Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:37])[CH2:30][CH:31]5[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)[CH:23]=4)=[CH:20][C:13]=3[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[C:38](O)(=O)C.C=O.C([BH3-])#N.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.CO>[CH:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:15]([CH3:16])[C:14]3[CH:17]=[CH:18][C:19]([O:21][C:22]4[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29](=[O:37])[CH2:30][CH:31]5[CH2:32][CH2:33][N:34]([CH3:38])[CH2:35][CH2:36]5)[CH:23]=4)=[CH:20][C:13]=3[N:12]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(NC(=O)CC5CCNCC5)c4)ccc3n2C)c1
Agent: C=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cccc(Nc2nc3cc(Oc4ccnc(NC(=O)CC5CCN(C)CC5)c4)ccc3n2C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture containing N-(4-(2-(3-isopropylphenylamino)-1-methyl-1H-benzo[d]imidazol-5-yloxy)pyridin-2-yl)-2-(piperidin-4-yl)acetamide (1 eq), glacial acetic acid (2 eq), and formaline (7.5 eq) in tetrahydrofuran:methanol (1:1) was added sodium cyanoborohydride (2 eq) and stirred at room temperature for one hour. Reaction neutralized with saturated sodium carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give crude product. Purification by HPLC to yield N-[4-({2-[(3-isopropylphenyl)amino]-1-methyl-1H-benzimidazol-5-yl}oxy)pyridin-2-yl]-2-(1-methylpiperidin-4-yl)acetamide.
Reaction SMILES: [NH3:1].O.Cl[C:4]1[C:5]([CH3:11])=[N:6][CH:7]=[C:8]([CH3:10])[N:9]=1>>[CH3:11][C:5]1[C:4]([NH2:1])=[N:9][C:8]([CH3:10])=[CH:7][N:6]=1
Reactant: Cc1cnc(C)c(Cl)n1
Reactant: N
Solvent: O
Product: Cc1cnc(C)c(N)n1
Temperature: 165 °C
Reaction time: 16 h

Procedure:
Ammonia in water (3 mL, 48.5 mmol) was added to 3-chloro-2,5-dimethylpyrazine (0.121 mL, 1 mmol) and the mixture heated by microwaves to 165° C. for 7 hours. Following LCMS analysis, the reaction was then reheated to 165° C. for a further 16 hours, by microwaves. After cooling, the solvent was removed under a stream of nitrogen and the crude redissolved in dichloromethane (20 mL). Water (25 mL) was added and the mixture basified to pH14 using sodium hydroxide solution (18 N). The organic layer was removed and the aqueous layer extracted with dichloromethane (5×25 mL). The organic phases were combined and dried using a hydrophobic frit, then evaporated in vacuo to give the title product (109 mg). This was used directly in the next step with no further purification. LCMS (2 min, high pH) Rt 0.47 min, m/z (ES+) 124 (M+H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14].[C:16]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([NH:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:14])=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nn1cccc1C(=O)c1ccccc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nn1cccc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 143.4 %

Procedure:
1-Amino-2-(2-chlorobenzoyl)pyrrole (24.3 g, 0.12 mol) and t-butoxycarbonyl glycine (22.7 g, 0.13 mol) were dissolved in 300 ml of dichloromethane. Dicyclohexylcarbodiimide (26.8 g, 0.13 mol) was added over 3 minutes and the reaction mixture stirred at ambient temperature for 4 hours. The resultant slurry was filtered, and the filtrate evaporated to give 65 g of oil. This oil was purified by flash chromatography (silica, 2:1 hexane-ethyl acetate) to give 21.9 g (48%) of crystals, m.p. 156°-158°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][C:29]=4[O:31][CH3:32])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c(OC)c1
Yield: 57.4 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (5.0 g, 13.05 mmol) with 2,4-dimethoxyphenylboronic acid (3.56 g, 19.57 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.512 g, 0.652 mmol), and potassium carbonate (4.5 g, 32.62 mmol) generally according to the procedure described for Intermediate 37 provided 3.3 g (57%) of (±)-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a light yellow solid. mp 120-123° C.; Anal. calcd. for C24H24O6S: C, 65.44; H, 5.49. Found: C, 64.99; H, 5.46.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])=[C:4]([O:29][CH3:30])[CH:3]=1.[Br-].[CH2:32]([Zn+])[C:33]([CH3:36])([CH3:35])[CH3:34]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.C1COCC1>[F:8][C:7]1[C:2]([CH2:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:3][C:4]([O:29][CH3:30])=[C:5]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[CH:27]=[CH:26][O:25][N:24]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]2=[O:28])[CH:6]=1
Reactant: CC(C)(C)C[Zn+]
Reactant: COc1cc(Br)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(CC(C)(C)C)c(F)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 70 °C
Reaction time: 1 h
Yield: 24.43 %

Procedure:
A vial was charged with 1-(4-bromo-5-fluoro-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.100 g, 0.202 mmol) and PdCl2(dppf)-CH2Cl2 (0.017 g, 0.020 mmol). The vial was flushed with Ar (g), then THF (1.012 ml) and neopentylzinc bromide, 0.5 M in THF (1.5 ml, 0.750 mmol) were added. The reaction was heated to 70° C. and stirred for one hour. The reaction was purified via column chromatography (RediSep Gold 40 g, gradient elution 10-75% [3:1 EtOAc/EtOH]:Heptane) to afford 1-(5-fluoro-2-methoxy-4-neopentylphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.024 g, 0.049 mmol, 24.43% yield) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=11.66 (s, 1 H), 8.72 (d, J=1.8 Hz, 1 H), 8.35 (d, J=2.2 Hz, 1 H), 8.21 (d, J=9.6 Hz, 1 H), 7.85 (dd, J=2.2, 9.0 Hz, 1 H), 7.29 (d, J=9.5 Hz, 1 H), 7.10 (d, J=6.6 Hz, 1 H), 6.77 (t, J=9.8 Hz, 2 H), 6.44 (d, J=1.8 Hz, 1 H), 3.64 (s, 3 H), 2.62 (s, 2 H), 0.99 (s, 9 H). m/z (ESI) 486.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[NH:18][C:19]3[C:24]([CH:25]=2)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=3)(=[O:16])=[O:15])[CH2:10][CH:9]1[CH2:27][C:28]([OH:30])=O)=O)(C)(C)C.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:43][S:44]([NH2:47])(=[O:46])=[O:45].C1CCN2C(=NCCC2)CC1.[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62]>O1CCCC1.C(Cl)Cl>[F:59][C:60]([F:65])([F:64])[C:61]([OH:63])=[O:62].[Cl:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH:9]([CH2:27][C:28]([NH:47][S:44]([CH3:43])(=[O:46])=[O:45])=[O:30])[CH2:10]1)(=[O:16])=[O:15])=[CH:25]2
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CC1CC(=O)O
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NC(=O)CC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In tetrahydrofuran (5 ml) was dissolved 1-(tert-butoxycarbonyl)-2-[(carboxy)methyl]-4-[(5-chloroindol-2-yl)sulfonyl]piperazine (772 mg), followed by the addition of carbonyldiimidazole (820 mg). The resulting mixture was heated under reflux for 1 hour. After cooling to room temperature, the reaction mixture was added with methanesulfonamide (322 mg) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.50 ml), followed by stirring overnight. The reaction mixture was concentrated under reduced pressure. To the residue was added a 1N aqueous solution of hydrochloric acid. After removal of the supernatant, the precipitate was washed with water and dried, whereby a colorless foam was obtained. The substance was dissolved in methylene chloride (10 ml), followed by the addition of trifluoroacetic acid (10 ml). The resulting mixture was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure. Diethyl ether was added to the residue and the precipitate thus obtained was collected by filtration, whereby the title compound (863 mg) was obtained as a colorless solid.
Reaction SMILES: [NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7]C(OCC1C=CC=CC=1)=O>C(OCC)(=O)C.CO.[Pd]>[NH:1]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@H:2]([C:18]([O:20][CH3:21])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7]
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C

Procedure:
A total amount of Boc-Lys(Cbz)-OMe was dissolved in a mixed solvent of 40 ml of ethyl acetate and 40 ml of methanol, and then the resultant solution was stirred at room temperature for 4 hours under a hydrogen atmosphere while gradually adding 0.223 g of Pd/C. The reaction product was passed through 3.56 g of celite (Sigma Aldrich) to remove Pd/C, and was then washed with 20 ml of methanol (MeOH) two times to obtain a filtrate. The filtrate was evaporated to obtain light viscous solid Boc-Lys-OMe.
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=O)C.C(OC1C(=CC=CC=1)C(O)=O)(=O)C.S(Cl)(Cl)=O.[NH2:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([OH:39])=[C:34]([Cl:40])[CH:33]=1>>[Cl:38][C:36]1[CH:37]=[C:32]([CH:33]=[C:34]([Cl:40])[C:35]=1[OH:39])[NH:31][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[OH:4]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Agent: CC(=O)Oc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1ccccc1O

Procedure:
Acetylsalicylic acid chloride prepared from acetylsalicylic acid and thionyl chloride was condensed with 4-amino-2,6-dichlorophenol followed by deacetylation to yield 3',5'-dichloro-2,4'-dihydroxybenzanilide (4 g.).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][N:60]1[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][N:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCN(N)CC1
Reactant: C=CC1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=CC1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NN4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-amino 4-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-2.05 (m, 8H) 2.22 (br. s., 3H) 2.42 (m, 4H) 2.93 (t, J=4.55 Hz, 4H) 3.28 (br. s., 3H) 3.72 (m, 2H) 3.93 (br. s., 3H) 4.87 (m, 1H) 5.39 (d, 2H) 5.99 (m, 1H) 7.43 (br. s, 2H) 7.82 (s, 1H) 8.12 (br. s., 1H) 8.32 (d, J=8.0 Hz, 1H) 9.36 (s, 1H). Melting point: 253-263° C. [M+H] calculated for C28H37FN8O3, 553. found 553.
Reaction SMILES: [B-](F)(F)(F)[CH:2]=[CH2:3].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:28]1[C:33]([F:34])=[CH:32][C:31]([S:35]([N:38]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][C:44]=2[CH3:50])[CH2:39][CH:40]([CH3:42])[CH3:41])(=[O:37])=[O:36])=[CH:30][C:29]=1[F:51].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.O.[Pd](Cl)Cl>[CH3:50][C:44]1[CH:45]=[C:46]([CH3:49])[CH:47]=[CH:48][C:43]=1[N:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[S:35]([C:31]1[CH:32]=[C:33]([F:34])[C:28]([CH:2]=[CH2:3])=[C:29]([F:51])[CH:30]=1)(=[O:37])=[O:36]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2cc(F)c(Br)c(F)c2)c(C)c1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: C=Cc1c(F)cc(S(=O)(=O)N(CC(C)C)c2ccc(C)cc2C)cc1F
Temperature: 140 °C
Reaction time: 1 h

Procedure:
To a vial was added potassium trifluoro(vinyl)borate (0.744 g, 5.55 mmol), triphenylphosphine (0.073 g, 0.278 mmol), 4-bromo-N-(2,4-dimethylphenyl)-3,5-difluoro-N-isobutylbenzenesulfonamide (2 g, 4.63 mmol) suspension in tetrahydrofuran (THF) (22 mL), cesium carbonate (4.52 g, 13.88 mmol), water (2.200 mL) and palladium(II) chloride (0.016 g, 0.093 mmol). The mixture was divided evenly between two microwave vials and the vessels then sealed and heated by microwaves (Biotage Initiator) to 140° C. for 30 minutes. LCMS analysis showed some conversion, so additional 0.5 equivalent of potassium trifluoro(vinyl)borate was added to each reaction, along with extra water (2 mL) and THF (2 mL). The reactions were reheated by microwaves for a further 1 hour at 140° C. The reactions were then diluted with dichloromethane (5 mL) and water (2 mL), filtered through celite and dried using a hydrophobic frit. The organics were concentrated and purified by flash silica (Si) chromatography (0-25% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and evaporated in vacuo to give two batches of the required product, 769 mg and 856 mg, as yellow oils. LCMS [LCMS2] Rt 1.60 min, m/z (ES+) 380 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[NH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]([C:21](=O)[CH3:22])=[CH:12][C:13]([Cl:20])=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:6]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[CH3:1][O:2][C:3](=[O:24])[NH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]2[C:11]([CH:21]([NH2:31])[CH3:22])=[CH:12][C:13]([Cl:20])=[C:14]3[C:19]=2[N:18]=[CH:17][CH:16]=[CH:15]3)[CH2:6]1
Reactant: COC(=O)N[C@H]1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC#N
Product: COC(=O)N[C@H]1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of methyl[(3S)-1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidin-3-yl]carbamate (0.047 g, 0.14 mmol) and ammonium acetate (0.104 g, 1.35 mmol) in methanol (0.5 mL) and acetonitrile (0.5 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.34 mL, 0.34 mmol). The reaction was heated at 65° C. overnight. The mixture was then cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4 and concentrated to give the desired product. LCMS calculated for C17H22ClN4O2 (M+H)+: m/z=349.1; Found: 349.1.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Br:5][C:6]1[CH:7]=[N:8][C:9](Cl)=[N:10][CH:11]=1.C(N(CC)CC)C>C(O)C>[Br:5][C:6]1[CH:7]=[N:8][C:9]([NH:3][CH2:2][CH2:1][NH2:4])=[N:10][CH:11]=1
Reactant: NCCN
Reactant: Clc1ncc(Br)cn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: NCCNc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethane-1,2-diamine (200 mg) was added to a solution of 5-bromo-2-chloro-pyrimidine (500 mg) and triethylamine (1 mL) in ethanol (10 mL) at 0° C. The reaction mixture was stirred under nitrogen at room temperature overnight. The formed mixture was concentrated to give crude N1-(5-bromopyrimidin-2-yl)ethane-1,2-diamine. Yield: 687 mg (100% of theory).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:20]3[S:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)=[N:18][N:19]=[C:13]2[CH2:12]1)=O)C1C=CC=CC=1.S1C2C=CC=CC=2N=C1C(NN)=O.B(Br)(Br)Br>ClCCl>[S:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[C:17]1[N:14]2[CH2:15][CH2:16][NH:11][CH2:12][C:13]2=[N:19][N:18]=1
Reactant: O=C(OCc1ccccc1)N1CCn2c(nnc2-c2nc3ccccc3s2)C1
Agent: BrB(Br)Br
Agent: NNC(=O)c1nc2ccccc2s1
Solvent: ClCCl
Product: c1ccc2sc(-c3nnc4n3CCNC4)nc2c1
Temperature: 25 °C

Procedure:
To a solution of 3-benzothiazol-2-yl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazine-7-carboxylic acid benzyl ester (prepared according to the method of Example 259, Step B, 580 mg, contaminated with benzothiazole-2-carboxylic acid hydrazide) in dichloromethane (10 mL) at 0° C. was added a solution of boron tribromide (1 M in dichloromethane, 4.45 mL, 4.45 mmol). This mixture was warmed to room temperature overnight, quenched by addition of water, and concentrated. The residual aqueous layer was washed with ether (6×), neutralized with saturated aqueous sodium bicarbonate, and extracted with 10% isopropanol/chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1→10% methanol/chloroform) to give 175 mg (36%, two steps) of the title compound of Example 259, Step C as a white solid. 1H NMR (CDCl3, 300 MHz) δ 8.05 (d, 1H), 7.96 (d, 1H), 7.57-7.41 (c, 2H), 4.62 (t, 2H), 4.36 (s, 2H), 3.35 (t, 2H); MS (APCI) 258 (MH+).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:28][C@@H:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([N:33]3[CH2:32][CH2:31][NH:30][C@H:29]([CH3:28])[CH2:34]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: C[C@@H]1CNCCN1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1)c1ccc(Cl)nc1
Product: C[C@@H]1CN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(F)cc4)c3)cn2)CCN1

Procedure:
6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide (0.18 mmol) was used in general procedure 3 with (R)-2-methylpiperazin (0.54 mmol). The product was purified by RP-HPLC to give (R)—N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 468.0 (M)+
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]1[CH2:21][CH2:20][N:19]([C:22]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:18]1>>[CH3:30][C:28]1[CH:27]=[CH:26][C:25]([C:31]([F:34])([F:32])[F:33])=[C:24]([C:22]([N:19]2[CH2:20][CH2:21][C@@H:17]([NH:16][C:2]3[CH:11]=[N:10][C:9]4[C:4](=[CH:5][CH:6]=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=4)[N:3]=3)[CH2:18]2)=[O:23])[CH:29]=1
Reactant: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](N)C2)c1
Reactant: FC(F)(F)c1ccc2nc(Cl)cnc2c1
Product: Cc1ccc(C(F)(F)F)c(C(=O)N2CC[C@@H](Nc3cnc4cc(C(F)(F)F)ccc4n3)C2)c1

Procedure:
In analogy to the procedure described for example 200, the title compound was prepared from 2-chloro-6-trifluoromethyl-quinoxaline and ((R)-3-amino-pyrrolidin-1-yl)-(5-methyl-2-trifluoromethyl-phenyl)-methanone (intermediate 13). (M+H+) 469.2.
Reaction SMILES: Br[C:2]1[C:27]([F:28])=[CH:26][C:5]([O:6][CH2:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:29].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Br-].[C:65]([O:69][C:70](=[O:73])[CH2:71][Zn+])([CH3:68])([CH3:67])[CH3:66]>C1COCC1.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.[Pd].[Pd]>[F:29][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)[CH:26]=[C:27]([F:28])[C:2]=1[CH2:71][C:70]([O:69][C:65]([CH3:68])([CH3:67])[CH3:66])=[O:73]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(Br)c(F)c3)CC2)nc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: COc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)OC(C)(C)C)c(F)c3)CC2)nc1
Temperature: 60 °C

Procedure:
To 2-(4-((1R,2S)-2-(2-(4-bromo-3,5-difluorophenoxy)ethyl)cyclopropyl)piperidin-1-yl)-5-methoxypyrimidine (1.86 g, 3.97 mmol) in THF (5 ml) was added tris(dibenzylideneacetone)dipalladium(0) (0.364 g, 0.397 mmol) and X-PHOS (0.379 g, 0.794 mmol), followed by (2-tert-butoxy-2-oxoethyl)zinc(II) bromide (0.5 M in ethyl ether, 23.83 ml, 11.91 mmol). The mixture was degassed under N2 for 10 min then heated at 60° C. overnight. The mixture was diluted with sat. NH4Cl (50 ml), and the aqueous phase extracted with EtOAc (50 ml×2). The organic fractions were combined, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g SNAP, 5˜30% EtOAc in hexane) to afford the titled compound. LC/MS (m/z): 504 (M+H)+. Rf was 0.28 @ 25% EtOAc in hexanes (blue spot on CAM stain)
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](=[NH:10])[NH2:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].[C:16](OCC)(=[O:23])[CH2:17][C:18](OCC)=[O:19]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]2[N:9]=[C:18]([OH:19])[CH:17]=[C:16]([OH:23])[N:10]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: N=C(N)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc(-c2nc(O)cc(O)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
In a 50 mL round-bottomed flask was placed 4-nitrobenzimidamide (55, 0.435 g, 2.63 mmol) in MeOH (4 mL) to give a yellow suspension. Sodium methanolate (25% by wt in MeOH) (1.867 mL, 8.17 mmol) was added. The mixture was stirred at room temperature for 30 min. Diethyl malonate (0.480 mL, 3.16 mmol) was added in drops and stirring was continued at room temperature over 6 days, resulting in an orange suspension. The mixture was concentrated, dissolved in hot water and filtered. The filtrate was made acidic with AcOH to pH3. The resulting light yellow solids were collected by filtration and dried under vacuum to give the title compound (499 mg, 81%) as a light yellow solid. HRMS: For [M+H]+ mass error=−0.0 mDa or −0.17 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8](O)=[O:9].C(Cl)(=O)C([Cl:18])=O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:12]([O-:14])=[O:13])=[C:7]([CH:11]=1)[C:8]([Cl:18])=[O:9]
Reactant: COc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])c(C(=O)Cl)c1

Procedure:
A mixture of 5-methoxy-2-nitrobenzoic acid (15.8 g, 0.08 mol), oxalyl chloride (25 g, 0.197 mol) and N,N-dimethylformamide (2 drops) is stirred at reflux for 4 hours, cooled, stirred at room temperature under nitrogen for several days and concentrated in vacuo to give the title product as a yellow oil which is identified by 1HNMR spectral analysis.