Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1]/[C:2](/[C:6]1[CH:11]=[CH:10][N:9]=[C:8]([Cl:12])[CH:7]=1)=[CH:3]\[C:4]#[N:5].[C:13](O)(=O)[C:14](O)=O.C([NH:21]N)C.Cl>CO>[Cl:12][C:8]1[CH:7]=[C:6]([C:2]2[CH:3]=[C:4]([NH2:21])[N:5]([CH2:13][CH3:14])[N:1]=2)[CH:11]=[CH:10][N:9]=1
Reactant: CCNN
Reactant: N#C/C=C(\N)c1ccnc(Cl)c1
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: CO
Product: CCn1nc(-c2ccnc(Cl)c2)cc1N
Temperature: 80 °C
Reaction time: 2 h
Yield: 410.5 %

Procedure:
To a solution of (Z)-3-amino-3-(2-chloropyridin-4-yl)acrylonitrile 20.2.A (2590 mg, 14420 μmol), and ethylhydrazine oxalate (3220 mg, 2144 μmol) in MeOH (70 mL) was added 2N HCl (18 mL). The reaction was stirred at 80° C. for 2 hr, when LC/MS indicated the completion of the reaction (m/e: 223). The reaction was concentrated and worked up between saturated NaHCO3. and iPrOH/CHCl3. Silica gel chromatography afforded the desired product 20.2.B 1.96 g (61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@:6]1([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C@H:10]([OH:12])[C@@H:9]2[C@H:7]1[C@H:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2].N1C=CC=CC=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:3][C:4]([C@:6]1([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:11][C@H:10]([O:12][C:32](=[O:34])[CH3:33])[C@@H:9]2[C@H:7]1[C@H:8]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1[C@H]2[C@@H]1[C@](NC(=O)OC(C)(C)C)(C(=O)OCC)C[C@@H]2OC(C)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
To a solution of (1S,2S,4S,5R,6R)-2-(tert-butoxycarbonyl)amino-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (1.50 g, 4.20 mmol, U.S. Pat. No. 5,958,960), pyridine (0.365 mL, 4.62 mmol) and DMAP (0.513 g, 4.20 mmol) in dichloromethane (40 mL) under nitrogen add acetic anhydride (0.514 mL, 5.0 mmol). Stir at room temperature for 16 hours, dilute with dichloromethane, and pour into 10% aqueous citric acid solution (50 mL). Wash the organic layer with water (50 mL) and brine (50 mL). Dry over MgSO4, filter and concentrate in vacuo, to produce the title compound as a white solid (1.295 g, 75%).
Reaction SMILES: [CH3:1][C:2]([CH3:6])(O)[C:3]#[N:4].[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1N.[OH2:15]>>[CH3:1][C:2]1([CH3:6])[NH:7][CH:8]2[CH:13]([CH2:12][CH2:11][CH2:10][CH2:9]2)[NH:4][C:3]1=[O:15]
Reactant: N[C@@H]1CCCC[C@@H]1N
Reactant: CC(C)(O)C#N
Reactant: O
Product: CC1(C)NC2CCCCC2NC1=O
Temperature: 25 °C
Reaction time: 2000 h

Procedure:
3,3-dimethyl-decahydroquinoxalin-2-one is prepared as described by Bindler (U.S. Pat. No. 2,920,077) as follows: 17 parts of acetone cyanohydrin are added dropwise at room temperature to a solution of 22.8 parts of cis-1,2-diamino cyclohexane in 100 parts of water. The solution becomes cloudy and an oil is split off. After stirring for half an hour at room temperature, the dispersion is heated to 90°-95° and stirred for another 8 hours at room temperature while ammonia is evolved. The reaction solution is then evaporated to dryness under vacuum and a yellow residue is recrystallized from acetone. The compound melts at 165°-6° C. and is identified as 3,3-dimethyl-decahydroquinoxalin-2-one. 0.5 phr (parts per hundred parts resin) is blended into Hercules Profex 6501 polypropylene and extruded into film. The film is weathered in a Xenon Weather-O-Meter until initiation of decomposition which occurs at about 2000 hours (See Table I).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([NH:14][C@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[CH:11]=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32].O>C1COCC1>[C:17]1([C@@H:15]([NH:14][C:12]2[N:13]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:7][CH:6]=3)[CH:9]=[N:10][CH:11]=2)[CH3:16])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](Nc1cncc(-c2ccc(N)cc2)n1)c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](Nc1cncc(-c2ccc(NS(C)(=O)=O)cc2)n1)c1ccccc1
Temperature: 0 °C
Yield: 73.3 %

Procedure:
To a stirred solution of 6-(4-aminophenyl)-N-[(1S)-1-phenylethyl]pyrazin-2-amine (58 mg, 0.2 mmol) in dry THF (3 mL) was added triethylamine (70 μL, 0.5 mmol). The solutions was cooled to 0° C. and methanesulphonyl chloride (18.6 μL, 0.24 mmol) was added dropwise. The mixture was allowed to warm to RT and stirred overnight, before dilution with water (15 mL). The product was extracted into ethyl acetate (2×15 mL) and the combined extracts washed with 10% aqueous Na2CO3 and brine, and then dried (Na2SO4). The solvent was removed under reduced pressure and the product purified by chromatography eluting with ethyl acetate-hexane (3:2) to afford the product as a pale yellow solid (54 mg, 73%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([OH:25])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH2:30][CH:31]=[CH2:32].S(O)(C(F)(F)F)(=O)=O>C1CCCCC1.CCOCC>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:11]2[C@H:7]1[CH2:8][C@@H:9]([O:25][CH2:32][CH:31]=[CH2:30])[C@@:10]2([N:22]=[N+:23]=[N-:24])[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1[C@@H]2C[C@@H](O)[C@@](N=[N+]=[N-])(C(=O)OCc3ccccc3)[C@@H]21
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: CCOCC
Product: C=CCO[C@@H]1C[C@H]2[C@H](C(=O)OCC)[C@H]2[C@]1(N=[N+]=[N-])C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 13.9 %

Procedure:
To a solution of (1S,2R,3R,5R,6S)-2-azido-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (VII) (200 mg, 0.58 mmol) and allyl 2,2,2-trichloroacetimidate (0.18 mL, 1.16 mmol) in cyclohexane (0.7 mL) was added TfOH (29 □L), whereupon the solution became hot and stirring was continued at 23° C. for 1 h. The reaction mixture was poured on ice, diluted with ether, washed with sat. NaHCO3 -sol., brine and dried over MgSO4. The crude product was purified by silica gel column chromatography with hexane/EtOAc 4:1 to give (1S,2R,3R,5R,6S)-3-allyloxy-2-azido-bicyclo [3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester (XXIII-2) (31 mg, 14%) as a yellow oil. 1H-NMR (250 MHz, CDCl3) □1.26 (3H, t, J=7.1 Hz), 1.76 (1H, t, J=3.5 Hz), 2.03-2.26 (3H, m), 2.32 (1H, dd, J=12, 7 Hz), 3.58 (1H, dd, J=9, 7 Hz), 3.92 (1H, m), 4.02 (1H, m), 4.13 (2H, q, J=7.1 Hz), 5.10-5.22 (2H, m), 5.25 (1H, d,J=12 Hz), 5.34 (1H, d,J=12 Hz), 5.75 (1H, m), 7.30-7.42 (5H, m);MS[EI] 284 [(M-CO2Et-N2)+ ]; □D20 17.85° (c=0.50, CHCl3).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:29]([C:31]1([C:34](O)=[O:35])[CH2:33][CH2:32]1)#[N:30]>>[C:29]([C:31]1([C:34]([N:20]2[CH2:21][CH2:22][C:16]3[C:15]([N:23]4[CH2:24][CH2:25][O:26][CH2:27][CH2:28]4)=[N:14][C:13]([C:10]4[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=4)=[N:18][C:17]=3[CH2:19]2)=[O:35])[CH2:33][CH2:32]1)#[N:30]
Reactant: N#CC1(C(=O)O)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(=O)C2(C#N)CC2)C3)cc1

Procedure:
Compound fe was prepared according to the procedure described in Example 213 by reacting 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 1-cyanocyclopropanecarboxylic acid. LC-MS: m/z=+476 (M+H)−.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]([CH2:14][CH3:15])[C:4]=1[C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](O)=[O:23])=[CH:18][CH:17]=1)#[N:2].C(Cl)Cl.[C:30](Cl)(=[O:34])[C:31](Cl)=O.[CH3:36][N:37](C=O)[CH3:38]>>[CH2:14]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)[C:3]([C:1]#[N:2])=[C:4]1[C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([N:37]2[CH2:38][CH2:31][CH:30]([OH:34])[CH2:36]2)=[O:23])=[CH:25][CH:26]=1)[CH3:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCn1c(-c2ccc(OCC(=O)O)cc2)c(C#N)c2ccc(OC)cc21
Reactant: CN(C)C=O
Solvent: ClCCl
Product: CCn1c(-c2ccc(OCC(=O)N3CCC(O)C3)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
[4-(3-Cyano-1-ethyl-6-methoxy-1H-indol-2-yl)-phenoxy]-acetic acid (40 mg, 0.12 mmol) was suspended in CH2Cl2 (1.65 mmol) and DMF (2 μL). Oxalyl chloride (17 μL, 0.19 mmol) was added. This was stirred at room temperature for 30 minutes. The resulting solution was then pipetted into a stirring solution of S-3-hydroxypyrrolidine (150 μL) and CH2Cl2 (3.0 mL). The mixture was washed with aqueous HCl. The organic layer was dried and concentrated. Purification by silica gel chromatography (3/2 CH2Cl2/acetone) yielded 1-ethyl-2-{4-[2-(3-hydroxy-pyrrolidin-1-yl)-2-oxo-ethoxy]-phenyl}-6-methoxy-1H-indole-3-carbonitrile (40 mg, 79%), compound 285 as a white solid.
Reaction SMILES: Br[C:2]1[N:19]([CH2:20][C@H:21]2[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]2)[C:5]2[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=3)=[N:7][C:8]([C:10]#[N:11])=[CH:9][C:4]=2[N:3]=1.[CH3:28][CH:29]([C@H:31]1[NH:35][CH2:34][C@H:33]([OH:36])[CH2:32]1)[CH3:30].[F-].[K+].C(N(CC)C(C)C)(C)C>C(OCC)(=O)C.CS(C)=O>[Cl:18][C:16]1[CH:17]=[C:12]([C:6]2[C:5]3[N:19]([CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)[C:2]([N:35]4[CH2:34][C@H:33]([OH:36])[CH2:32][C@H:31]4[CH:29]([CH3:30])[CH3:28])=[N:3][C:4]=3[CH:9]=[C:8]([C:10]#[N:11])[N:7]=2)[CH:13]=[N:14][CH:15]=1
Reactant: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Reactant: CC(C)[C@@H]1C[C@@H](O)CN1
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H]1C[C@@H](O)CN1c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 100 °C

Procedure:
To a vial was added 2-bromo-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (150 mg, 0.337 mmol), (3R,5S)-5-(propan-2-yl)pyrrolidin-3-ol(TFA salt, 164 mg, 0.675 mmol), potassium fluoride (98 mg, 1.68 mmol), DMSO (1 mL), and N,N-diisopropylethylamine (0.589 mL, 3.37 mmol). The vial was sealed and heated to 100° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water and then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford 4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-hydroxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ESI calc'd. for C27H33ClN6O [M+H]+ 493. found 493.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=O)[CH:5]=[CH:6][CH:7]=1.B.CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:24]2([OH:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:9][N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2cccc(Br)c2)C2(O)CCCCC2)CC1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(Br)c2)C2(O)CCCCC2)CC1
Temperature: 70 °C
Yield: 98.2 %

Procedure:
A solution of tert-butyl 4-[(3-bromophenyl)(1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate (2.12 g, 4.40 mmol) in dry tetrahydrofuran (10 mL) under nitrogen was treated dropwise with a solution of borane (1.0 M in tetrahydrofuran, 13.2 mL, 13.2 mmol). The resulting solution was heated at 70° C. for 2 h, after which time the reaction was cooled in an ice bath, treated dropwise with methanol (15 mL) and concentrated. The resulting viscous, colorless oil was re-dissolved in ethyl acetate (25 mL), washed with a saturated aqueous solution of sodium bicarbonate, water, brine, dried over sodium sulfate, filtered, and concentrated to give a white solid, which was purified via flash column chromatography (silica, gradient from 10% ethyl acetate/hexane to 20% ethyl acetate/hexane) to yield 2.02 g (98%) tert-butyl 4-[2-(3-bromophenyl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate as a white powder. MS (ESI) m/z 467/469 ([M+H]+); HRMS: calcd for C23H35BrN2O3, 466.1831; found (ESI), 467.1899; Anal. Calcd for C23H35BrN2O3: C, 59.10; H, 7.55; N, 5.99. Found: C, 59.14; H, 7.72; N, 5.77.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([O:36][CH3:37])[CH2:5][C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.[Li+].[OH-]>C1COCC1.CO>[CH3:37][O:36][CH:4]([CH2:5][C:6]1[CH:15]=[C:14]([O:16][CH2:17][CH2:18][C:19]2[C:20]([CH3:35])=[N:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:34])[F:33])=[CH:27][CH:26]=3)=[CH:23][CH:24]=2)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)[C:3]([OH:38])=[O:2]
Reactant: COC(=O)C(Cc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc2c1)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(Cc1cc(OCCc2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)c2ccccc2c1)C(=O)O
Reaction time: 1 h

Procedure:
0.43 g (0.82 mmol) of the above prepared [rac]-2-methoxy-3-(4-{2-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethoxy}-naphthalen-2-yl)-propionic acid methyl ester was dissolved in 15 ml of THF/MeOH (2:1); to the stirred solution was then added 1.64 ml of LiOH-solution (1 molar in water). After one hour, the reaction mixture was poured onto crashed ice/HCl and extracted twice with CH2Cl2; the organic layers were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by chromatography [SiO2, CH2Cl2/MeOH (0 to 5% MeOH)] to give 0.42 g of pure title compound as light yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:34][CH2:33]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:30][CH2:31][CH:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][CH2:41][C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)=[O:39])[CH2:34][CH2:33]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2]
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OCc5ccccc5)CC4)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a suspension of 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (2 g, 6.53 mmol, INTERMEDIATE 2) in dichloromethane (25 ml) were added oxalyl chloride (9.79 ml, 19.59 mmol) and a drop (ca. 10 μl) of dimethylformamide. The mixture was stirred for 1 h at 25° C., at which point a clear solution formed. The mixture was concentrated and then co-concentrated with 5 ml of toluene. To a solution of the residue in dichloromethane (25 ml) was added 4-aminomethyl-1-N-Cbz-piperidine (2 g, 8.05 mmol) and diisopropylethylamine (1.711 ml, 9.79 mmol). The mixture was stirred overnight at 25° C. and then concentrated. The residue was purified by flash chromatography on a Biotage Horizon, 65i column, eluting with 1 column volume of 10% ethyl acetate in hexanes followed by a gradient of 10 to 100% ethyl acetate in hexanes over 10 column volumes to provide the title compound (2.53 g, 72.2%). Mass spectrum (ESI) 537.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.29 (m, 2H), 7.94 (d, J=8.5 Hz 2H), 7.90 (m, 1H), 7.49 (s, 1H), 7.27-7.35 (m, 4H), 6.69 (m, 1H), 5.11 (s, 2H), 4.09-4.30 (m, 2H), 3.31-3.49 (m, 3H), 2.79 (m, 2H), 1.86 (m, 1H), 1.77 (m, 2H), 1.45 (d, J=6.5 Hz, 6H), 1.18-1.30 (m, 2H).
Reaction SMILES: C(O)(=O)C[SH:3].[H-].[Na+].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]#[N:16])[N:10]=1.Cl.[C:18]([O:21]CC)(=O)[CH3:19]>CN(C=O)C>[C:15]([C:11]1[N:10]=[C:9]([CH2:19][C:18]([OH:21])=[S:3])[CH:14]=[CH:13][CH:12]=1)#[N:16]
Reactant: O=C(O)CS
Reactant: CCOC(C)=O
Reactant: N#Cc1cccc(Cl)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(CC(O)=S)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
A mixture of thioglycolic acid (6.91 g, 75.0 mmol), sodium hydride (60% in oil, 6.00 g, 150.0 mmol) and DMF (100 ml) was stirred at room temperature for 1 hr. 2-Chloro-6-cyanopyridine (7.00 g, 50.0 mmol) was added thereto, and the mixture was stirred at room temperature for 18 hrs. The reaction mixture was combined with ethyl acetate and 10% hydrochloric acid. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (4.56 g, 47%) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:22]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:32])[CH3:31]>ClCCl>[C:30]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:21])[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:22]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: Nc1ccc2snc(NCCNC(=O)c3ccccn3)c2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc2snc(NCCNC(=O)c3ccccn3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-(2-(5-Aminobenzo[d]isothiazol-3-ylamino)ethyl)picolinamide (95 mg, 0.30 mmol) was dissolved in anhydrous dichloromethane (5 mL) with triethylamine (50 μL, 0.36 mmol). The solution was cooled on an ice-water bath and a solution of acetyl chloride (26 μL, 0.36 mmol) in dichloromethane (0.5 mL) was added dropwise. The reaction mixture was allowed to stir for 2.5 h while warming to room temperature. The solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, then dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to yield N-(2-(5-acetamidobenzo[d]isothiazol-3-ylamino)ethyl) picolinamide as a white solid. 1H NMR (300 MHz, CDCl3): 8.48 (d, 1H), 8.30 (s, 1H), 8.20 (d, 1H), 7.80 (t, 1H), 7.52 (s, 1H), 7.42 (m, 1H), 7.31 (d, 1H), 7.18 (s, 1H), 6.82 (d, 1H), 3.70 (m, 2H), 3.50 (m, 2H), 2.20 ppm (s, 3H). MW=355 confirmed by LC-MS, tr=9.35 min (Method Y) MH+=356.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:8]=1[C:9]([N:11]1[CH:16]=[CH:15][C:14](=[O:17])[CH2:13][CH2:12]1)=[O:10]>C1COCC1>[CH3:23][O:22][C:19]1[CH:18]=[C:8]2[C:7](=[CH:21][CH:20]=1)[CH:12]1[CH2:13][C:14](=[O:17])[CH2:15][CH2:16][N:11]1[C:9]2=[O:10]
Reactant: COc1ccc(Br)c(C(=O)N2C=CC(=O)CC2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)N1CCC(=O)CC21
Reaction time: 2 h
Yield: 43.2 %

Procedure:
Butyl lithium (3.1 ml, 0.9 M in hexanes, 2.8 mmol) was added dropwise to a solution of 1-(2-bromo-5-methoxybenzoyl)-2,3-dihydro-4-pyridinone (0.75 g, 2.4 mmol) in THF (20 ml) at -78° C. After stirring for 2 h, the reaction was quenched with water, extracted with ethyl acetate, the extract dried over magnesium sulphate and evaporated. The residue was purified by flash column chromatography on silica eluting with 50% ethyl acetate in hexane to yield the title compound as a colourless oil (240 mg). MS (+EI) m /z 231 [M+ ].
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:19])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.[N:20]([O-])=O.[Na+].[CH3:24][C:25]1([CH3:41])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N:34]3[C:38](=[O:39])[CH2:37][C:36]([CH3:40])=[N:35]3)[CH:32]=2)[CH2:27][CH2:26]1.C(=O)(O)[O-].[Na+]>Cl>[CH3:24][C:25]1([CH3:41])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N:34]3[C:38](=[O:39])[C:37](=[N:20][NH:2][C:3]4[C:4]([OH:19])=[C:5]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=5)[CH:6]=[C:7]([CH3:9])[CH:8]=4)[C:36]([CH3:40])=[N:35]3)[CH:32]=2)[CH2:27][CH2:26]1
Reactant: CC1=NN(c2ccc3c(c2)C(C)(C)CC3)C(=O)C1
Reactant: Cc1cc(N)c(O)c(-c2cccc(C(=O)O)c2)c1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=NN(c2ccc3c(c2)C(C)(C)CC3)C(=O)C1=NNc1cc(C)cc(-c2cccc(C(=O)O)c2)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.8 %

Procedure:
3′-Amino-2′-hydroxy-5′-methyl-biphenyl-3-carboxylic acid hydrochloride 11f (257 mg, 0.92 mmol) was dissolved in 3.1 mL of hydrochloric acid (1 N) upon cooling by an ice-water bath, followed by dropwise addition of 1.2 mL of aqueous sodium nitrite (70 mg, 1.01 mmol). After the mixture was stirred for 20 minutes, 2-(3,3-dimethyl-indan-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 8i (200 mg, 0.83 mmol) was added. The mixture was adjusted to pH 8˜9 by batch addition of aqueous sodium bicarbonate (1.157 g, 13.8 mmol). The generated bubbles were quenched with 2 mL of ethanol. The reaction mixture was warmed up to room temperature and reacted overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was dissolved in 30 mL of water. After mixing well, the mixture was adjusted to pH 3˜4 with concentrated hydrochloric acid, filtered and dried. The crude product was purified by HPLC to obtain the title compound 3′-{N′-[1-(3,3-dimethyl-indan-5-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-2′-hydroxy-5′-methyl-biphenyl-3-carboxylic acid 16 (160 mg, yield 39.0%) as an orange solid.
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]([C:19]([O:21][CH3:22])=[O:20])=[C:11]([CH2:23][CH3:24])[N:10]=1)C1C=CC=CC=1.C1COCC1.[H][H]>[C].[Pd].C(O)C>[CH2:23]([C:11]1[C:12]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:9]([OH:8])[N:10]=1)[CH3:24]
Reactant: [H][H]
Reactant: CCc1nc(OCc2ccccc2)c(C(=O)OC)cc1C(=O)OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1nc(O)c(C(=O)OC)cc1C(=O)OC
Yield: 72.6 %

Procedure:
A mixture of dimethyl 2-(benzyloxy)-6-ethylpyridine-3,5-dicarboxylate (2.37 g), 10% palladium carbon (containing 55% water, 2.00 g), THF (20 mL), and ethanol (20 mL) was stirred at room temperature for 1 hour in a hydrogen atmosphere. The catalyst was filtered off, and then, the obtained filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl acetate to obtain the title compound (1.25 g).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.N1C=CC=CC=1.[C:15](Cl)(=[O:18])[CH2:16][CH3:17].O>C(#N)C>[C:15]([N:2]1[C:3](=[O:8])[CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)(=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: O=C1NC2C=CC1C2
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: CCC(=O)N1C(=O)C2C=CC1C2
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.4 %

Procedure:
47 g of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one were dissolved in acetonitrile (325 ml) and pyridine (41 ml) under nitrogen. At 12° C., 43.9 g of propionyl chloride were added dropwise over the course of 1 h. The reaction was then stirred at room temperature for 5 h. 145 ml of water were added to the mixture, and the acetonitrile was evaporated off in vacuo. The aqueous phase was extracted 3 times with 115 ml of ethyl acetate. The combined organic phases were washed with 1N HCl (140 ml), saturated NaHCO3 (40 ml) and NaCl (40 ml) solutions, dried with sodium sulphate and completely evaporated. The residue was purified by distillation. 55.8 g of title compound were obtained and solidified on leaving to stand. The yield was 81.6%.