Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([CH2:14][N:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:5]([C:3]([OH:2])=[O:4])[C:6]=4[CH:7]=[CH:8]3)=[CH:16][CH:17]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1cccc2c1ccn2Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cn3ccc4c(C(=O)O)cccc43)cc2)cc1

Procedure:
The title compound was prepared from 1-(4-nitro-benzyl)-1H-indole-4-carboxylic acid methyl ester and 4-tert-butylbenzenesulfonyl chloride followed the procedure of Example 3 Step 2 as a pale pink solid: 1H NMR (DMSO-d6) δ 1.24 (s, 9H), 5.35 (s, 2H), 6.96 (d, J=3.1 Hz, 1H), 7.03 (d, J=8.7 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 7.15 (t, J=7.8 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.57 (d, J=3.2 Hz, 1H), 7.62-7.68 (m, 3H), 7.70 (dd, J=7.5, 0.9 Hz, 1H), 10.26 (br s, 1H), 12.59 (br s, 1H); MS (ESI) m/z 463 (MH+), 461 ([M−H]−); HRMS calcd for C26H27N2O4S: 463.1690; found (ESI+): 463.1674.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]1=2.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:15]1([S:21]([N:1]2[CH2:6][CH2:5][O:4][C:3]3[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]2=3)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cnc2c(c1)NCCO2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)N(S(=O)(=O)c1ccccc1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.3 %

Procedure:
To a solution of methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (278.9 mg, 1.436 mmol) in DCM (20 mL) was added benzenesulfonyl chloride (278 μL, 2.156 mmol), DIPEA (753 μL, 4.31 mmol) and DMAP (88 mg, 0.719 mmol). The reaction was stirred at room temperature for 16 hours. LCMS analysis indicated a predominance of product in the reaction mixture. The solvent was removed under reduced pressure and the resulting oil was purified by flash column chromatography using a gradient elution of hexanes with 25-70% EtOAc to provide methyl 1-(phenylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (280 mg, 0.837 mmol, 58.3% yield) as a yellow glass. LCMS (+ESI) m/z=334.8 [M+H]+.
Reaction SMILES: [CH:1]1([C:4](Cl)=O)[CH2:3][CH2:2]1.Cl.[CH3:8][C:9]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:10]=1[O:11][CH2:12][C@H:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH:1]1([CH2:4][N:15]2[CH2:16][CH2:17][CH2:18][C@H:13]([CH2:12][O:11][C:10]3[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:9]=3[CH3:8])[CH2:14]2)[CH2:3][CH2:2]1
Reactant: Cc1cccc(C)c1OC[C@H]1CCCNC1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1cccc(C)c1OC[C@H]1CCCN(CC2CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropylcarbonyl chloride (1.7 mL, 18 mmol) was added dropwise during 15 minutes to an ice cold mixture containing (S)-3-(2,6-dimethylphenoxymethyl)piperidine hydrochloride (4.4 g, 17 mmol), aqueous sodium bicarbonate (75 mL), and ethyl acetate (100 mL). After the addition was complete, the reaction was stirred at room temperature for 1 hour, and the resulting ethyl acetate layer was separated and concentrated. The residue was dissolved in dry tetrahydrofuran (125 mL) under a dry nitrogen atmosphere and a 1M solution of lithium aluminum hydride in tetrahydrofuran (18.9 mL) was added dropwise. When the addition was complete, the reaction mixture was heated to reflux for 2 hours, then cooled to room temperature. Solid sodium sulfate decahydrate (10 g) was slowly added with stirring and the mixture was filtered. The filtrate was concentrated and chromatographed on silica gel, eluting with acetone/hexanes (1:3) to give (S)-1-cyclopropylmethyl-3-(2,6-dimethylphenoxymethyl)-piperidine as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].[NH:27]1[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]1>>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:27]2[CH2:32][CH2:31][O:30][CH:29]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH2:28]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)CCC1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Product: CCOC(=O)C1=C(CN2CCOC(CCC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(Cl)cc1Cl
Yield: 45.2 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2,4-dichlorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.67 g, 1.4 mmol) was reacted with 3-(morpholin-2-yl)propanoic acid (0.22 g, 1.4 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.35 g, 45%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([N+]([O-])=O)=[CH:7][CH:6]=1)(O)(=O)=O.[O:14]=[C:15]([N:18]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:19]1([CH2:25][O:26][CH3:27])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[CH2:16][CH3:17].COC(C)(C)C>C(N(CC)CC)C>[CH3:17][CH2:16][C:15]([N:18]([C:19]1([CH2:25][O:26][CH3:27])[CH2:20][CH2:21][N:22]([CH2:7][CH2:6][C:5]2[S:1][CH:8]=[CH:12][CH:13]=2)[CH2:23][CH2:24]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:14]
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2cccs2)CC1
Yield: 84.2 %

Procedure:
To a suitably sized reaction flask (e.g., a jacketed glass reactor with stirring, nitrogen blanket, internal temperature recorder, and reflux capabilities) is charged 4-[(1-oxopropyl)phenylamino]-4-methoxymethyl piperidine nosylate (100.0 g), 2-(2-thiophenylethyl) 4-nitro-benzene sulfonate (79.2 g), tert-butyl methyl ether (MTBE, 333 mL), and triethylamine (TEA, 666 mL). The reaction mixture is warmed to 55°±5° C. and allowed to react at that temperature for not less than 24 hours. As the reaction progresses, a slurry is formed. The extent of the reaction can be followed by HPLC until most of the initial reactants are consumed. At that point, the reaction mixture is cooled to 20°±5° C. and charged with MTBE (400 mL) and water (400 mL). The diluted slurry is mixed for at least 10 minutes and then aqueous and organic phases are allowed to separate in a separatory funnel. The aqueous phase is discarded and then the organic phase is washed with water two additional times. Carbon (20 g) is then added to the resultant organic phase, mixed for at least 10 minutes and the carbon is filtered from the organic phase through a CELITE® diatomaceous earth bed. The CELITE® diatomaceous earth bed is washed with 200 ml of MTBE, the organic phases are combined and then solvent exchanged with ethanol under vacuum distillation conditions (by concentrating the organic phase to minimum stir volume three times and thereafter adding 400 mL of ethanol following each step of concentrating). The final volume should be about 600 mL. The solution is warmed to 45°±5° C. and then water (834 mL) is added slowly to give a turbid system. The hazy slurry is cooled slowly to 5°±5° C., and held at that temperature for at least 16 hours. The resultant slurry is filtered, washed with 30% aqueous ethanol and then dried in a vacuum oven at 50° C. to yield 67.9 g of the desired sufentanil product (expected yield 84%; expected purity 99.7%).
Reaction SMILES: [CH:1]([C:3]1[CH:27]=[CH:26][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1)=O.[C:28]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:30][CH3:31])=[O:29]>CO>[CH3:31][O:30][C:28]([CH:32]=[CH:1][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]2[CH2:14][CH2:13][CH:12]([N:15]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18][C:16]3=[O:17])[CH2:11][CH2:10]2)=[O:8])=[CH:26][CH:27]=1)=[O:29]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Solvent: CO
Product: COC(=O)C=Cc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 145.2 %

Procedure:
1-[1-(4-Formylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (4.77 g) is dissolved in methanol (100 ml) and thereto is added carbomethoxymethylenetriphenylphosphorane (5.3 g) and the mixture is stirred at room temperature for 1 hour. The solvent is concentrated and the residue is purified roughly by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to give a mixture (8 g) of 1-{1-[4-(2-methoxycarbonylvinyl)benzoyl]4-piperidinyl}-3,4-dihydrocarbostyril and triphenylphosphineoxide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([F:31])([F:30])[F:29])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([C:37]1([C:40]2[CH:45]=[CH:44][C:43]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:15])[C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:28]([F:30])([F:31])[F:29])[CH:20]=4)=[CH:6][CH:7]=3)=[CH:42][CH:41]=2)[CH2:38][CH2:39]1)=[O:36])[CH3:33]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2C(F)(F)F)nn1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccccc5C(F)(F)F)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-trifluoromethyl-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([C:22]([F:21])([F:32])[F:33])=[CH:24][CH:25]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc(C(F)(F)F)cc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-(trifluoromethyl)benzoic acid.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[CH3:17]O>>[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:11]=1
Reactant: Nc1ccc(CCC(=O)O)cc1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCc1ccc(N)cc1
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Under ice-cooling, thionyl chloride (15 mL, 206 mmol) was added dropwise to methanol (60 mL), and the mixture was stirred for 10 min. 3-(4-Aminophenyl)propanoic acid (10.1 g, 61.1 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hr. The solvent and excess thionyl chloride were evaporated under reduced pressure, and water and saturated aqueous sodium hydrogencarbonate were added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained solid was washed with hexane to give the title compound (10.9 g, yield 99%) as pale-brown prism crystals.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH:9]=[C:10]([CH3:12])[N:11]=2)[C:7]=1[Cl:8].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:8][C:7]1[N:6]2[CH:9]=[C:10]([CH3:12])[N:11]=[C:5]2[CH:4]=[N:3][C:2]=1[C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13]
Reactant: Cc1cn2c(Cl)c(Br)ncc2n1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cn2c(Cl)c(C#C[Si](C)(C)C)ncc2n1
Temperature: 45 °C
Reaction time: 14 h
Yield: 51.3 %

Procedure:
A mixture of 6-bromo-5-chloro-2-methylimidazo[1,2-a]pyrazine (0.710 g, 2.88 mmol), bis(triphenylphosphine)palladium(II) chloride (0.1 g, 0.1 mmol), (trimethylsilyl)acetylene (0.90 mL, 6.3 mmol), copper(I) iodide (0.04 g, 0.2 mmol), and triethylamine (0.803 mL, 5.76 mmol) in N,N-dimethylformamide (8.5 mL) was heated in an oil bath at 45° C. and stirring for 14 h. The reaction was quenched with water (20 ml) and was extracted with ethyl acetate (2×100 ml). The combined organic extracts were washed with water (10 ml), saturated NaCl (10 ml), dried over Na2SO4 and the solvent removed in vacuo. The product was purified by silica gel chromatography eluting with 10-20% EtOAc in hexanes to give the desired product (0.39 g, 76%). LCMS calculated for C12H15ClN3Si (M+H)+: m/z=264.1. Found: 264.0.
Reaction SMILES: ClC(OCCCC)=O.[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10]=1[CH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=1.[CH2:28]([N:30](CC)CC)C.Cl.CN>CN(C)C=O.O>[CH3:28][NH:30][C:23](=[O:25])[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:10]2[NH:9][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)=[CH:27][CH:26]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Agent: CCCCOC(=O)Cl
Agent: CN
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(Cc2nc3ccccc3[nH]2)cc1
Reaction time: 18 h
Yield: 37.7 %

Procedure:
2.8 ml of butyl chloroformate are added dropwise at -5° to a solution of 5.0 g (0.020 mol) of p-[(2-benzimidazolyl)methyl]benzoic acid and 2.8 ml (0.020 mol) of triethylamine in 68 ml of dimethylformamide. After stirring at 0°-5° for 30 minutes 1.32 g (0.020 mol) of methylamine hydrochloride and 2.8 ml (0.020 mol) of triethylamine in 28 ml of dimethylformamide and 1.4 ml of water are added. The temperature is then left to rise to room temperature and the mixture is stirred for a further 18 hours. After concentration under reduced pressure the residue is chromatographed on 400 g of silica gel with chloroform/ethanol (4:1) as the elution agent. The uniform fractions give 2.0 g (38%) of N-methyl-p-[(2-benzimidazolyl)methyl]benzamide, m.p. 250°-255° (dec.), as a colourless powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([NH2:16])=[N:6][CH:5]=1.N1C=CC=CC=1.[C:24](Cl)(=[O:26])[CH3:25]>ClCCl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]#[C:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[C:7]([NH:16][C:24](=[O:26])[CH3:25])=[N:6][CH:5]=1
Reactant: COC(=O)c1cnc(N)c(C#C[Si](C)(C)C)c1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cnc(NC(C)=O)c(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 6-amino-5-trimethylsilanylethynyl-nicotinic acid methyl ester (6.05 g, 24.4 mmol) and pyridine (4 mL, 49.4 mmol) in dichloromethane (80 mL) was added acetyl chloride (2.6 mL, 35.6 mmol) at 0° C. The mixture was allowed to warm up to 25° C. and stirred for 12 h. The reaction mixture was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to afford 6-acetylamino-5-trimethylsilanylethynyl nicotinic acid methyl ester which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:34])[CH2:14][N:15]([C@@H:26]([C:31](=[O:33])[NH2:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[S:16]([C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])(C)(C)C>C(Cl)Cl>[C:31]([C@H:26]([N:15]([CH2:14][C:13]([OH:34])=[O:12])[S:16]([C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)(=[O:17])=[O:18])[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:33])[NH2:32]
Reactant: CC(C)C[C@H](C(N)=O)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@H](C(N)=O)N(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (15 mL) was added to a solution of {N-[(1R)-1-carbamoyl-3-methyl-butyl]-N-(4-chlorobenzenesulfonyl)amino}acetic acid tert-butyl ester (0.50 g, 1.2 mmol) in CH2Cl2 (15 mL). The reaction was stirred at rt for 4 h. The reaction was then concentrated to a white solid (0.40 g, 92%), which was used without further purification. MS(ESI), (M+H)+363.1; 1H NMR (DMSO-d6, 500 MHz) δ7.90 (dd, 2H, J=2.0, 6.8), 7.65 (dd, 2H, J=2.0, 6.8), 7.60 (s, 1H), 7.06 (s, 1H), 4.32 (d, 1H, J=18), 4.12 (t, 1H, J=8.0), 4.02 (d, 1H, J =18), 1.55-1.65 (m, 1H), 1.35-1.45 (m, 2H), 0.78 (d, 3H, J=6.1), 0.73 (d, 3H, J =6.1).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:18]=[N:17][CH:16]=[CH:15][C:9]=3/[C:10](=[N:13]/[OH:14])/[C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:19]([OH:22])(=[O:21])C>C(OCC)(=O)C.O>[OH:14][N:13]1[C:10]2[C:9]3[CH:15]=[CH:16][N:17]=[CH:18][C:8]=3[NH:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:11]=2[N:13]=[C:10]1[C:9]1[CH:15]=[CH:16][N:17]=[CH:18][C:8]=1[NH:7][C:19](=[O:21])[O:22][C:5]([CH3:11])([CH3:6])[CH3:4]
Reactant: CC(=O)O
Reactant: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cnccc1-c1nc2c(n1O)-c1ccncc1Nc1ncccc1-2
Temperature: 80 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of (6Z)-5H-dipyrido[2,3-b:4′,3′-f]azepine-5,6(11H)-dione 6-oxime (80.0 mg, 0.333 mmol), tert-butyl-(4fprmylpyridin-3yl)carbamate lammonium acetate (0.513 g, 6.66 mmol), water (0.12 mL) and acetic acid (0.76 mL) was stirred at 80° C. for 3 h. The solution was diluted with ethyl acetate and water, the organic solution was washed with brine, dried over MgSO4 and concentrated. The crude residue was purified by preparative LCMS to yield the desired product (102 mg, 69%). LCMS for C23H22N7O3(M+H)+: m/z=444.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26]([OH:28])=O)=[CH:9]2.Cl.[CH3:30][O:31][C:32](=[O:56])[C@@H:33]([CH2:35][S:36][C:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH2:34].N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(N(CC)CC)C>[CH3:30][O:31][C:32](=[O:56])[C@@H:33]([CH2:35][S:36][C:37]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:34][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:28]
Reactant: COC(=O)[C@H](N)CSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)N[C@H](CSC(c3ccccc3)(c3ccccc3)c3ccccc3)C(=O)OC)cc2c1
Temperature: 25 °C
Reaction time: 64 h
Yield: 70.7 %

Procedure:
A mixture of 5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.45 g), S-trityl-D-cysteine methyl ester hydrochloride (0.46 g), 1H-1,2,3-benzotriazol-1-ol (0.26 g), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.32 g), triethylamine (0.19 mL) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 64 hr. The reaction mixture was concentrated, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio) to give the title compound (0.60 g, yield 72%) as a colorless amorphous solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[C:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]4[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C(Cl)Cc1ccc(Nc2ccccc2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2cc(Cc3ccc(Nc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 81.6 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenylamino-phenyl)-acetohydroximoyl chloride (150 mg, 0.576 mmol) described in Manufacturing Example 69-1-4 and 3-ethynyl-pyridin-2,6-diamine (48.9 mg, 0.367 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (201 μL, 1.44 mmol). This mixture was stirred for 6.5 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (107 mg, 52%).
Reaction SMILES: C(OC([N:8]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:12][CH:11]=1)[NH2:9])=O)(C)(C)C.O1CCOCC1.[ClH:27]>C(Cl)Cl>[ClH:27].[N:16]1([C:13]2[CH:14]=[CH:15][C:10]([NH:8][NH2:9])=[CH:11][CH:12]=2)[CH:17]=[CH:18][CH:19]=[CH:20]1
Reactant: CC(C)(C)OC(=O)N(N)c1ccc(-n2cccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NNc1ccc(-n2cccc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
Title compound 50A, N-(4-Pyrrol-1-yl-phenyl)-hydrazinecarboxylic acid tert-butyl ester (0.32 g, 1.0 eq, 1.2 mmol) was suspended in a mixture of 4M HCl in Dioxane (4.9 ml, 17.0 eq, 19.7 mmol) and DCM (5 ml). The mixture was then stirred at room temperature for 24 hr solvent was then removed in vacuo to yield the title compound as an off-white solid (0.25 g, 1.12 mmol, 95%). LCMS: [M+H]+=157/174, rt=0.98 min, 98% purity.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>O1CCCC1>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][C:19](=[O:22])[CH:20]=[CH2:21])[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1cccc2cccnc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cccc2cccnc12

Procedure:
A solution of 8-aminoquinoline (14.4 g, 0.1 mole) and triethylamine (15 ml, 0.11 mole) in dry tetrahydrofuran (50 ml) was treated dropwise at 0° (under a nitrogen atmosphere) with a solution of acryloyl chloride (8.5 ml, 0.1 mole) in tetrahydrofuran (25 ml). The reaction was filtered and the filtrate was partitioned between methylene chloride and water. The organic phase was separated, dried over sodium sulphate and concentrated to an oil. The oil was dissolved in ethyl acetate, treated with charcoal, filtered and again concentrated by vacuum distillation to an oil. Seed crystals were added and the oil cooled to -18°. The solid mass was stirred with petroleum ether and filtered affording 15.7 g of crude product of sufficient purity for further synthetic steps. Recrystallization from acetone/pentane afforded N-(8-quinolyl)-2-propenamide of analytical purity (m.p. 76.5°-78.5°).