Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1]/[C:2](/[O-:7])=[CH:3]/[C:4]([CH3:6])=[O:5].[Na+].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:17][C:18](=[O:21])[CH2:19]Br)[CH3:16].[CH3:22][C:23](C)=O>>[CH2:15]([O:17][C:18](=[O:21])[CH2:19][CH2:22][CH2:23][CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:5])[CH3:6])[CH3:16]
Reactant: CC(C)=O
Reactant: CCOC(=O)CBr
Reactant: CC(=O)/C=C(/C)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Product: CCOC(=O)CCCC(C(C)=O)C(C)=O

Procedure:
10 g of sodium acetylacetonate and 20 g of potassium carbonate in 50 ml of acetone were heated to reflux and 15 g of bromoacetic acid ethyl ester was added dropwise over 15 minutes. After refluxing for several days, the solid was filtered off and washed with petroleum ether and acetone. Fractional distillation yielded 6.4 g of 5-acetyl-6-oxo-heptanoic acid ethyl ester.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C@H:13]1[CH2:17][CH2:16][NH:15][CH2:14]1)[CH:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]2=[O:23].C=O.O.[C:27]([BH3-])#N.[Na+]>CO>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C@H:13]1[CH2:17][CH2:16][N:15]([CH3:27])[CH2:14]1)[CH:8]=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]2=[O:23]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)c1cn([C@H]2CCNC2)c2ccc(I)cc2c1=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cn([C@H]2CCN(C)C2)c2ccc(I)cc2c1=O
Temperature: 23 °C
Reaction time: 16 h
Yield: 82.3 %

Procedure:
(S)-Ethyl 6-iodo-4-oxo-1-(pyrrolidin-3-yl)-1,4-dihydroquinoline-3-carboxylate hydrochloride (Intermediate 136, 484 mg, 1.08 mmol) was suspended in methanol (15 mL) then 37% formaldehyde in water (405 μl, 5.4 mmol) and sodium cyanoborohydride (612 mg, 9 7 mmol) were added. The reaction was stirred at 23° C. for 16 h. The volume of the reaction was reduced by half and water (25 mL) was added. The suspension was extracted with 2:1 ethyl acetate: tetrahydrofuran (3×, 10 mL). The organic phases were combined, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was passed through a plug of silica gel (2 g) eluting with 10% methanol in dichloromethane to remove any remaining borohydride. The solid was then dried in a vacuum oven at 50° C. for 18 h to give 379 mg (82% yield) of (S)-ethyl 6-iodo-1-(1-methylpyrrolidin-3-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as an off white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[S:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:22])=[O:21]
Reactant: COC1CN(C(=O)c2csc(N3CC(O)C3)n2)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1CN(C(=O)c2csc(N3CC(OS(C)(=O)=O)C3)n2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a solution of 3-hydroxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (480 mg, 1.71 mmol) (obtained as described in Reference Example 31(3)) in methylene chloride (25 ml) were added methanesulfonyl chloride (397 μl, 5.13 mmol) and triethylamine (719 μl, 5.13 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 1 hour. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate:methanol (95:5) as the eluant to afford 3-methanesulfonyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-thiazol-2-yl]azetidine (568 mg, yield 96%) as a pale yellow solid.
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([N:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:4].[C:10](Cl)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl>[CH2:3]([N:5]1[CH2:8][CH2:9][CH:7]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:2][CH3:1])=[O:17])[CH2:6]1)[C:4]1[CH:15]=[CH:16][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)c1ccccc1C1CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
0.778 g of (R)-1-benzylpyrrolidin-3-yl)methylamine is dissolved in 20 ml of dichloromethane. 0.521 ml of triethylamine is added and the solution is cooled to 0° C. in an ice bath. 0.434 ml of benzoyl chloride is added dropwise and the reaction solution is subsequently stirred at 0° C. over 50 minutes. The reaction solution is diluted with 20 ml of dichloromethane and washed with 20 ml of saturated aqueous sodium hydrogencarbonate solution and 20 ml of brine, dried over sodium sulphate and concentrated by evaporation. The residue is purified by means of flash chromatography (SiO2 60F). The title compound is obtained as a colourless oil. Rf=0.75 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=3.08
Reaction SMILES: [CH2:1]1[O:12][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2Br)[O:3][CH2:2]1.CON(C)[C:16](=[O:24])[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([CH2:17][C:16]([C:8]2[CH:9]=[CH:10][C:5]([CH:4]3[O:12][CH2:1][CH2:2][O:3]3)=[CH:6][CH:7]=2)=[O:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CON(C)C(=O)CC1CCCCC1
Reactant: Brc1ccccc1C1OCCO1
Product: O=C(CC1CCCCC1)c1ccc(C2OCCO2)cc1
Yield: 84 %

Procedure:
Following the procedure of Example D, 11 g (0.048mole) of p bromobenzaldehyde ethylene acetal and 8.9 g of the product of Example I were combined to give after chromatography on silica gel using 15% ethyl acetate/hexane 11 g of the title compound (84% yield).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:2]1.[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:2]2[C:3]([C:6]([O:8][CH3:9])=[O:7])=[N:4][CH:5]=[N:1]2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: COC(=O)c1nc[nH]n1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ncnn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 12.4 %

Procedure:
A mixture of methyl 1H-1,2,4-triazole-3-carboxylate (7.06 g), 4-nitrobenzyl bromide (10 g), potassium carbonate (16.6 g) and N,N-dimethylformamide (60 ml) was stirred at room temperature for 4 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give methyl 1-(4-nitrobenzyl)-1H-1,2,4-triazole-5-carboxylate (1.50 g, 12%) as crystals from a fraction eluted with hexane-ethyl acetate (1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 126-130° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].O[CH2:5][C:6]1(O[CH2:14][C@@H:12](O)[C@@H:10](O)[C@H:8]1O)O.[CH3:16][OH:17]>[Pd]>[CH3:16][O:17][C:5]1[CH:14]=[CH:12][C:10]([CH2:5][CH2:6][CH:8]([N:1]=[N+:2]=[N-:3])[CH3:10])=[CH:8][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Reactant: CO
Agent: [Pd]
Product: COc1ccc(CCC(C)N=[N+]=[N-])cc1

Procedure:
The azide (5) (300 mg) was dissolved in methanol (20 ml) and to it was added palladium charcoal (30 mg) and stirred under hydrogen for 6 hrs at 55 Psi; catalyst was then filtered off, the filtrate was concentrated to give a residue which crystallized from acetone-hexane mixture as needles to give compound having formula (1) (208 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:6]([C:18]([F:21])([F:20])[F:19])[CH:5]=1)([O-])=O.[H][H]>C(O)C.[C].[Pd]>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][C:6]=2[C:18]([F:19])([F:20])[F:21])=[CH:13][CH:14]=1
Reactant: O=[N+]([O-])c1ccc(C#Cc2ccncc2)c(C(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(CCc2ccncc2)c(C(F)(F)F)c1
Yield: 84.4 %

Procedure:
In 20 mL of ethanol, 1.3 g (4.45 mmol) of 4-(4-nitro-2-(trifluoromethyl)phenylethynyl)pyridine was dissolved and stirred on 100 mg of 10% palladium carbon overnight at room temperature in a hydrogen atmosphere. The catalyst was removed by filtration and the filtrate was concentrated and the residue was purified by a silica gel column (n-hexane:ethyl acetate=1:2) to obtain 1.0 g (85%) of a target product as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:8]3=[CH:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:23]#[N:24].[Cl:25][C:26]1[C:32]([O:33][CH3:34])=[CH:31][C:29]([NH2:30])=[C:28]([CH3:35])[CH:27]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[Cl:25][C:26]1[C:32]([O:33][CH3:34])=[CH:31][C:29]([NH:30][C:4]2[C:3]([C:23]#[N:24])=[CH:2][C:11]3[CH:6]=[CH:7][C:8]4[N:14]([CH2:15][CH2:16][N:17]5[CH2:22][CH2:21][O:20][CH2:19][CH2:18]5)[CH:13]=[N:12][C:9]=4[C:10]=3[N:5]=2)=[C:28]([CH3:35])[CH:27]=1
Reactant: N#Cc1cnc2cc3c(cc2c1Cl)ncn3CCN1CCOCC1
Reactant: COc1cc(N)c(C)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3c(ccc4c3ncn4CCN3CCOCC3)cc2C#N)c(C)cc1Cl
Temperature: 132.5 °C
Yield: 69.9 %

Procedure:
A mixture of 86.5 mg (0.25 mmol) of 8-chloro-3-[2-(4-morpholinyl)ethyl]-3H-imidazo[4,5-g]quinoline-7-carbonitrile, 67.2 mg (0.39 mmol) of 4-chloro-5-methoxy-2-methyl aniline and 28.9 mg (0.25 mmol) of pyridine hydrochloride in 3 mL of 2-ethoxyethanol is heated at 130-135° C. for 11 hours. After cooling, the mixture is diluted with water and neutralized with 2 equivalents of sodium carbonate, and then extracted with ethyl acetate. The separated organic layer is washed with brine and dried over sodium sulfate. Removal of the solvent yields a residue which is purified on preparative TLC (developing solvent: 1:9 methanol/methylene chloride), giving 83.3 mg (69.9%) of the product as a beige solid, mp 246-248° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)[CH:11]=2)=[O:8])=[CH:5][N:4]=1.[C:29]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)(=[O:31])[CH3:30]>>[C:29]([N:32]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2[CH:28]=[CH:27][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([NH:17][C:18](=[O:26])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:34][CH2:33]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2cccc(Cl)c2)c1)c1ccc(CBr)nc1
Product: CC(=O)N1CCN(Cc2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4cccc(Cl)c4)c3)cn2)CC1

Procedure:
6-(bromomethyl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide (0.2 mmol) was used in general procedure 5 with 1-acetylpiperazine (0.4 mmol). The product was purified by RP-HPLC to give 6-((4-acetylpiperazin-1-yl)methyl)-N-(4-chloro-3-(3-chlorobenzamido)phenyl)nicotinamide. MS (Q1) 526.0 (M)+
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[C:10]([O:14][C:15]([NH:17][CH2:18][C:19](O)=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11].C1CCC(N=C=NC2CCCCC2)CC1.CN1CCOCC1>ClCCl>[C:10]([O:14][C:15]([NH:17][CH2:18][C:19]([NH:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])=[O:20])=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCN
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)CCNC(=O)CNC(=O)OC(C)(C)C
Yield: 62 %

Procedure:
A solution of β-alanine ethyl ester hydrochloride salt (5) (3.07 g; 0.02 mmol), N-(tertbutoxycarbonyl)glycine (3.5 g; 0.02 mmol), DCCI (4.12 g; 0.02 mmol) and 4-methylmorpholine (2.2 ml) in dichloromethane (60 ml) was stirred overnight under argon atmosphere at ambient temperature. After filtration the residue was purified by flash chromatography eluting with dichloromethane/ethanol (96/4) to give ethyl 3-[(2-tertbutoxycarbonylaminoacetyl)amino]propanoate (6).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=3)[C@H:11]([CH2:24][N:25]3[CH:29]=[C:28]([C:30]([OH:32])=O)[N:27]=[N:26]3)[O:10][C:9]2=[O:33])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:67][N:68]1[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]1>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@@H:12]([C:13]3[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[C:15]([F:23])[CH:14]=3)[C@H:11]([CH2:24][N:25]3[CH:29]=[C:28]([C:30]([NH:67][N:68]4[CH2:73][CH2:72][CH2:71][CH2:70][CH2:69]4)=[O:32])[N:27]=[N:26]3)[O:10][C:9]2=[O:33])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cn(C[C@@H]2OC(=O)N(c3ccc(Cl)cc3)[C@H]2c2cc(F)cc(C(F)(F)F)c2)nn1
Reactant: NN1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NN1CCCCC1)c1cn(C[C@@H]2OC(=O)N(c3ccc(Cl)cc3)[C@H]2c2cc(F)cc(C(F)(F)F)c2)nn1
Reaction time: 0.08 h
Yield: 36.6 %

Procedure:
(4S,5S)-1-((3-(4-Chlorophenyl)-4-(3-fluoro-5-(trifluoromethyl)phenyl)-2-oxooxazolidin-5-yl)methyl)-1H-1,2,3-triazole-4-carboxylic acid (40 mg, 0.082 mmol) is dissolved in CH3CN (2 mL) and is successively treated with DIEA (14 μL, 0.082 mmol) and HATU (31 mg, 0.082 mmol) at ambient temperature. After 5 minutes, 1-aminopiperidine (10 μL, 0.097 mmol) is added and the reaction stirred for 2 h as judged complete by LC-MS. The reaction is quenched with 1 mL 1M HCl and diluted with water and ethyl acetate. The organic layer is washed successively with NaHCO3, brine, dried over MgSO4, filtered and concentrated. Purification by flash chromatography on silica gel (0-5% methanol/dichloromethane) gives the title compound (17 mg, 37%) as a white film. 1H NMR (acetone-d6, 400 MHz) δ 8.49 (s, 1H), 8.39 (s, 1H), 7.72 (s, 1H), 7.66 (d, 1H, J=9.2 Hz), 7.52 (d, 1H, J=8.5 Hz), 7.45-7.49 (m, 2H), 7.30-7.33 (m, 2H), 5.85 (d, 1H, J=5.5 Hz), 5.21 (d, 2H, J=5.6 Hz), 5.11 (q, 1H, J=5.6 Hz), 2.89 (t, 4H, J=5.3 Hz), 1.65 (pentet, 4H, J=6.0 Hz), 1.48-1.51 (m, 1H), 1.39-1.45 (m, 1H). HPLC-MS calculated C25H23ClF4N6O3 (M+H+): 567.2, found: 567.2.
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42]([OH:44])=O)[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)=[O:44])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: Nc1ccccc1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)Nc2ccccc2)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with aniline to give the title compound. HR-MS (ES, m/z) calculated for C41H47Cl2N6O3 [(M+H)+] 741.3081, observed 741.3079.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[C:6]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1.[C:23]([O:27][C:28](=[O:38])[CH2:29][C@H:30]([NH2:37])[C:31]([N:33]([O:35][CH3:36])[CH3:34])=[O:32])([CH3:26])([CH3:25])[CH3:24].N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:12])(=[O:11])[NH:37][C@H:30]([C:31](=[O:32])[N:33]([O:35][CH3:36])[CH3:34])[CH2:29][C:28]([O:27][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:38])=[C:6]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:5]=1
Reactant: CON(C)C(=O)[C@@H](N)CC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)N(C)OC)c(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
To a solution of 3-benzyloxy-4-chlorosulfonyl-benzoic acid methyl ester (9.25 g, 27.1 mmol) in dichloromethane (270 mL) was added (S)-3-amino-N-methoxy-N-methyl-succinamic acid tert-butyl ester (6.30 g, 27.1 mmol) followed by pyridine (6.59 mL, 81.4 mmol). The reaction was allowed to stir over night at room temperature. The reaction was then diluted with ethyl acetate (500 mL) and washed sequentially with 5% citric acid, saturated sodium bicarbonate, and saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield an orange oil. The crude residue was chromatographed (silica gel, 40% ethyl acetate-60% hexane) to give 3-benzyloxy-4-[(S)-2-tert-butoxycarbonyl-1-(methoxy-methyl-carbamoyl)-ethylsulfamoyl]-benzoic acid methyl ester as a white foam (8.20 g, 56%). 1H NMR(300 MHz, DMSO) 7.84 (d, 1H), 7.60 (m, 1H), 7.57 (m, 2H), 7.52 (d, 2H), 7.36 (t, 2H), 7.28 (t, 1H), 5.35 (s, 2H), 4.60 (m, 1H), 3.81 (s, 3H), 3.48 (bs, 3H), 2.82 (bs, 3H), 2.46 (dd, 1H), 2.33 (dd, 1H), 1.27 (s, 9H). MS(APCI) m/z 535.2 (M−H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:12]([NH:13][CH2:14][C:15]([OH:17])=O)=[C:11]([CH3:22])[C:10]=1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([N:31]1[CH2:36][CH2:35][CH:34]([NH2:37])[CH2:33][CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C:9]1[C:19]([CH3:20])=[C:18]([CH3:21])[C:12]([NH:13][CH2:14][C:15]([NH:37][CH:34]2[CH2:35][CH2:36][N:31]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[O:17])=[C:11]([CH3:22])[C:10]=1[CH3:23])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1c(C)c(NC(=O)OC(C)(C)C)c(C)c(C)c1NCC(=O)O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(C)c(NC(=O)OC(C)(C)C)c(C)c(C)c1NCC(=O)NC1CCN(Cc2ccccc2)CC1
Yield: 73 %

Procedure:
A mixture solution of 2.2 g of 2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]acetic acid, 1.67 ml of 1-benzyl-4-aminopiperidine, 10.47 g of 25% propanephosphonic acid anhydride and 4.76 ml of triethylamine in 40 ml of methylene chloride was stirred over night at room temperature. Then, 20 ml of saturated sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with brine, dried and concentrated under reduced pressure to give a residue. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1) to give 2.48 g (73%) of 2-[4-(tert-butoxycarbonylamino)-2,3,5,6-tetramethylanilino]-N-(1-benzyl-4-piperidinyl)acetamide. Then, a mixture of 438 mg of the compound obtained and 40 mg of 20%-palladium hydroxide on carbon in 4 ml of methanol was stirred for 6 hours under 5 atm of hydrogen. Then, the catalyst was filltered off a Celite (trade name) pud and the filtrate was concentrated under reduced pressure to give a residue. The obtained residue was purified by amine-coated silica gel (Fuji Silysia Chemical Ltd.; NH-DM1020) column chromatography (methylene chloride:methanol=10:1) to give 293 mg (81%) of the above-mentioned compound (21).
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=2[N:5](C(OC(C)(C)C)=O)[CH:4]=1)=O.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.[B-]C#N.[Na+]>CO.C(O)(=O)C>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][CH2:1][C:3]2[C:11]3[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=[N:7][C:6]=3[NH:5][CH:4]=2)[CH2:25]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: COC(=O)c1ccnc2c1c(C=O)cn2C(=O)OC(C)(C)C
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccnc2[nH]cc(CNC3CCCN(C(=O)OC(C)(C)C)C3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
To a solution of 1-tert-butyl 4-methyl 3-formyl-1H-pyrrolo[2,3-b]pyridine-1,4-dicarboxylate (304 mg, 1.00 mmol) in 9:1 MeOH-Acetic Acid (2 mL) at 0° C. was added tert-butyl 3-aminopiperidine-1-carboxylate (300 mg, 1.50 mmol) and the reaction mixture was stirred at rt for 1 h. Sodium cyanotrihydroborate (314 mg, 5.00 mmol) was added slowly portion wise and the reaction mixture was stirred at rt over night, quenched with water, and extracted with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 and with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (30% to 70% Hexane-EtOAc) to give 307 mg of methyl 3-((1-(tert-butoxycarbonyl) piperidin-3-ylamino)methyl)-1H-pyrrolo[2,3-b]pyridine-4-carboxylate as a colorless oil. [M+H] found 389.
Reaction SMILES: [C:1]1([C:7](B(O)O)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:13]1[CH:14]=[N:15][N:16]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][C:19]=23)[CH:17]=1.C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C:7]([C:13]2[CH:14]=[N:15][N:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][C:19]=34)[CH:17]=2)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(B(O)O)c1ccccc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-n3cc(Br)cn3)ccnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: C=C(c1ccccc1)c1cnn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)c1
Temperature: 100 °C

Procedure:
A mixture of (1-phenylvinyl)boronic acid (24.0 mg, 0.000162 mol) and 4-(4-bromo-1H-pyrazol-1-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (50.0 mg, 0.000127 mol) in toluene (2.00 mL, 0.0188 mol) and ethanol (0.50 mL, 0.0086 mol) was treated with potassium carbonate (35 mg, 0.00025 mol) in water (1.00 mL, 0.0555 mol). The mixture was degassed by bubbling nitrogen. Tetrakis(triphenylphosphine)palladium(0) (10 mg, 0.00001 mol) was added and nitrogen was bubbled for 3 min. The reaction was heated in a sealed tube in the microwave at 100° C. for 30 min. The reaction was allowed to cool to rt and partitioned between ethyl acetate and water. The combined organic layer was dried over MgSO4, filtered and concentrated to give the crude material. The crude product was purified by FCC on silica gel eluting with EtOAc/Hexanes (1:5) to give 4-[4-(1-phenylvinyl)-1H-pyrazol-1-yl]-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]-pyridine as a solid residue, LC/MS (M+H)+: 417.