Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C(N(CC)CC)C.[O:17](C(OC(C)(C)C)=O)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=O>CN(C=O)C>[C:21]([O:20][C:18](=[O:17])[NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: NCc1cccc(O)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCc1cccc(O)c1
Temperature: 25 °C
Yield: 22.1 %

Procedure:
3-hydroxybenzylamine (Apin, 1.0 g, 8.1 mmole) was dissolved in DMF(25 ml). Triethylamine (0.33 ml, 2.4 mmole) and (BOC)2O (1.8 g, 8.1 mmole) were added, the mixture stirred over night at room temperature under argon atmosphere. The reaction was concentrated, chromatographed on silica gel (0 to 20% EtOAc/hexanes) to give the titled compound (400 mg, 22%). MH+223.0
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[C:12]([F:22])[C:11]2[C:7](=[C:8]([CH3:24])[N:9]([CH3:23])[N:10]=2)[CH:6]=1)=[O:4].C1C(=O)N([I:32])C(=O)C1.C(O)(C(F)(F)F)=O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:32])=[CH:17][C:16]=2[F:21])=[C:12]([F:22])[C:11]2[C:7](=[C:8]([CH3:24])[N:9]([CH3:23])[N:10]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2c(C)n(C)nc2c(F)c1Nc1ccccc1F
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(C)n(C)nc2c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of 7-fluoro-6-(2-fluoro-phenylamino)-2,3-dimethyl-2H-indazole-5-carboxylic acid methyl ester (141 mg, 0.43 mmol) in DMF (5 ml) were added NIS (144 mg, 0.64 mmol) and TFA (0.20 mL), and the reaction was stirred at room temp for 4 h. The crude was diluted with EtOAc and washed with H2O. The organic fraction is dried over MgSO4 and concentrated under reduced pressure. Silica gel chromatography (EtOAc:Hexanes=75:25) yielded 137 mg (70%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH:14]=[C:15]([C:17]([OH:19])=O)[N:16]=[C:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C@@H:21]([CH3:37])[CH2:22][N:23]1[CH:27]=[CH:26][C:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[C:30]([Cl:36])[CH:29]=2)=[N:24]1>>[Cl:36][C:30]1[CH:29]=[C:28]([C:25]2[CH:26]=[CH:27][N:23]([CH2:22][C@@H:21]([NH:20][C:17]([C:15]3[N:16]=[C:10]4[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12][N:11]4[CH:14]=3)=[O:19])[CH3:37])[N:24]=2)[CH:35]=[CH:34][C:31]=1[C:32]#[N:33]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(C)(C)OC(=O)N1CCn2cc(C(=O)O)nc2C1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2c(n1)CN(C(=O)OC(C)(C)C)CC2

Procedure:
The title compound was prepared using the method of Example 34(d) starting from 7-(tert-butoxycarbonyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid (0.044 g, 0.165 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.033 g, 0.127 mmol). The product was purified by flash chromatography. LC-MS: [M+1]=510.988.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH3:21])[C:10]=2[CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])[CH:7]=1.[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.C(O)(C)C.[Pd]>[CH3:21][C:9]1[C:10]([CH2:11][N:12]2[CH2:16][CH:15]([CH2:17][CH2:18][CH3:19])[CH2:14][C:13]2=[O:20])=[C:5]2[N:4]=[CH:3][C:2]([C:29]#[C:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:7][N:6]2[N:8]=1
Reactant: C#Cc1ccccc1
Reactant: CCCC1CC(=O)N(Cc2c(C)nn3cc(Br)cnc23)C1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)O
Product: CCCC1CC(=O)N(Cc2c(C)nn3cc(C#Cc4ccccc4)cnc23)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
To a solution of 1-[(6-bromo-2-methylpyrazolo[1,5-a]pyrimidin-3-yl)methyl]-4-propylpyrrolidin-2-one 184 (0.66 mmol, 1 eq, 0.26 g) in 2 ml of water and 2 ml of isopropyl alcohol are added successively palladium on activated carbon (10%, 0.284 mmol, 0.5 eq, 30 mg), phenyl acetylene (0.68 mmol, 1.2 eq, 70 mg), and K3PO4 (1.13 mmol, 2 eq, 0.24 g) dissolved in 2 ml of water. The mixture is degassed and stirred vigorously overnight at 100° C. The solvent is removed under reduce pressure. The crude product is purified by chromatography on silicagel (AcOEt/hexane: 4/6) to afford 25 mg of 1-{[2-methyl-6-(phenylethynyl)pyrazolo[1,5-a]pyrimidin-3-yl]methyl}-4-propylpyrrolidin-2-one 199.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl[CH2:11][C:12](=O)[CH3:13].Cl.[OH-:16].[Na+]>>[CH3:13][C:12]1[C:11]([OH:16])=[CH:8][C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=1
Reactant: CC(=O)CCl
Reactant: [OH-]
Reactant: Nc1ncccc1C=O
Agent: Cl
Agent: [Na+]
Product: Cc1nc2ncccc2cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
2-Amino-pyridine-3-carbaldehyde (2.0 g) and chloroacetone (1.5 g) were suspended in a 5 N aqueous sodium hydroxide solution (10 ml) and was allowed to stand in a hermetically sealed state for 3 days. The reaction solution was neutralized with 10% hydrochloric acid, and the precipitated crystal was then collected by filtration. Isopropanol was added to the crystal, and the mixture was heated under reflux. The reaction solution was cooled to room temperature, and the solvent was then removed by distillation. Hexane was added to the residue, and the precipitated crystal was collected by filtration and was washed with hexane to give 2-methyl-[1,8]naphthyridin-3-ol (1.05 g, yield 40%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([OH:19])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>CC(C)=O.O>[Cl:1][C:2]1[C:3]([C:12]2[C:17]([F:18])=[CH:16][C:15]([O:19][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:14]([N+:20]([O-:22])=[O:21])[CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:8])[F:9]
Reactant: CCOC(=O)CBr
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(O)cc2F)c(Cl)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)COc1cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
At 25° C., 6.11 g (0.018 mole) 4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenol, 2.5 g (0,019 mole) K2CO3, and 2.0 mL (0.019 mole) ethyl bromoacetate were slurried in 100 mL acetone. The reaction mixture was stirred at 40° C. for 4 hours. The mixture was cooled, diluted with 100 mL cold water, and extracted four times with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and stripped in vacuo. The residue was recrystallized from methylcyclohexane to give 7.5 g (99%) of (4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenoxy)acetic acid, ethyl ester as a light yellow solid, mp 95°-96° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10](=S(C)(C)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[ClH:21]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[CH:10]([Cl:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Cl
Reactant: CCOC(=O)C(C(=O)Nc1ccc(Cl)cc1)=S(C)(C)=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(Cl)C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.5 grams (0.05 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-(dimethyloxosulfuranylidene)-3-oxopropanoate prepared in Example XLVII (Compound 205) in 25 milliliters of chloroform was stirred at room temperature for two hours while passing in a flow of anhydrous hydrogen chloride. After ceasing the gas feed the solution was stirred at ambient temperature for about 64 hours after which the solvent was removed under reduced pressure. Flash chromatography of the residue, eluting with hexane-ethyl acetate (7:3), gave a white solid which was recrystallized from ethyl acetate-hexane to give 0.20 gram (0.001 mole) of ethyl 3-[(4-chlorophenyl)amino]-2-chloro-3-oxopropanoate having a melting point of 104° C.-105° C. Elemental analysis of the product indicated the following:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])[CH:7]=[CH:6]2.C(N(CC)CC)C.[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1.O>C1COCC1>[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[CH:7]=[CH:6]3)=[O:36])=[CH:33][CH:32]=1
Reactant: COc1ccccc1CNc1ccc2cc(CN)ccc2n1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccccc1CNc1ccc2cc(CNC(=O)c3ccc(F)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
To a cooled (ice bath) and stirred solution of (6-aminomethyl-quinolin-2-yl)-(2-methoxy-benzyl)-amine (200 mg, 0.68 mmol) and triethyl amine (75 mg, 0.76 mmol) in THF (4 ml) was added 4-fluorobenzoyl chloride (119 mg, 0.75 mmol) and the mixture was allowed to stir at room temperature for 16 h. The reaction mixture was poured into water (15 ml) and extracted with diethyl acetate (2×20 ml). The combined organic layers were washed with brine (1×20 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel and crystallization (dichloromethane/hexane) to yield the title compound as white foam (250 mg, 88%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:26]=[CH:25][C:22](C=O)=[C:21]([O:27][CH3:28])[CH:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[C:46](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:26]=[CH:25][C:22]([CH2:39][N:40]6[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]6)=[C:21]([O:27][CH3:28])[CH:20]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(-c2cnc3c(c2)c(-c2ccc4[nH]ccc4c2)cn3S(=O)(=O)c2ccc(C)cc2)ccc1C=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(-c2cnc3[nH]cc(-c4ccc5[nH]ccc5c4)c3c2)ccc1CN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of 4-[3-(1H-Indol-5-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methoxy-benzaldehyde (0.066 g, 0.128 mmol) in CH2Cl2 (3 mL) was added 1-methylpiperazine (22 mL, 0.19 mmol) and sodium triacetoxyborohydride (81 mg, 0.38 mmol). The reaction mixture was stirred for 1 hr at room temperature, after which it was partitioned between CH2Cl2 and 1 M NaOH. The organic layer was separated, dried over MgSO4, and concentrated in vacuo. The residue was dissolved in 3:2 MeOH:acetone (5 mL), and 2 M NaOH (1.5 mL) was added. The resulting mixture was stirred at 65° C. for 30 min, after which it was partitioned between EtOAc and 1 M NaOH. The organic layer was separated, dried over MgSO4, filtered, and stripped to provide a residue that was subjected to preparatory HPLC to yield 3-(1H-Indol-5-yl)-5-[3-methoxy-4-(4-methyl-piperazin-1-ylmethyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine (0.037 g, 63% yield). 1H NMR (CDCl3, 400 MHz): δ 11.81 (s, 1H), 11.06 (s, 1H), 8.55 (d, J=2.1 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H), 7.88 (d, J=1.6 Hz, 1H), 7.74 (d, J=1.6 Hz, 1H), 7.46 (s, 2H), 7.37 (dd, J=6.4 Hz, 1H), 7.35 (d, J=6.4 Hz, 1H), 7.26 (dd, J=1.8, 6.4 Hz, 2H)), 6.46 (s, 1H), 3.86 (d, J=1.2 Hz, 2H), 3.32 (s, 3H), 2.49-42 (m, 8H), 2.13 (s, 3H); MS ESI (m/z) 452 (M+1)+, calc. 451.56.
Reaction SMILES: [CH3:1][N:2]([C@H:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[C@H:3]([C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)[CH3:4].[CH3:20]O.C[I:23]>C(OCC)(=O)C>[I-:23].[OH:11][C:7]1[CH:6]=[C:5]([C@@H:3]([N+:2]([CH3:20])([CH3:1])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:4])[CH:10]=[CH:9][CH:8]=1
Reactant: C[C@@H](c1ccccc1)N(C)[C@@H](C)c1cccc(O)c1
Reactant: CI
Reactant: CO
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Product: [I-]
Temperature: 60 °C
Yield: 87 %

Procedure:
Mix 5.1 g (0.02 mol) of 3-[(S)-1-(methyl-[(S)-1-phenylethyl]amino)ethyl]phenol (formula V) with 10 ml of methanol and 11.3 g (0.08 mol) of methyl iodide at room temperature, and heat the mixture to 60° C. for 10 hours. Cool it to room temperature and add 100 ml of ethyl acetate. A yellow solid is produced. Filter and dry it to receive 6.9 g yellow solid with a yield of 87%.
Reaction SMILES: C([NH:8][C@@H:9]([C:18]([OH:20])=O)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(OC(C)(C)C)=O.[CH2:21]1[C@@H:30]2[C@@H:25]([CH2:26][CH2:27][CH2:28][CH2:29]2)[CH2:24][CH2:23][NH:22]1.[NH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([S:39](Cl)(=[O:41])=[O:40])=[CH:34][C:33]=1[Cl:43]>>[NH2:31][C:32]1[C:37]([Cl:38])=[CH:36][C:35]([S:39]([NH:8][C@@H:9]([C:18]([N:22]2[CH2:23][CH2:24][C@H:25]3[C@H:30]([CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:21]2)=[O:20])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:41])=[O:40])=[CH:34][C:33]=1[Cl:43]
Reactant: C1CC[C@@H]2CNCC[C@@H]2C1
Reactant: Nc1c(Cl)cc(S(=O)(=O)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N[C@H](CCc1ccccc1)C(=O)O
Product: Nc1c(Cl)cc(S(=O)(=O)N[C@H](CCc2ccccc2)C(=O)N2CC[C@@H]3CCCC[C@@H]3C2)cc1Cl

Procedure:
Example 116 is prepared from Boc-(D)-homophenylalanine, (±)-cis-decahydroisoquinoline, and 4-amino-3,5-dichlorobenzenesulfonyl chloride in the same manner that Example 1 is synthesized. ESI MS: Calc: 523.2; Found: 524.3 (M+H)+.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([Cl:10])=[CH:8][N:7]=[CH:6][C:5]=1[Cl:11].[F:12][CH:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[O:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23].O>CN(C)C=O>[Cl:11][C:5]1[CH:6]=[N:7][CH:8]=[C:9]([Cl:10])[C:4]=1[NH:3][C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:27]([O:28][CH3:29])=[C:19]([O:18][CH:14]2[CH2:15][CH2:16][CH2:17][CH:13]2[F:12])[CH:20]=1
Reactant: Nc1c(Cl)cncc1Cl
Reactant: COc1ccc(C(=O)Cl)cc1OC1CCCC1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1F
Reaction time: 0.67 h

Procedure:
A suspension of sodium hydride (0.3; 60% oil dispersion) in dimethylformamide (5 mL) is treated with 4-amino-3,5-dichloropyridine (0.62 g) and the mixture is stirred for 40 minutes. A solution of 3-(2-fluorocyclopentyloxy)-4-methoxybenzoyl chloride in dimethylformamide (12 mL) is added, and the mixture is stirred at 80°-90° C. for 1 day. The solution is cooled, poured into water (75 mL) and extracted with dichloromethane (3×50 mL). The combined organic extracts are washed with brine (50 mL), dried over magnesium sulfate and concentrated. The residue is subjected to flash chromatography, eluting with a mixture of ethyl acetate and petroleumether (1:3 v/v), to give N-(3,5-dichloropyrid-4-yl)-3-(2-fluorocyclopentyloxy)-4-methoxybenzamide (0.26 g), m.p. 167°-169° C. [Elemental analysis: C,53.8; H,4.2; N,6.75; Cl,17.8%; calculated: C,54.15; H,4.3; N,7.0; Cl,17.8%].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([CH2:25]N)=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].C([N:33](CC)CC)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:28])([F:29])[F:30])[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[C:19]([C:21]([F:23])([F:24])[F:22])[C:18]([CH2:25][C:38]4([C:41]([NH2:33])=[O:42])[CH2:40][CH2:39]4)=[CH:17][N:16]=3)[CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: NCc1cnc(N2CCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)nc1C(F)(F)F
Reactant: CCN(CC)CC
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Product: NC(=O)C1(Cc2cnc(N3CCC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)nc2C(F)(F)F)CC1
Reaction time: 8 h

Procedure:
1-{2-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-4-(trifluoromethyl)pyrimidin-5-yl}methanamine (0.15 g) and triethylamine (0.051 ml) were dissolved in methylene chloride (3 ml), and to the solution was added cyclopropane carbonyl chloride (0.033 ml, 0.37 mmol) at room temperature. The reaction mixture was stirred overnight and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography to obtain the target compound (0.135 g).
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([NH:35][CH2:36][C:37](O)=[O:38])(OC(C)(C)C)=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:73]>CN(C=O)C.O1CCOCC1>[ClH:73].[NH2:35][CH2:36][C:37]([N:13]1[CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9][C@@H:8]1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:38]
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(C(=O)CN)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2) (73 mg, 0.2 mmol) and BOC-glycine (35 mg, 0.2 mmol) in DMF (1.0 mL) at room temperature was treated with diisopropylethylamine (35 μL, 0.2 mmol) followed by HATU (84 mg, 0.22 mmol). The reaction mixture was stirred for 2 h then partitioned between EtOAc (10 mL) and a saturated aqueous NaHCO3 solution (10 mL). The organic component was isolated and further washed with brine (10 mL) then dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 40% EtOAc/hexane as eluant to afford BOC-containing coupled product as a foam (85 mg, 81%). LC/MS 7.46 min, [M+1]+ 524. The BOC-protected intermediate was dissolved in a 4 N solution of hydrogen chloride in dioxane, and stirred for 2 h then evaporated to a solid which was filtered and washed with diethyl ether to afford product as a colorless solid (42 mg, 49% based on trihydrochloride salt). LC/MS 4.66 min, [M+1]+ 424.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][CH3:10])=[CH:17][CH:16]=2)(=[O:20])=[O:19])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Nc1cc(F)cc(Br)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2cc(F)cc(Br)c2)cc1
Yield: 87.8 %

Procedure:
3-Bromo-5-fluoroaniline (500 mg, 2.63 mmol) was treated with 4-methoxybenzene-1-sulfonyl chloride (572 mg, 2.77 mmol) according to the method described in Preparation 15b to give 832 mg (88% yield) of the title compound as an oil. Purity 70%.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4](F)[N:3]=1.[N:10]1([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.CN1C(=O)CCC1.CCN(C(C)C)C(C)C>CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:12][CH2:11][N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15][CH2:14]2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(F)nc1Br
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1Br
Temperature: 120 °C

Procedure:
To microwave vial was added 2-bromo-6-fluoro-3-methylpyridine (1355 mg, 7.13 mmol), tert-butyl piperazine-1-carboxylate (1338 mg, 7.18 mmol), anhydrous NMP (3.5 mL), and DIPEA (1.65 ml, 9.45 mmol). The resulting mixture was heated at 120° C. for 16 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (100 mL), washed with water (20 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated. The crude residue was purified by flash chromatography (80 g SiO2, 0-25% EtOAc in hexanes) to afford tert-butyl 4-(6-bromo-5-methylpyridin-2-yl)piperazine-1-carboxylate (46-1) as a waxy tan solid. HRMS m/z (M+H) 356.0971 measured, 356.0968 calculated.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[CH2:4][S:3]1(=[O:15])=[O:14].CCOC(C)=O.[O:22]1[CH2:24][C@@H:23]1[CH2:25][NH:26][C:27](=[O:29])[CH3:28].FC(F)(F)S([O-])(=O)=O.[Mg+2].FC(F)(F)S([O-])(=O)=O>[Pd].CC#N>[OH:22][C@H:23]([CH2:24][NH:11][C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[S:3](=[O:15])(=[O:14])[CH2:4][C:5]=2[CH:10]=1)[CH2:25][NH:26][C:27](=[O:29])[CH3:28]
Reactant: CC(=O)NC[C@H]1CO1
Reactant: CN1c2ccc([N+](=O)[O-])cc2CS1(=O)=O
Agent: [Pd]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H](O)CNc1ccc2c(c1)CS(=O)(=O)N2C
Reaction time: 2 h
Yield: 83.4 %

Procedure:
The product of Step 1 (0.20 g, 0.88 mmol) is dissolved into EtOAc (30 mL) in a Parr bottle and 10% Pd/C (100 mg) added under nitrogen. The mixture is hydrogenated on a Parr apparatus for 2 hrs at 30 psi. Filtration and evaporation of solvent gave a white solid. This material is added to a mixture of N-[(2S)oxiranylmethyl] acetamide (0.81 g, 7.0 mmol) and magnesium trifluoromethanesulfonate (0.42 g, 1.3 mmol) in dry CH3CN (10 mL) at room temperature. After 20 hrs solvent is evaporated and the residue purified by chromatography (4%MeOH/CH2Cl2) to give a foamy solid (0.23 g, 79%). HRMS (FAB) calcd for C13H19N3O4S +H1 314.1174, found 314.1174.
Reaction SMILES: C([O:8][C:9](=[O:59])[CH2:10][CH2:11][C:12]([O:14][C:15]1([CH2:39][O:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:51][C@H:50]([CH2:52][NH:53][C:54](=[O:56])[CH3:55])[O:49][C:48]3=[O:57])=[CH:43][C:42]=2[F:58])[CH2:20][CH2:19][N:18]([C:21]2[C:30]([F:31])=[CH:29][C:28]3[C:27](=[O:32])[C:26]([C:33]([OH:35])=[O:34])=[CH:25][N:24]([CH:36]4[CH2:38][CH2:37]4)[C:23]=3[N:22]=2)[CH2:17][CH2:16]1)=[O:13])C1C=CC=CC=1>[OH-].[Pd+2].[OH-].O1CCCC1.CO>[C:54]([NH:53][CH2:52][C@@H:50]1[O:49][C:48](=[O:57])[N:47]([C:44]2[CH:45]=[CH:46][C:41]([O:40][CH2:39][C:15]3([O:14][C:12](=[O:13])[CH2:11][CH2:10][C:9]([OH:59])=[O:8])[CH2:16][CH2:17][N:18]([C:21]4[C:30]([F:31])=[CH:29][C:28]5[C:27](=[O:32])[C:26]([C:33]([OH:35])=[O:34])=[CH:25][N:24]([CH:36]6[CH2:38][CH2:37]6)[C:23]=5[N:22]=4)[CH2:19][CH2:20]3)=[C:42]([F:58])[CH:43]=2)[CH2:51]1)(=[O:56])[CH3:55]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)CCC(=O)O)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1

Procedure:
In analogy to example 74 step 5 with 22 mg succinic acid 4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-1-(6-carboxy-8-cyclopropyl-3-fluoro-5-oxo-5,8-dihydro-[1,8]naphthyridin-2-yl)-piperidin-4-yl ester benzyl ester (MW: 817.80, 0.026 mmol) and 2 mg of palladium hydroxide 20% on activated carbon in 20 ml of a 1/1 tetrahydrofuran/methanol mixture. Yield: 16 mg, 81%. MS: 729 (M+H)+, 727 (M+H)−, Method ESI+, ESI−.