Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1.[OH-].[K+].CN(C)[CH:20]=[O:21]>O>[CH3:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH:20]=[O:21])=[CH:12][NH:13]2)=[CH:9][CH:8]=1
Reactant: Cc1ccc2cc[nH]c2c1
Reactant: CN(C)C=O
Agent: [K+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A 12-l. three-necked flask, equipped with a mechanical stirrer, a thermometer and a dropping funnel provided with a Drierite drying tube was charged with 610 ml (7.9 moles) of N,N-dimethylformamide. The flask was immersed in an ice bath and 217 g (1.42 moles) of phosphorus oxychloride was added at 5°-10° with stirring over 1 hour. The dropping funnel was rinsed with 20 ml of dimethylformamide and the light pink orange oil was stirred for further 10 minutes in the ice bath. Then a solution of 156 g (1.19 moles) of 6-methylindole in 156 ml of dimethylformamide was added at 5°-10° C. over a period of 1 hour. The ice bath was removed and the red orange solution was stirred for an additional hour, while the flask content warmed up to room temperature. At the end of the reaction period, 1.17 kg of crushed ice was added. The temperature fell to -10° and after a short time a light yellow slurry was formed. The reaction mixture was stirred for 1 hour, as the temperature came to 15°. Then a solution of 840 g (13.0 moles) of potassium hydroxide pellets (87% assay) in 2 l of water was added over 30 minutes, during which time the pot temperature rose to 50°. After the addition was complete, the dropping funnel was replaced by a reflux condenser and the orange solution was heated rapidly with stirring on a steam bath to 93° and kept at this temperature for 30 minutes. The mixture was allowed to stand at room temperature overnight. The precipitate was collected by suction filtration, washed with water and dried at 60° (constant weight) to give 186.5 g (98%) of product as orange crystals, m.p. 183°-186°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[S:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1>>[S:19]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)=[CH:20]1
Reactant: OB(O)c1ccsc1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Product: c1cc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cs1

Procedure:
The title compound was prepared from the product of Example 65A and thien-3-ylboronic acid according to General Method B: LC-MS Method D (ESI+) m/z 312.0 (M+H)+, retention time 1.25 minutes.
Reaction SMILES: [F:1][CH2:2][CH:3]([C:5]1[C:6]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)[OH:4].[C:19](OC(=O)C)(=[O:21])[CH3:20].O.OS(O)(=O)=O>C1COCC1>[C:19]([O:4][CH:3]([C:5]1[C:6]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:8]=[CH:9][CH:10]=1)[CH2:2][F:1])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: OC(CF)c1cccnc1SCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)OC(CF)c1cccnc1SCc1ccccc1
Yield: 92.7 %

Procedure:
A solution of 3-(2-fluoro-1-hydroxyethyl)-2-(phenylmethylthio)pyridine (16 g) in dry THF and acetic anhydride (7.4 g) is stirred with a catality amount of4-dimethylaminopyridine at room temperature for 12 hours. The reaction mixture is then poured into water and neutralized with dilute H2SO4. The mixture is extracted three times with methylene chloride, the combined extracts are dried (MgSO4), evaporated to obtain the desired product (oil, 17.2 g, Yield: 93%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:14][C@@H:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]1[NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: [H][H]
Reactant: C[C@@H]1CCN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1CCNC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.5 %

Procedure:
A mixture of tert-butyl trans-1-benzyl-4-methylpiperidin-3-ylcarbamate (0.64 g, 2.1 mmol) and 10% Pd/C (0.22 g, 0.21 mmol) in methanol (10 mL) was charged with 1 atmosphere hydrogen and stirred at room temperature for 18 hours. The catalyst was removed by filtration and washed with methanol (20 mL). The filtrate was concentrated in vacuo to give tert-butyl trans-4-methylpiperidin-3-ylcarbamate (0.43 g, 95%) as a solid.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[Cl:9][C:10]1[CH:11]=[C:12]([CH:17]2[CH2:21][NH:20][CH2:19][CH:18]2[N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:13]=[CH:14][C:15]=1[Cl:16].C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([N:20]1[CH2:19][CH:18]([N:22]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:32])[F:33])=[C:27]([F:35])[CH:26]=2)[CH3:23])[CH:17]([C:12]2[CH:13]=[CH:14][C:15]([Cl:16])=[C:10]([Cl:9])[CH:11]=2)[CH2:21]1)=[O:7]
Reactant: O=C(Cl)CCCCBr
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)CCCCBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 83.4 %

Procedure:
To a stirred solution of 5-bromo-pentanoyl chloride (0.167 ml, 1.25 mmol) in THF (10 ml) at RT was added over 1 hour a solution of [(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (Intermediate VIII-1, 0.50 g, 1.19 mmol) and triethyl amine (0.18 ml, 1.30 mmol) in THF (5 mL). The reaction was stirred over night, quenched by addition of an aqueous solution of NaHCO3, and the product extracted with EtOAC. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 0.58 g (83%) of the title compound as a white solid. ES-MS m/e: 584.4 (M+H+).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[F:17][C:18]1[CH:19]=C([Mg]Br)[CH:21]=[CH:22][CH:23]=1.[Cl-].[NH4+].O>C1COCC1>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: Fc1cccc([Mg]Br)c1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1cccc(F)c1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 12 (23.45 g, 104 mmole) in absolute THF (100 ml) was added dropwise to a 1M solution of 3-fluorophenyl magnesium bromide in THF (208 ml, 208 mmole) under argon and while cooling with ice, and stirred for 20 hours at RT. To work up the reaction mixture saturated ammonium chloride solution (100 ml) and water (100 ml) were added while cooling with ice and the mixture was extracted with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated by evaporation.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[N:5]([CH3:13])[C:3]1=[O:4].C(=O)([O-])[O-].[K+].[K+].[O:20]([C:28]1[CH:43]=[CH:42][C:31]([C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=2)=[O:33])=[CH:30][CH:29]=1)[Si](C(C)(C)C)(C)C>CN(C=O)C.O>[OH:20][C:28]1[CH:29]=[CH:30][C:31]([C:32]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38][N:9]3[C:10]4[C:11](=[O:12])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:13])[C:6]=4[N:7]=[CH:8]3)=[CH:36][CH:35]=2)=[O:33])=[CH:42][CH:43]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(O)cc3)cc2)n(C)c1=O
Yield: 109.7 %

Procedure:
A solution of 1,3-dimethylxanthine (742 mg), potassium carbonate (569 mg) and 4-(4-t-butyldimethylsiloxybenzoyl)benzyl bromide (2292 mg) in DMF (10 ml) was stirred at 60° C. for 5 hours. This reaction mixture was poured in water and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =1:3) and recrystallized from chloroform-isopropyl ether to provide the title compound as colorless solid (1763 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][NH:10][CH:11]1[CH2:27][CH2:26][C:14]2([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH2:15]2)[CH2:13][CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:10]([CH3:9])[CH:11]2[CH2:27][CH2:26][C:14]3([CH2:18][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: CNC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Reactant: Clc1ccnc(Cl)n1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN(c1ccnc(Cl)n1)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To a solution of 2,4-dichloropyrimidine (596 mg, 4.0 mmol) and tert-butyl 8-(methylamino)-2-azaspiro[4.5]decane-2-carboxylate (1.29 g, 4.8 mmol) in EtOH (10 mL) was added Et3N (0.92 g, 9.1 mmol) and the reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/2) to give the product as a pale yellow solid (580 mg, 38.1%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH2:41])=[CH:30][CH:29]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C([O-])=O.[CH2:52]([N:55]=[C:56]=[O:57])[CH2:53][CH3:54]>>[CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:44])([CH3:43])[C:13]([NH:15][C@@H:16]1[CH2:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[CH2:40][NH:41][C:56]([NH:55][CH2:52][CH2:53][CH3:54])=[O:57])=[CH:32][CH:33]=2)[C:17]1=[O:42])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3CN)cc2)C1=O
Reactant: CCCN=C=O
Agent: O=C([O-])C(F)(F)F
Product: CCCNC(=O)NCc1ccccc1-c1ccc(CN2C(=O)[C@H](NC(=O)C(C)(C)NC(=O)OCc3ccccc3)CCc3ccccc32)cc1

Procedure:
Prepared from 2-benzyloxycarbonylamino-2-methyl- N-[2,3,4,5-tetrahydro-2-oxo-1-[[2'-(aminomethyl) [1,1'-biphenyl]-4-yl]methyl]-1H-benzazepin-3(R)-yl]propanamide, trifluoroacetate (Example 36, Step A) and 1-propyl isocyanate according to the procedure described in Example 37, Step A. 1H NMR (200 MHz, CD3OD): δ 0.86 (t, 7.5 Hz, 3H), 1.39 (s, 6H), 1.42 (m, 2H), 1.82 (m, 1H), 2.19-2.55 (m, 3H), 3.01 (t, 7 Hz, 2H), 4.12 (s, 2H), 4.32 (m, 1H), 4.85 (d, 15 Hz, 1H), 5.00 (s, 2H), 5.31 (d, 15 Hz, 1H), 7.08-7.40 (m, 17H), 7.63 (d, 8 Hz, 1H). FAB-MS: calculated for C40H45 N5O5 675; found 676 (M+H, 85%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][CH2:11][NH2:12])[CH:6]=[CH:7][CH:8]=1.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][CH2:10][CH2:11][NH:12][C:14](=[O:15])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(SCCN)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cccc(SCCNC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of compound 20 (1.0 g) in EtOAc (50 mL) cooled to ˜0° C. was added benzyl chloroformate (1.1 eq.) and triethylamine (1.2 eq.). The reaction mixture was stirred for 4 hours at r.t. and washed with 1N HCl, and sat. NaHCO3 (2×10 mL). The solvents were removed by evaporation under reduced pressure to give crude title product. Purification by chromatography gave 21 as white solid. Yield: 1.61 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([NH:26][C:27]([C:29]2[N:33]3[C@@:34]([CH2:47][C:48]4[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=4)([CH3:46])[C:35](=[O:45])[N:36]([C:37]4[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=4)[C:32]3=[N:31][CH:30]=2)=[O:28])([C:14](=[O:25])[NH:15][C:16]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:18][CH2:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1([NH:15][C:14]([C:11]2([NH:26][C:27]([C:29]3[N:33]4[C@@:34]([CH2:47][C:48]5[CH:53]=[CH:52][C:51]([C:54]#[N:55])=[CH:50][CH:49]=5)([CH3:46])[C:35](=[O:45])[N:36]([C:37]5[CH:42]=[C:41]([Cl:43])[CH:40]=[C:39]([Cl:44])[CH:38]=5)[C:32]4=[N:31][CH:30]=3)=[O:28])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:25])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)cc(Cl)c2)(C(=O)NC2(c3ccccn3)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)cc(Cl)c2)c2ncc(C(=O)NC3(C(=O)NC4(c5ccccn5)CC4)CCNCC3)n21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To a solution of 4-{[(R)-5-(4-cyanobenzyl)-7-(3,5-dichlorophenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carbonyl]-amino}-4-(1-pyridin-2-yl-cyclopropyl-carbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (140 mg, 0.18 mmol) in CH2Cl2 (0.5 mL) was added TFA (0.5 mL) and stirred at room temperature for 1 h. The solvent was removed in vacuo to afford (R)-5-(4-cyanobenzyl)-7-(3,5-dichlorophenyl)-5-methyl-6-oxo-6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid [4-(1-pyridin-2-yl-cyclopropylcarbamoyl)-piperidin-4-yl]-amide as a white solid (120 mg), m/z 683.8 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:12]/[CH:13]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([O:16][C:15](=[O:17])/[CH:14]=[CH:13]/[CH:12]=[C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[CH:33][CH:32]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=C/C=C/C(=O)O)c2ccc(OC)c(OC)c2)cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)c(OC)c2)cc1OC
Temperature: 0.5 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
As in Example 115, (E)-5,5-bis (3,4-dimethoxyphenyl)-2,4-pentadienoic acid (16 g) and 4-nitrophenol (6.6 g) in dichloromethane (160 mL) was treated with 1,3-dicyclohexylcarbodiimide (9.3 g). The mixture was stirred at 0.5° C. for 1 hour, then at room temperature for 18 hours. After the usual work up, the crude product was triturated with ether to give 13.2 g of (E)-5,5-bis (3,4-dimethoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester. Crystallization of a portion from ether afforded the analytical sample, mp 140°-142° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH2:29][CH3:30])=[CH:19][C:20]([CH2:27][CH3:28])=[C:21]([CH:26]=3)[C:22]([NH:24][NH2:25])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].O.C(=O)(O)[O-].[Na+].Br[C:38]#[N:39]>O1CCOCC1>[NH2:39][C:38]1[O:23][C:22]([C:21]2[C:20]([CH2:27][CH3:28])=[CH:19][C:18]([CH2:29][CH3:30])=[C:17]([CH:26]=2)[C:15]([N:12]2[CH2:13][CH2:14][CH:9]([C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[CH2:10][CH2:11]2)=[O:16])=[N:24][N:25]=1
Reactant: N#CBr
Reactant: CCc1cc(CC)c(C(=O)N2CCC(c3ccc(C#N)cc3)CC2)cc1C(=O)NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cc(CC)c(-c2nnc(N)o2)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reaction time: 0.08 h
Yield: 105.8 %

Procedure:
To a round-bottom flask was added a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2,4-diethylbenzohydrazide (compound 204.7, 100 mg, 0.220 mmol, 1.00 equiv, 90%) in a solvent mixture of water (2 mL) and dioxane (3 mL). Sodium bicarbonate (62 mg, 0.740 mmol, 3.00 equiv) was added to the reaction mixture at room temperature, and stirred for 5 minutes. BrCN (75 mg, 0.740 mmol, 3.00 equiv) was then added to the reaction at room temperature. The resulting solution was stirred for 2 h at room temperature, then quenched with 30 mL of FeSO4 (aq., sat.) and diluted with ethyl acetate. The resulting mixture was stirred vigorously then filtered through celite and washed with 1 M FeSO4, water, and ethyl acetate. The layers were separated and the aqueous phase was extracted with 2×50 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. This resulted in 100 mg (89%) of the title compound as a yellow solid. The compound was used in the next step reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:27][OH:28])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:29](Cl)(=[O:31])[CH3:30]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1[NH:3][C:4]([CH2:27][O:28][C:29](=[O:31])[CH3:30])=[C:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(COC(C)=O)=C(C(=O)OCC)C1c1ccccc1[N+](=O)[O-]
Yield: 68.4 %

Procedure:
To a mixture of diethyl 2-methyl-4-(2-nitrophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (2.35 g) in pyridine (30 ml), as dropwise added a solution of acetyl chloride (942 mg) in methylene chloride (5 ml) under stirring and ice-cooling over the period of 7 minutes. The mixture was further stirred for 70 minutes at room temperature. The pyridine was distilled off under reduced pressure and ethyl acetate was added to the residue. The resultant mixture was washed twice with water and adjusted to pH 4 with hydrochloric acid and then an aqueous solution of sodium chloride, dried and concentrated under reduced pressure to give an oily substance. This oily substance was crystallized by treating with a mixture of diethyl ether and a small amount of n-hexane, and collected crude crystals (2.5 g) were washed with n-hexane and thus obtained crystals were recrystallized from diethyl ether to give pure crystals (1.78 g) of diethyl 2-methyl-4-(2-nitrophenyl)-6-acetoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 89° to 90° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[C:9]1=[O:18])[CH2:15]2)([CH3:4])([CH3:3])[CH3:2].[Li][CH3:21]>C1COCC1>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[C:9]1([OH:18])[CH3:21])[CH2:15]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: [Li]C
Reactant: CC(C)(C)OC(=O)NC12CC3CC(CC(C3)C1=O)C2
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC12CC3CC(CC(C3)C1(C)O)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
At −78° C., to a solution of ketone 20C (500 mg, 1.9 mmol) in 20 mL of THF was added MeLi (1.6 M in ether, 5 mL, 8.0 mmol) dropwise. The mixture was stirred at −78° C. for 30 minutes before it was quenched by 5 mL of NH4Cl aq (Sat'd) solution. The mixture was extracted by DCM (5 mL×3) and the combined DCM layers were dried over Na2SO4. Solvent was remove under vacuum and the residue was purified by silica gel chromatography Hexane:EtOAc 1:1(v/v)) to give the title compounds 20D (410 mg, 77%) as a mixture of equatorial and axial isomers. LC-MS (ESR): m/z=282 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([C:24]([F:27])([F:26])[F:25])=[CH:18][C:19](=[O:23])[O:20]2)=[CH:15][CH:14]=1.Cl>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[F:27][C:24]([F:25])([F:26])[C:17]1[C:16]2[C:21](=[CH:22][C:13]([NH:12][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)(=[O:10])=[O:9])=[CH:14][CH:15]=2)[O:20][C:19](=[O:23])[CH:18]=1
Reactant: Nc1ccc2c(C(F)(F)F)cc(=O)oc2c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1cc(C(F)(F)F)c2ccc(NS(=O)(=O)c3ccc(Cl)cc3)cc2o1
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 72 %

Procedure:
203 mg (0.96 mmol) of 4-chlorobenzenesulfonyl chloride was added to a pyridine solution (3 ml) containing 200 mg (0.87 mmol) of 7-amino-4-trifluoromethylcumarin and 1 mg of 4-dimethylaminopyridine, followed by stirring at 70° C. for 50 minutes. An aqueous 2 N hydrochloric acid was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated. The resulting residue was crystallized from ethyl acetate-diisopropyl ether, to give 253 mg of the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:21](O)=[O:22])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)=[O:8].CN.O.O[N:30]1[C:34]2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:21]([NH:30][CH3:34])=[O:22])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)=[O:8]
Reactant: O=C(Nc1nc(-c2ccccc2)c(C(=O)O)s1)c1cc(Br)ccc1O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.4 %

Procedure:
A mixture of 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid (0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2 ml), 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC.HCl (137.2 mg, 0.72 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2), and crystallized (dichloromethane/n-hexane) to give the title compound (87.9 mg, 42.6%) as a white powder.
Reaction SMILES: [Br:1][C:2]1([Br:12])[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[Br:13]Br.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.O>[Br:12][C:2]1([Br:1])[C:10]2[C:5](=[N:6][CH:7]=[C:8]([Br:13])[CH:9]=2)[NH:4][C:3]1=[O:11]
Reactant: O=C1Nc2ncccc2C1(Br)Br
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1Nc2ncc(Br)cc2C1(Br)Br

Procedure:
A solution of 3,3-dibromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (5.0 g, 13.4 mmol) in tert-BuOH (100 mL) and water (100 mL) was stirred at room temperature and bromine (5.5 g, 34.3 mmol) was added dropwise over 20 min. A saturated aqueous solution of sodium bicarbonate (approx. 15 mL) was added dropwise over 30 min to raise the pH of the solution to 6.5. The yellow solid formed was collected by filtration. The filtrate was condensed to approx. 100 mL and extracted with CHCl3 (2×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to leave a yellow solid. The solids were combined and dried under vacuum to give 3,3,5-tribromo-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one as a yellow solid, 6.25 g (98%). 1H NMR (CDCl3) δ 9.4 (br s, 1 H), 8.28 (d, 1H, J=2 Hz), 7.95 (d, 1H, J=2 Hz).