H, CH2), 7.29-7.38 (m, 5H, Ar), 7.66 (s, 1H, Ar), 7.73 (s, 1H, Ar), 8.16 (s, 1H, Ar), 8.19 (s, 1H, Ar); MS: m/e (ES+) 541 (M+1).
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH:10]=O)=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2].Cl.[CH3:28][NH:29][CH3:30]>CCOCC.C(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][N:29]([CH3:30])[CH3:28])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:7]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[C:6]([CH:24]([CH3:26])[CH3:25])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CNC
Reactant: CCCCCc1c(C(C)C)nc(C(C)C)c(C=O)c1-c1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CN(C)C)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-4-(4-fluorophenyl)-5-pentyl-3-pyridinecarboxaldehyde (Example 114, Step A) and dimethylamine hydrochloride, according to the procedures described in Example 120. 1H NMR (300 MHz, CDCl3): δ 7.09 (m, 4 H), 3.49 (septet, J=6.6 Hz, 1 H), 3.21 (septet, J=6.6 Hz, 1 H), 3.05 (s, 2 H), 2.22 (t, J=5.2 Hz, 2 H), 1.99 (s, 6 H), 1.18 (m, 18 H), 0.790 (t, J =6.3 Hz, 3 H). FAB-MS: calcd for (C25H37FN2) 384, found 385 (M+H). Anal. Calcd for C23H37FN2: C, 78.08; H, 9.70; N, 7.28; F, 4.94. Found: C, 77.95; H, 9.66; N, 7.12; F, 5.25. mp 69-71° C. Rf=0.4 (20% ether/CH2Cl2).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.Br[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Br:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([N:7]([C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=3)[C:4]3[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=3)=[CH:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: Cc1ccc(Nc2ccc(C)cc2)cc1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(Br)cc3)cc2)cc1
Temperature: 80 °C
Yield: 72.2 %

Procedure:
Di-p-tolylamine (6.0 g, 30.4 mmol), 4,4′-dibromobiphenyl (23.7 g, 76.0 mmol), sodium tert-butoxide (7.26 g, 91.2 mmol), and [1,1-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)Cl2) (666 mg, 0.912 mmol, 3 mol %) were added to anhydrous toluene (about 250 ml) and degassed in argon for about 30 minutes. The resulting mixture was heated to about 80° C. for about 6 hours, after which a TLC analysis indicated that most of the di-p-tolylamine was consumed. After being cooled to RT, the mixture was poured into saturated aqueous sodium bicarbonate and extracted with 2 portions of ethyl acetate. The organic layers were pooled and washed with water and brine, then dried over MgSO4. After filtration the extract was concentrated to dryness on a rotary evaporator, then loaded onto silica gel. A flash column (gradient of 100% hexane to 1% methylene chloride in hexane) resulted in 9.4 g (72%) of a white solid Compound 7 confirmed by 1H NMR in CDCl3.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1.BrC[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH2:27]([O:26][C:24]([CH2:23][CH2:22][CH2:21][CH2:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:4]=1)=[O:25])[CH3:28]
Reactant: CCOC(=O)CCCCBr
Reactant: COc1nc(-c2ccccc2)nc2ccccc12
Product: CCOC(=O)CCCCOc1nc(-c2ccccc2)nc2ccccc12
Yield: 79.4 %

Procedure:
According to the preparation of 69, ethyl 5-bromovalerate (1.88 g, 9.00 mmol) was used to yield 73 (1.25 g, 79.4%) as colorless powder.
Reaction SMILES: C(O[N:9]([C:12]1[CH:17]=[C:16]([C@@H:18]2[CH2:20][O:19]2)[CH:15]=[CH:14][CH:13]=1)[CH:10]=[O:11])C1C=CC=CC=1.[CH2:21]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]#[CH:39])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([N:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]#[CH:39])[CH2:20][C@@H:18]([C:16]1[CH:15]=[CH:14][C:13]([O:19][CH2:18][C:16]2[CH:17]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[C:12]([NH:9][CH:10]=[O:11])[CH:17]=1)[OH:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CN(OCc1ccccc1)c1cccc([C@@H]2CO2)c1
Reactant: C#CCCOCCCCCCNCc1ccccc1
Product: C#CCCOCCCCCCN(Cc1ccccc1)C[C@H](O)c1ccc(OCc2ccccc2)c(NC=O)c1
Yield: 159.6 %

Procedure:
A stirred mixture of 2-(benzyloxy-5-[(2R)-oxiran-2-yl]phenylformamide (R Hett et al, Organic Process Research & Development, 1998, 2, 96-99) (8.6 g) and N-benzyl-6-(but-3-ynyloxy)hexan-1-amine (9.1 g) was heated at 120° for 2 h. The mixture was purified by chromatography (Merck 9385) eluting with cyclohexane/ethyl acetate (2:1) to give the title compound (13.47 g). LCMS RT=2.68 min.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[C:5]1([CH3:13])[CH:10]=[CH:9][C:8]([Mg]Br)=[CH:7][CH:6]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23]>C1COCC1>[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23].[C:5]1([CH3:13])[CH:10]=[CH:9][C:8]([C:15]2([OH:23])[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14]2)=[CH:7][CH:6]=1
Reactant: Cc1ccc([Mg]Br)cc1
Agent: O=C1Cc2ccccc2C1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of anhydrous cerium chloride (40.60 g, 164.7 mmol) in THF(250 mL) was stirred at room temperature for 2 hours under nitrogen. p-Tolylmagnesium bromide (100.0 mL of 1.0 M solution in diethyl ether, 100.0 mmol) was added at 0° C. and stirred for 3.5 h. A solution of 2-indanone (14.21 g, 107.7 mmol) in THF (20 mL) was added at the same temperature. After stirring at 0° C. for 3 h, the mixture was allowed to warm to room temperature and kept at ambient temperature overnight (12 h). It was then treated with 5% aqueous hydrochloric solution. The solution was extracted with diethyl ether (4*200 mL). All etheral layers were combined, washed with water (100 mL), dried over anhydrous magnesium sulphate and concentrated to give the crude product. Kugelrohr distillation yielded 2.94 g of 2-indanone (110° C./0.3 mm Hg) and 17.27 g of 2-(p-tolyl)-2-indanol (160° C./0.3 mm Hg) in solid form. 1H-N.M.R. (CDCl3) d 2.17 (br s, 1H), d 2.35 (s, 3H), d 3.22 (d, J=16.2 Hz, 2H), d 3.50 (d, J=16.2 Hz, 2H), d 7.15-7.30 (m, 6H), d 7.45(br d, J=7.1 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH3:30])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.BrC1C=CC([C@@H](N2CC[C@@](C3C=CC(F)=CC=3)(C)OC2=O)C)=CC=1.CC1C=C(B(O)O)C=CN=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:30])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccc([C@H](C)N3CC[C@](C)(c4ccc(F)cc4)OC3=O)cc2)ccn1
Agent: C[C@@H](c1ccc(Br)cc1)N1CC[C@](C)(c2ccc(F)cc2)OC1=O
Agent: Cc1cc(B(O)O)ccn1
Product: Cc1cc(-c2ccc([C@H](C)N3CCC(C)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
Isomer 2 of the title compound, (R)-6-(4-fluorophenyl)-6-methyl-3-((S)-1-(4-(2-methylpyridin-4-yl)phenyl)ethyl)-1,3-oxazinan-2-one, was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-methyl-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.18, m/z=405 (M+1); 1H NMR (CDCl3) 8.83 (s, 1H), 7.72 (s, 1H), 7.66 (s, 1H), 7.48 (d, 2H, J=7.3 Hz), 7.32 (br m, 2H), 7.16 (d, 2H, J=6.7), 7.04 (t, 2H, J=7.6 Hz), 5.77 (q, 1H, J=6.7 Hz), 3.05 (br m, 1H), 2.89 (s, 3H, 2.42-2.32 (m, 2H), 2.23 (br m, 1H), 1.64 (s, 3H), 1.59 (d, 3H, J=6.7 Hz).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[C:24]1([N:30]=[C:31]=[S:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1>[OH:16][CH2:15][C:3]1([CH2:2][O:1][C:31](=[S:32])[NH:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][CH2:8][O:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14]
Reactant: O=C1c2ccccc2OCCC1(CO)CO
Reactant: S=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2OCCC1(CO)COC(=S)Nc1ccccc1

Procedure:
To a solution of 4,4-bis(hydroxymethyl)-3,4-dihydro-2H-benzo[b]oxepin-5-one (500 mg, 2.25 mmol) in 28 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.34 ml, 2.5 mmol) and phenyl isothiocyanate (672 μl, 5.63 mmol). The mixture was heated to reflux for 72 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:1 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 149 mg (19%).
Reaction SMILES: N[C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19].N([O-])=O.[Na+].[ClH:24]>Cl[Cu]>[Cl:24][C:2]1[N:7]=[C:6]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: Cl
Reactant: N#Cc1ccc(-c2ncccc2C(F)(F)F)nc1N
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Product: N#Cc1ccc(-c2ncccc2C(F)(F)F)nc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Dissolve 6-amino-3′-trifluoromethyl-[2,2′]bipyridinyl-5-carbonitrile (1.0 g, 7.6 mmol) in 12 N HCl (20 mL) and cool to 0° C. Add NaNO2 (731 mg, 10.6 mmol) in portions over the course of 15 minutes. Allow the mixture to stir for 1 hour at 0° C. Add CuCl (2.24 g, 22.7 mmol), allow the mixture to warm to room temperature and stir for 1 hour. Pour the mixture onto ice water (100 mL) and extract with EtOAc (3×100 mL);. Dry the combined organic extracts over Na2SO4 and remove the solvent under reduced pressure. Purify the crude product by silica gel chromatography eluting with EtOAc/hexane (1:1) to yield the title compound. MS 284.04 (M+1).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:18][O:19][C:20](=[O:41])[CH2:21][CH2:22][NH:23][C:24](=[O:40])[C:25]1[CH:30]=[CH:29][C:28]([CH:31]([CH2:38]O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:27][CH:26]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:18][O:19][C:20](=[O:41])[CH2:21][CH2:22][NH:23][C:24](=[O:40])[C:25]1[CH:26]=[CH:27][C:28]([CH:31]([CH2:38][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:16])([F:17])[F:1])=[CH:4][CH:5]=3)=[CH:10][CH:11]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:29][CH:30]=1
Reactant: Oc1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCCCCCC(CO)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: CCCCCCC(COc1ccc(-c2ccc(C(F)(F)F)cc2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4′-trifluoromethyl-biphenyl-4-ol (213 mg, 0.90 mmol) and 3-[4-(1-hydroxymethyl-heptyl)-benzoylamino]-propionic acid methyl ester (240 mg, 0.72 mmol) in anhydrous toluene (5 mL) is degassed and filled with nitrogen 3 times. Tributylphosphine (270 μL, 1.07 mmol) is added to the reaction mixture under nitrogen at 0° C., followed by addition of 1,1′-(azodicarbonyl)-dipiperidine (271 mg, 1.07 mmol). The reaction mixture is allowed to warm to room temperature and stirred overnight. The mixture is loaded on a silica gel column and purified using hexanes/ethyl acetate. Some racemic ester is hydrolyzed in the next step, and the remaining intermediate ester is sent to chiral chromatography for resolution (see Example 15, Step C). MS (ES): 554.2 [M+H]−.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:3]=1[CH3:19].[O:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:31]([NH2:32])=[CH:30][C:29]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:28][N:27]=2)[CH2:22][CH2:21]1.Cl.O1CCOCC1>CO>[N:23]1([C:26]2[C:31]([NH:32][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=4)[C:3]=3[CH3:19])=[CH:30][C:29]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)=[CH:28][N:27]=2)[CH2:22][CH2:21][O:20][CH2:25][CH2:24]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2cccnc2)nc2cccc(F)c2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2cccnc2)nc2cccc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-5-fluoro-3-methyl-2-(pyridin-3-yl)quinoline (83 mg, 0.30 mmol), 2,5-dimorpholinopyridin-3-amine (80 mg, 0.30 mmol) and a 4.0M solution of HCl in dioxane (0.015 mL, 0.061 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinyl-3-pyridinyl)-5-fluoro-3-methyl-2-(3-pyridinyl)-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.87 (1H, d, J=2.3 Hz), 8.73 (1H, dd, J=4.9, 1.8 Hz), 7.93-8.03 (2H, m), 7.84 (1H, d, J=12.1 Hz), 7.66 (1H, d, J=2.7 Hz), 7.59-7.64 (1H, m), 7.49 (1H, dd, J=7.8, 5.1 Hz), 7.16-7.24 (1H, m), 6.37 (1H, d, J=2.7 Hz), 3.87-3.98 (4H, m), 3.75-3.86 (4H, m), 3.22 (4H, br. s.), 2.95-3.07 (4H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=501.2 (M+1).
Reaction SMILES: Cl.Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][CH:59]([OH:62])[CH2:58][CH2:57]2)CC1>>[OH:62][CH:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[C:40]([Cl:43])[CH:41]=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[CH2:57][CH2:58]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (97, see example 42) and amine 21 analogously to the method described in example 1.