Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH:22]=O)=[O:19])=[O:12].Cl.[NH2:28][OH:29].N1C=CC=CC=1>CN(C)C=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH2:10][C:11]([CH:13]1[S:17][CH2:16][NH:15][C@@H:14]1[C:18]([N:20]1[CH2:26][CH2:25][CH2:24][C@H:21]1[CH:22]=[N:28][OH:29])=[O:19])=[O:12]
Reactant: O=C[C@@H]1CCCN1C(=O)[C@H]1NCSC1C(=O)CC1Cc2ccccc2C1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(CC1Cc2ccccc2C1)C1SCN[C@@H]1C(=O)N1CCC[C@H]1C=NO
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 31 %

Procedure:
1-[3-(Indan-2-ylacetyl)-L-thioprolyl]-L-prolinal (372 mg), hydroxylamine hydrochloride salt (76 mg) and pyridine (89 μl) were dissolved in 5 ml of dimethylformamide, and stirred at 70° C. for 1.5 hours. After concentrating the reaction solution under reduced pressure, the resulting residue was dissolved in 30 ml of methylene chloride, washed by saturated aqueous sodium chloride solution, and dried over magnesium sulfate, followed by distillation of the solvent under reduced pressure. The resulting residue was purified by column chromatography to obtain 120 mg of (2S)-1-[3-(indan-2-ylacetyl)-L-thioprolyl]-2-pyrrolidine aldoxime. Yield; 31%.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21](COCC[Si](C)(C)C)[CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[N:24]=3)=[CH:16][CH:15]=2)=[CH:10][N:9]=1)[C:3]([OH:5])=[O:4]>FC(F)(F)C(O)=O.O>[CH3:1][C:2]([CH3:37])([CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[NH:24][C:23]([C:25]([F:28])([F:26])[F:27])=[CH:22][N:21]=3)=[CH:18][CH:19]=2)=[CH:10][N:9]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C)(COc1ccc(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)cc2)cn1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(COc1ccc(-c2ccc(-c3ncc(C(F)(F)F)[nH]3)cc2)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
In trifluoroacetic acid (10 mL) and water (1 mL) was dissolved 2,2-dimethyl-3-[(5-{4-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-phenyl}pyridin-2-yl)oxy]propanoic acid (287 mg), and the mixture was stirred at room temperature overnight. The residue obtained by concentrating the reaction mixture under reduced pressure was dissolved in acetic acid, and the mixture was concentrated under reduced pressure. The obtained solid residue was pulverized by adding ether, collected by filtration, washed with ether and dried to obtain 2,2-dimethyl-3-[(5-{4-[5-(trifluoromethyl)-1H-imidazol-2-yl]phenyl}pyridin-2-yl)oxy]propanoic acid (175 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:27][CH3:28])[CH2:4][CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:10]([O:11][CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)=[CH:9][CH:8]=1)[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:27]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][O:6][C:7]1[CH:26]=[CH:25][C:10]([O:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:9][CH:8]=1)[CH3:28]
Reactant: CCN(CC)CCOc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC)CCOc1ccc(OC2CCNCC2)cc1
Temperature: 25 °C

Procedure:
10.1 g tert-butyl 4-[4-(2-diethylaminoethoxy)-phenoxy]-piperidine-1-carboxylate are placed in 20 ml dichloromethane and combined with 30 ml trifluoroacetic acid while being cooled. The reaction mixture is stirred at ambient temperature. After 2 hours the reaction mixture is evaporated to dryness. The residue is combined with an NaOH solution (1M) and the product is extracted with dichloromethane. 5.6 g (V-3) are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH3:14])[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:17][Si:18]([CH3:25])([CH3:24])[CH2:19][CH2:20][O:21][CH2:22]Cl.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:22][O:21][CH2:20][CH2:19][Si:18]([CH3:25])([CH3:24])[CH3:17])[C:11](=[O:13])[N:10]([CH3:14])[N:9]=2)=[CH:6][CH:7]=1
Reactant: Cn1nc(-c2ccc(Br)cc2)[nH]c1=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccc(Br)cc2)n(COCC[Si](C)(C)C)c1=O
Reaction time: 0.33 h

Procedure:
To a solution of compound 51b (1.0 g, 3.9 mmol) in DMF (5 mL) was added sodium hydride (0.2 g, 5.0 mmol) in portions at 0° C. The mixture was stirred for 20 min, then 2-(trimethylsilyl)ethoxymethyl chloride (0.73 g, 4.4 mmol) was added dropwise. The reaction mixture was stirred at rt for 2 h. EtOAc (100 mL) was added. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel (EtOAc/petroleum ether (1:5 v/v)) to afford compound 51c as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C15H22BrN3O2Si: 384.1 (M+H). Found 384.1.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([OH:23])=O)[CH2:9]1.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:39]=[CH:40][CH:41]=1>>[F:33][C:2]([F:32])([F:1])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([N:45]2[CH2:44][CH2:43][N:42]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([C:35]([F:48])([F:49])[F:34])[CH:37]=3)[CH2:47][CH2:46]2)=[O:23])[CH2:9]1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)N(Cc2cccc(Cl)c2)C1
Yield: 10 %

Procedure:
As described for Example 64e, [(2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(3-chloro-benzyl)-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 4-(3-trifluoromethyl-phenyl)-piperazine instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title product (71 mg) in 10% yield as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C@@H:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])=[C:4]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)[CH:3]=1.[F:26][C:27]1([F:39])[O:31][C:30]2[CH:32]=[CH:33][C:34]([C:36](Cl)=[O:37])=[CH:35][C:29]=2[O:28]1>C(Cl)Cl>[NH2:10][C@@H:8]([CH3:9])[CH2:7][O:6][C:5]1[CH:18]=[CH:19][C:2]([NH:1][C:36]([C:34]2[CH:33]=[CH:32][C:30]3[O:31][C:27]([F:39])([F:26])[O:28][C:29]=3[CH:35]=2)=[O:37])=[CH:3][C:4]=1[C:20]1[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=1
Reactant: C[C@@H](COc1ccc(N)cc1-c1ccnn1C)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc2c(c1)OC(F)(F)O2
Solvent: ClCCl
Product: C[C@H](N)COc1ccc(NC(=O)c2ccc3c(c2)OC(F)(F)O3)cc1-c1ccnn1C
Temperature: 40 °C

Procedure:
To a solution of tert-butyl(S)-1-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)propan-2-ylcarbamate (40.0 mg, 115 μmol) in DCM was added 2,2-difluorobenzo[d][1,3]dioxole-5-carbonyl chloride (28.0 mg, 127 μmol) followed by TEA (32.411, 231 μmol). The reaction was mixed in a rotary shaker at 25° C. for 1 hour then quenched with MeOH (100 μl). After mixing for 20 minutes TFA (400 μl) was added and the resulting mixture was heated to 40° C. and mixed for 1 hour. The organic solvent was removed under vacuum; the crude residue was dissolved in acetonitrile (0.5 mL), neutralized with saturated bicarbonate and subjected to purification by preparative LCMS. The proper fractions were pooled, frozen and lyophilized to afford the title compound as an off white solid (16.7% yield). LCMS m/z=431.3 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.16 (d, J=6.82 Hz, 3H), 3.48-3.58 (m, 1H), 3.71 (s, 3H), 3.99-4.08 (m, 2H), 6.36 (d, J=1.77 Hz, 1H), 7.25 (d, J=9.09 Hz, 1H), 7.50 (d, J=1.77 Hz, 1H), 7.60 (d, J=8.59 Hz, 1H), 7.71 (d, J=2.53 Hz, 2H), 7.82-7.91 (m, 2H), 10.35 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Cl:8].S(=O)(=O)(O)O.[N+:15]([O-])([OH:17])=[O:16]>>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH3:9])=[C:5]([N+:15]([O-:17])=[O:16])[CH:6]=1
Reactant: Cc1ccc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]

Procedure:
3,4-Dichlorotoluene was nitrated with concentrated sulfuric acid and fuming nitric acid (d=1.52).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][C:9]1[CH2:16][S:15][CH:14]2[N:11]([C:12](=[O:27])[CH:13]2[NH:17]C(=O)CC2C=CC=CC=2)[C:10]=1[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:34])[Cl:33])=[O:29].O>N1C=CC=CC=1.C1C=CC=CC=1>[CH3:8][C:9]1[CH2:16][S:15][CH:14]2[N:11]([C:12](=[O:27])[CH:13]2[NH:17][C:3](=[O:4])[C:2]([Cl:7])([Cl:6])[Cl:1])[C:10]=1[C:28]([O:30][CH2:31][C:32]([Cl:35])([Cl:33])[Cl:34])=[O:29]
Reactant: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)Cc3ccccc3)C2SC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: c1ccccc1
Product: CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(Cl)(Cl)Cl)C2SC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trichloroacetyl chloride (1.04 cc.) is added, over the course of 30 minutes and with vigorous stirring, to a solution, cooled to -10°C, of 3-methyl-8-oxo-7-phenylacetamido-2-trichloroethoxycarbonyl-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (1.38 g) in pyridine (15 cc.). Thereafter, the mixture is stirred for 2 hours 30 minutes at a temperature of between -3° and -1°C. The mixture is then poured into water and crushed ice (100 cc.) and a maroon paste-like product settles out. After removing the liquid phase by decanting, this product is triturated in water (50 cc.) and is then taken up in ethyl acetate (200 cc.). The organic phase is washed with water (3 times 200 cc.), dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (12 mm Hg) at 30°C. The solid obtained is dissolved in benzene (20 cc.) and the solution obtained is chromatographed on a column of silica gel (20 g) (0.05-0.20 mm, pH neutral; diameter of the column: 1.5 cm, height: 20 cm). Elution is carried out successively with benzene (300 cc.), a mixture of benzene and ethyl acetate (99.5/0.5 by volume) (300 cc.) and a mixture of benzene and ethyl acetate (99/1 by volume) (600 cc.), collecting 25 cc. fractions. Fractions 6 to 36 are combined and concentrated to dryness under reduced pressure (12 mm Hg) at 30°C. 3-methyl-8-oxo-7-trichloroacetamido-2-trichloroethoxycarbonyl-5-thia-1-aza-bicyclo[4,2,0]oct-2-ene (450 mg) is obtained in the form of a light maroon solid, the characteristics of which are as Follows:RF = 0.63 [silica gel; chloroform/ethyl acetate (80/20 by volume)]
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]3=4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C=O.[C:23](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]3[CH2:16][CH2:15][N:14]([CH3:23])[CH2:13][C:12]4[CH:17]=[CH:18][CH:19]=[CH:20][C:11]3=4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2c(c1)CNCCC2c1ccc2[nH]ccc2c1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC(c2ccc3[nH]ccc3c2)c2ccccc2C1
Yield: 50 %

Procedure:
5-(1H-indol-5-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine was subjected to reductive amination using formaldehyde and sodium triacetoxyborohydride in 1,2-dichloroethane to give 5-(1H-indol-5-yl)-2-methyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine as a white powder in 50% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([Cl:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][CH3:34])=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]([CH3:34])[C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:8]([C:6]4[CH:7]=[C:2]([NH2:1])[C:3]([F:23])=[CH:4][C:5]=4[Cl:22])[C:9](=[O:21])[N:10]3[CH2:19][CH3:20])=[CH:15][N:14]=2)=[CH:28][CH:27]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: CNCc1ccc(OC)cc1
Product: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(N(C)Cc3ccc(OC)cc3)cc21
Temperature: 200 °C
Yield: 73 %

Procedure:
A mixture of Example A3 (3 g, 8.5 mmol) and 1-(4-methoxyphenyl)-N-methylmethanamine (20 mL) was charged in a sealed vessel, and then the mixture was heated at 200° C. overnight. Volatiles were removed and the residue was purified by column chromatography to give 7-((4-methoxybenzyl)(methyl)amino)-3-(5-amino-2-chloro-4-fluorophenyl)-1-ethyl-1,6-naphthyridin-2(1H)-one (3 g, 73% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.47 (s, 1H), 7.70 (s, 1H), 7.18-7.17 (m, 3H), 6.86 (d, J=8.4 Hz, 2H), 6.73 (d, J=9.6 Hz, 1H), 6.30 (s, 1H), 5.31 (s, 2H), 4.84 (s, 2H), 4.17 (q, J=7.1 Hz, 2H), 3.70 (s, 3H), 3.12 (s, 3H), 1.11 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 467.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:45])[NH:4][CH:5]([C:19](=[O:44])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([N:28]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([F:43])[CH:37]=1)(=[O:35])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:26][OH:27])[CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:46][CH2:47][O:48][P:49](Cl)([O:51][CH2:52][CH3:53])=[O:50]>>[CH3:1][O:2][C:3](=[O:45])[NH:4][C@H:5]([C:19](=[O:44])[NH:20][CH2:21][CH2:22][CH2:23][CH2:24][C@H:25]([N:28]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([F:43])[CH:37]=1)(=[O:34])=[O:35])[CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:26][O:27][P:49]([O:51][CH2:52][CH3:53])([O:48][CH2:47][CH3:46])=[O:50])[CH:6]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)NC(C(=O)NCCCCC(CO)N(CC(C)C)S(=O)(=O)c1ccc(N)c(F)c1)C(c1ccccc1)c1ccccc1
Reactant: CCOP(=O)(Cl)OCC
Product: CCOP(=O)(OCC)OC[C@H](CCCCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)N(CC(C)C)S(=O)(=O)c1ccc(N)c(F)c1

Procedure:
The product of step A was phosphorylated with chlorodiethylphosphate following the procedure described in example 1A, step G. Yields 157 mg, 68%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]([CH3:12])([CH3:11])[C:5]2=[CH:4][CH:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CC(C)([O-])C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH2:15]([NH:22][C:2]1[N:7]=[C:6]2[N:8]([CH3:14])[C:9](=[O:13])[C:10]([CH3:12])([CH3:11])[C:5]2=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN1C(=O)C(C)(C)c2ccc(Cl)nc21
Reactant: NCc1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: CN1C(=O)C(C)(C)c2ccc(NCc3ccccc3)nc21
Temperature: 115 °C
Reaction time: 48 h

Procedure:
To a mixture of 6-chloro-1,3,3-trimethyl-1H-pyrrolo[2,3-b]pyridin-2-one (500 mg, 2.37 mmol), benzylamine (763 mg, 778 μl, 7.12 mmol) and sodium tert-butoxide (388 mg, 4.03 mmol) in toluene (10 ml) were added tris(dibenzylideneacetone)dipalladium (0) chloroform adduct (49.1 mg, 47.5 μmol) and BINAP (29.6 mg, 47.5 μmol). The reaction mixture was heated to 115° C. and stirred for 48 hours. The reaction mixture was diluted with EtOAc, silica gel was added and the mixture concentrated in vacuo. The obtained material was purified silica gel chromatography using heptane/ethyl acetate as eluent. The title compound was obtained as light yellow solid (616 mg).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[C@@H:18]3[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]3)[CH2:12][CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:25].C(=O)([O-])[O-].[K+].[K+].CNCCNC>COCCOC.C(Cl)Cl.[Cu]I>[N:9]1([C:7]([C:4]2[CH:3]=[C:2]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][C:20]3=[O:25])[S:6][CH:5]=2)=[O:8])[C@@H:18]2[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CNCCN1
Reactant: O=C(c1csc(Br)c1)N1CCC[C@@H]2CCCC[C@@H]21
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: O=C1CNCCN1c1cc(C(=O)N2CCC[C@@H]3CCCC[C@@H]32)cs1
Temperature: 120 °C
Yield: 61.4 %

Procedure:
cis-(5-Bromo-thiophen-3-yl)-(octahydro-quinolin-1-yl)-methanone (0.05 g, 0.15 mmol) was dissolved in DME (1 mL) and piperazin-2-one (0.3 mmol), potassium carbonate (0.15 mmol), copper (I) iodide (0.003 g) and dimethylethylenediamine (0.0013 g) were added. The mixture was heated to 120° C. for 65 hours. The mixture was diluted with DCM (10 mL) and the organic solution washed with water, then evaporated to give a brown oil. The residue was purified by flash chromatography on silica, eluting with 0-40% methanol in DCM. The fractions containing the desired product were combined and evaporated to give the title compound as a pale brown oil (0.032 g). LCMS m/z 348.05 [M+H]+ RT=6.24 min (Analytical Method 2). 1H NMR δ (ppm)(CHCl3-d): 7.0 (s, 1H), 6.7 (s, 1H), 4.6 (m, 1H), 4.0-3.6 (m, 5H), 3.3 (m, 2H), 3.0 (m, 1H), 2.0-1.0 (m, 16H).
Reaction SMILES: C(OC(=O)[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21](=[O:30])[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C@@H:13]([CH3:31])[CH2:12]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:21]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)=[O:30])[C@@H:13]([CH3:31])[CH2:12]1
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](NC(=O)OCc3ccccc3)C[C@@H]2C)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N)C[C@@H]2C)cc1
Reaction time: 4 h

Procedure:
(2S,4R)-[1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-carbamic acid benzyl ester (1.00 equiv.) was dissolved in ethanol (30 mL). The vessel in which resided the resulting solution was evacuated and backfilled with argon. A catalytic amount of Palladium on Carbon (10%, 0.10 equiv. by wt.) was added. The vessel was once again evacuated and this time was backfilled with hydrogen and shaken in a Parr bottle at 40 psi hydrogen. Reaction was complete after 4 h. The mixture was carefully filtered and concentrated to 10% volume. The resulting concentrated solution was filtered through a Celite® and concentrated to afford the crude amine, (2S,4R)-(4-amino-2-methyl-3,4-dihydro-2H-quinolin-1-yl)-(4-methoxy-phenyl)-methanone.
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:15][CH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13]3)[O:11][C:7]=2[C:6](F)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]=1[CH3:29])#[N:2].C(N(CC)CC)C.[CH3:37][N:38]([CH3:44])[C@H:39]1[CH2:43][CH2:42][NH:41][CH2:40]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:15][CH:14]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13]3)[O:11][C:7]=2[C:6]([N:41]2[CH2:42][CH2:43][C@H:39]([N:38]([CH3:44])[CH3:37])[CH2:40]2)=[C:5]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:4]=1[CH3:29])#[N:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCOC(=O)CC1CN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)C1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1CN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)C1
Temperature: 150 °C
Reaction time: 6 h
Yield: 41.4 %

Procedure:
Ethyl [1-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)azetidin-3-yl]acetate (I-190) (428 mg, 1.09 mmol) was dissolved in dimethyl sulfoxide (10 ml), then triethylamine (312 μl, 2.18 mmol) and (3S)-3-(dimethylamino)pyrrolidine (290 μl, 2.29 mmol) were added, followed by stirring in a sealed tube at 150° C. for 6 hours. After cooling, concentration under reduced pressure, dilution with chloroform, and washing with water, the organic layer was dried over anhydrous magnesium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with chloroform/methanol (10:1, v/v) gave the entitled compound (220 mg, 41.4%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([C@@H:57]([NH2:65])[CH2:58][C:59]3[N:63]([CH3:64])[CH:62]=[N:61][CH:60]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([C@@H:57]([NH:65][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[N:63]([CH3:64])[CH:62]=[N:61][CH:60]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cn1cncc1C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](Cc2cncn2C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(1-methyl-1H-imidazol-5-yl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.12 (silica gel: dichloromethane/ethanol=9:1); C26H27ClN6O2 (491.01); mass spectrum: (M+H)+=491/493 (chlorine isotope).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[C@@H:9]1([NH2:16])[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH2:15].Br[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1>[Cu]I.O1CCOCC1>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([NH:15][C@@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@H:9]2[NH2:16])=[CH:19][CH:20]=1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: Cc1ccc(Br)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(N[C@@H]2CCCC[C@H]2N)cc1
Temperature: 110 °C
Reaction time: 70 h
Yield: 63.6 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (190 mg, 0.998 mmol), K3PO4 (2.10 g, 9.89 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (0.60 mL, 5.00 mmol), 4-bromotoluene (0.70 mL, 5.69 mmol) and dioxane (3.0 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 70 h. The resulting dark brown suspension was cooled to room temperature and filtered through a 2×1 cm pad of Celite eluting with 50 mL of dichloromethane. The black filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; dichloromethane saturated with aq NH3-methanol 50:1; 15 mL fractions). Fractions 9-11 provided 650 mg (64% yield) of the product as a brown solid. 1H NMR (400 MHz, CDCl3): δ 7.00-6.95 (m, 2H), 6.62-6.57 (m, 2H), 3.30 (br s, 1H), 2.96-2.86 (br m, 1H), 2.49 (td, J=10.4, 3.6, 1H), 2.23 (s, 3H), 2.17-2.08 (m, 1H), 2.02-1.94 (m, 1H), 1.79-1.66 (m, 2H), 1.44 (br s, 2H), 1.38-1.17 (m, 3H), 1.07-0.95 (m, 1H). 13C NMR (100 MHz, CDCl3) δ 145.9, 129.7, 126.6, 113.9, 60.5, 56.1, 35.2, 32.4, 25.3, 25.0, 20.3.