Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:35])[CH2:5][CH2:6][CH2:7][N:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([C:11]1([CH3:26])[CH2:14][CH2:13][N:12]1[C:15](=[O:25])[CH2:16][C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[O:10])C.[NH3:36]>CO>[C:4]([CH2:5][CH2:6][CH2:7][N:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([C:11]1([CH3:26])[CH2:14][CH2:13][N:12]1[C:15](=[O:25])[CH2:16][C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[O:10])(=[O:35])[NH2:36]
Reactant: N
Reactant: CCOC(=O)CCCN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Solvent: CO
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CCCC(N)=O)Cc2ccc(Cl)cc2)c1
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of 4-((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-butyric acid ethyl ester, Intermediate 146 (1 eq.) in MeOH was added an aqueous solution of NH3 (20% in water). The reaction was stirred at 60° C. for 15 h then cooled to 20° C. The solvents were evaporated under reduced pressure and the crude was purified by preparative LCMS to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (3-carbamoyl-propyl)-(4-chloro-benzyl)-amide.
Reaction SMILES: C(OC([N:6]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:17]([CH2:18][CH2:19][O:20][CH2:21][CH3:22])[C:16]3[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=3[N:14]=2)[CH2:8][CH2:7]1)=O)C.O.NN.[OH-].[K+]>C(O)CO.O>[CH2:21]([O:20][CH2:19][CH2:18][N:17]1[C:16]2[CH:23]=[CH:24][CH:25]=[CH:26][C:15]=2[N:14]=[C:13]1[N:9]1[CH2:10][CH2:11][CH2:12][NH:6][CH2:7][CH2:8]1)[CH3:22]
Reactant: CCOCCn1c(N2CCCN(C(=O)OCC)CC2)nc2ccccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Reaction time: 5 h

Procedure:
Combine 1-ethoxycarbonyl-4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane (17.2 g, 47.6 mmol), hydrazine hydrate (40 mL), and potassium hydroxide (40.7 g, 725 mmol) in ethylene glycol (150 mL). Heat to reflux. After 5 hours, cool the reaction mixture and dilute with water (500 mL). Extract three times with dichloromethane. Combine the dichloromethane layers and extract with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf=0.25 (silica gel, dichloromethane/methanol, 90/10).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C@H:21]4[CH2:26][CH2:25][C@H:24]([CH2:27]C)[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC1C=C(C2N=CC(C3C=CC([C@H]4CC[C@H](CCCCC)CC4)=CC=3)=CN=2)C=CC=1F>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C@H:21]4[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(F)c(F)c4)nc3)cc2)CC1
Agent: CCCCC[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(F)c(F)c4)nc3)cc2)CC1
Product: C[C@H]1CC[C@H](c2ccc(-c3cnc(-c4ccc(F)c(F)c4)nc3)cc2)CC1

Procedure:
2-(3',4'-difluorophenyl)-5-[4'-(trans-4"-ethylcyclohexyl)phenyl] pyrimidine ##STR45## 2-(3',4'-difluorophenyl)-5-[4'-(trans-4"-butylcyclohexyl)phenyl] pyrimidine ##STR46## wherein S1 and S2 are the smectic phase. 2-(3',4'-difluorophenyl)-5-[4'-(trans-4"-pentylcyclohexyl)phenyl] pyrimidine ##STR47## 2-(3',4,-difluorophenyl)-5-[4'-(trans-4"-hexylcyclohexyl)phenyl] pyrimidine
Reaction SMILES: [C:1]1([C:15]([OH:17])=O)[C:10]2[C:9]3[N:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][CH2:5][C:4]=2[NH:3][N:2]=1.[N:18]1([CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]2)[CH2:21][CH2:20][CH2:19]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCCl.C(Cl)Cl>[N:18]1([CH2:22][CH2:23][CH2:24][N:25]2[CH:29]=[CH:28][C:27]([NH:30][C:15]([C:1]3[C:10]4[C:9]5[N:11]=[CH:12][CH:13]=[CH:14][C:8]=5[CH2:7][CH2:6][CH2:5][C:4]=4[NH:3][N:2]=3)=[O:17])=[N:26]2)[CH2:19][CH2:20][CH2:21]1
Reactant: O=C(O)c1n[nH]c2c1-c1ncccc1CCC2
Reactant: Nc1ccn(CCCN2CCC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(Nc1ccn(CCCN2CCC2)n1)c1n[nH]c2c1-c1ncccc1CCC2
Yield: 8.8 %

Procedure:
7.8 mL of 1.7 M of t-BuLi in pentane is added dropwise under argon to a stirred solution of 1-bromo-3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene (1.4 g) in 75 mL of anhydrous THF at −78° C. After addition, dry carbon dioxide is bubbled into the mixture at the same temperature for 2 hours. The reaction mixture is allowed to warm to room temperature, quenched with 1N HCl solution, and diluted with water. The mixture is basified with 1N NaOH to pH 8-9, and then extracted with EtOAc. The aqueous layer is then acidified with HOAc to pH 4-5 and extracted with CH2Cl2 eight times. The combined extracts are washed with water, dried, and concentrated to give 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid as a tan solid. 1H NMR(DMSO): 1.95(m, 2H), 2.96(m, 2H), 3.07(t, 2H), 7.45(m,1H), 7.97(d,1H), 8.52(d, 2H). LR-MS: MW 229.23, Found: 230.2(M+1). Step 6: A mixture of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid (80 mg), 1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-ylamine (68 mg), EDCI(85 mg) and DMAP(55 mg) in 10 mL of 1,2-dichloroethane is refluxed overnight, cooled and diluted with CH2Cl2. The mixture is washed with aqueous NaHCO3 solution, water, dried over Na2SO4 and concentrated under vacuum. Purification on a silica gel plate, eluting with 10% MeOH in CH2Cl2 yields 12 mg of 3,4,5,6-tetrahydro-2,3,10-triaza-benzo[e]azulene-1-carboxylic acid [1-(3-azetidin-1-yl-propyl)-1H-pyrazol-3-yl]-amide as a colorless foam. 1H NMR (CDCl3): 2.01-2.31(m, 6H), 2.67-2.92(m, 8H), 3.63(m, 2H), 4.17(t, 2H), 6.65(d, 1H), 7.23(m, 1H), 7.33(d, 1H), 7.65(d, 1H), 8.62(d, 1H), 14.13(bs, 1H). LR-MS: MW 391.48, Found: 392.2 (M+1).
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[N+:17]([O-])=O)[C:10]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH2:28][CH3:29])[CH2:24][CH2:23]3)=[O:21])=[CH:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[N:8]([CH2:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[CH:9]=[C:10]2[C:20]([N:22]1[CH2:23][CH2:24][N:25]([CH2:28][CH3:29])[CH2:26][CH2:27]1)=[O:21]
Reactant: CCN1CCN(C(=O)c2cn(CC3CCCCC3)c3c([N+](=O)[O-])cccc23)CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(C(=O)c2cn(CC3CCCCC3)c3c(N)cccc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-{[1-(Cyclohexylmethyl)-7-nitro-1H-indol-3-yl]carbonyl}-1-ethylpiperazine (200 mg, 0.5 mmol) was dissolved in methanol (10 ml) to which was added palladium (5 wt. % on activated carbon; 50 mg, cat.) as a slurry in methanol (3 ml). The system was then sealed and flushed with nitrogen before fixing a hydrogen source (balloon). The mixture was stirred at room temperature under hydrogen for 15 hours after which it was filtered through celite and concentrated. The resulting brown oil was purified by flash chromatography using 95% dichloromethane, 5% methanol as eluent to yield the title product as the free base. 1H NMR (400 MHz, CD3OD) δH 0.97-1.08 (2H, m), 1.12 (3H, t, J 7.5), 1.17-1.26 (3H, m), 1.53 (2H, d, J 12.5), 1.63-1.75)(3H m) 1.87-1.98 (1H, m), 2.44-2.55 (6H, m), 3.37 (4H, t, J 5.0), 4.20 (2H, d, J 7.5), 6.59 (1H, dd, J 7.5, 1.0), 6.93 (1H, t, J 7.5), 7.06 (1H, dd, J 8.0, 1.0), 7.39 (1H, s); EIMS: m/z=369.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=2)O)[CH2:3][CH2:2]1.[BrH:27].O>C(O)(=O)C>[Br:27][CH2:3][CH2:2][CH:1]=[C:4]([C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:26])[N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[CH:7]=1
Reactant: Br
Reactant: CCN(CC)C(=O)c1ccc(C(O)(c2cccc(OC)c2)C2CC2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)C(=O)c1ccc(C(=CCCBr)c2cccc(OC)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95 %

Procedure:
1-Cyclopropyl-1-(4-diethylcarbamoylphenyl)-1-(3-methoxyphenyl)Methanol (90.9 mg) was dissolved in acetic acid (1.8 ml), added with 48% hydrobromic acid (1.8 ml) with ice cooling and stirred at room temperature for 1.5 hours. The reaction mixture was added with water (5 ml) and extracted twice with dichloromethane (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain 102 mg of the title compound. Yield: 95%.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.[NH2:18][C:19]([CH3:26])([CH2:24][OH:25])[C:20]([O:22][CH3:23])=[O:21]>>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][NH:18][C:19]([CH3:26])([CH2:24][OH:25])[C:20]([O:22][CH3:23])=[O:21])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: COC(=O)C(C)(N)CO
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C=O)c1
Agent: Cl
Product: COC(=O)C(C)(CO)NCc1cccc(O[Si](C)(C)C(C)(C)C)c1
Yield: 97 %

Procedure:
Prepare as in Example 12-9c from 3-(tert-butyldimethylsilyloxy)benzaldehyde (Example 12-1c) and methyl 2-amino-3-hydroxy-2-methylpropanoate hydrochloride. Yield 97%, yellowish oil. MS 354 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([N+:19]([O-])=O)=[C:16]([CH3:18])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCC[CH2:23]1>C(OCC)(=O)C.CO.[Pd]>[CH2:1]([O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]2[C:15](=[CH:14][CH:13]=1)[NH:19][CH:23]=[CH:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCCOCc2ccccc2)ccc1[N+](=O)[O-]
Reactant: C1CCNC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc(COCCOc2ccc3[nH]ccc3c2)cc1
Temperature: 120 °C
Yield: 22 %

Procedure:
5(2-Benzyloxy-ethoxy)-2-nitro-toluene (12.4 g, 43.0 mmol), N-N-dimethylfomamide dimethyl acetal (6.55 g, 51.6 mmol) and pyrrolidine (3.68 g, 51.6 mmol) were dissolved in N-N-dimethylfomamide (25 mL). The mixture was heated to 120° C. for 16 h. The solvent was evaporated under vacuum and the crude reaction was dissolved in 70% ethyl acetate/methanol (250 mL). The reaction was placed in a Parr Hydrogenator under a hydrogen atmosphere for 16 h with 10% palladium on carbon [10% w/w] (3.00 g) at 50 psi. The reaction was filtrated over celite and the crude mixture was purified via column chromatography with silica gel eluting with hexane/ethyl acetate to give the title compound (22% yield). 1H NMR (CDCl3) δ 7.27–7.41 (m, 6H), 7.19 (t, 1H, J=2.5 Hz), 7.13 (d, 1H, J=2.3 Hz), 6.91 (dd, 1H, J=2.5, 8.8 Hz), 6.48 (m, 1H), 4.67 (s, 2H), 4.21 (m, 2H), 3.87 (m, 2H).
Reaction SMILES: C(OCC)(=O)C.C(OC(=O)[N:13]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][N:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]([O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][C:34]2=[O:51])[CH2:27][CH2:26]1)[CH2:14][C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1)(C)(C)C.[ClH:53].C(OCC)(=O)C>C(Cl)(Cl)Cl>[ClH:53].[CH2:44]([O:43][C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:33]([CH2:32][CH2:31][N:28]2[CH2:27][CH2:26][CH:25]([NH:13][CH2:14][C:15]3[CH:24]=[CH:23][C:18]4[O:19][CH2:20][CH2:21][O:22][C:17]=4[CH:16]=3)[CH2:30][CH2:29]2)[C:34](=[O:51])[CH:35]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(OCc3ccccc3)c3ccccc32)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=c1cc(OCc2ccccc2)c2ccccc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a mixed solution of 1 mL ethyl acetate and 3 mL chloroform containing 0.20 g of tert-butyl(1-(2-(4-benzyloxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 2 mL of 4 mol/L hydrogen chloride/ethyl acetate was added, and stirred at room temperature for 24 hours, thereafter the resulting solid was filtered to give 0.15 g of 4-benzyloxy-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)quinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.[H][H]>[Pd].CN(C)C=O>[NH2:17][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[C:7]([C:6]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:4]([NH2:1])[CH:5]=1)=[O:8]
Reactant: COc1ccc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2ccc(OC)c(N)c2)cc1N
Temperature: 80 °C
Yield: 39.2 %

Procedure:
To a sealed glass reaction vessel equipped with a stirrer, thermometer and reflux condenser, 84 g (0.253 mol) of the above 3,3'-dinitro-4,4'-dimethoxybenzophenone, 420 g of N,N-dimethylformamide and 2.52 g of 5% palladium/alumina catalyst (N.E. Chemcat Co.) were charged and reacted in a hydrogen atmosphere at 45°~55° C. for 3 hours. After finishing the reaction, the catalyst was filtered. The filtrate was heated to 80° C. and then 1275 g of water was added and cooled to temperature to crystallize the desired product. The precipitated crystals were filtered and recrystallized from isopropylalcohol (IPA) to obtain 27 g (39% yield) of 3,3'-diamino-4,4'-dimethoxybenzophenone as light yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)/[C:5](/[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1)=[N:6]/[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].ClC1C=CC=C(C(OO)=[O:30])C=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)/[C:5](/[C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N+:13]=1[O-:30])=[N:6]/[O:7][C:8]([CH3:11])([CH3:9])[CH3:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)O/N=C(/c1cccc(Br)c1)c1ncccc1O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)O/N=C(/c1cccc(Br)c1)c1c(O)ccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A mixture of (Z)-2-(3-bromo-α-t-butoxyiminobenzyl)-3-hydroxypyridine (0.49 g), 70% m-chloroperbenzoic acid (0.70 g) and tetrahydrofuran (30 mL) was stirred overnight at room temperature. To the reaction mixture was added an aqueous solution of sodium sulfite. The reaction mixture was stirred for 30 minutes, and extracted with ethyl acetate. The extract was washed with water and a saturated aqueous saline solution, successively, and dried (sodium sulfate) and then concentrated. The concentrate was crystallized from isopropyl ether, and recrystallized from ethanol-water to afford (Z)-2-(3-bromo-α-t-butoxyiminobenzyl)-3-hydroxypyridine 1-oxide (0.41 g) (compound 3). In substantially the same manner as above, compounds 4, 7, 8, 11, 12 and 15 were produced.
Reaction SMILES: O1C2C=CC=CC=2OB1.[Br:10][C:11]1[C:12]([N:27]2[CH2:30][CH:29]([CH:31]([CH3:33])[CH3:32])[CH2:28]2)=[C:13]([C:19](=[O:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17].CB1N2CCC[C@@H]2C(C2C=CC=CC=2)(C2C=CC=CC=2)O1>C1(C)C=CC=CC=1>[Br:10][C:11]1[C:12]([N:27]2[CH2:30][CH:29]([CH:31]([CH3:33])[CH3:32])[CH2:28]2)=[C:13]([C@H:19]([OH:26])[C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[C:14]([CH3:18])=[N:15][C:16]=1[CH3:17]
Reactant: Cc1nc(C)c(C(=O)C(=O)OC(C)C)c(N2CC(C(C)C)C2)c1Br
Agent: B1Oc2ccccc2O1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Product: Cc1nc(C)c([C@H](O)C(=O)OC(C)C)c(N2CC(C(C)C)C2)c1Br
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 70.7 %

Procedure:
The 0.7 mL of benzo[d][1,3,2]dioxaborole (396 mg, 3.3 mmol) was added to a nitrogen purged solution of isopropyl 2-(5-bromo-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-oxoacetate (875 mg, 2.2 mmol) and 0.66 mL of (R)-1-methyl-3,3-diphenylhexahydropyrrolo[1,2-c][1,3,2]oxazaborole (183 mg, 0.66 mmol) in toluene (20 mL) at −60° C. and allowed to warm to −15° C. before being placed in the freezer overnight. The reaction was quenched with 1M Na2CO3 (5 mL), diluted with EtOAc, and stirred for 20 min. The organic layer was washed with brine and dried (MgSO4). The crude product was charged (DCM) to a 80 g ISCO silica gel cartridge and gradient elution (5-35% EtOAc/hexanes) using an Isolera chromatography station gave (S)-isopropyl 2-(5-bromo-4-(3-isopropylazetidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-hydroxyacetate 621 mg (71%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 5.19 (d, J=4.4 Hz, 1H), 4.96-4.92 (m, 1H), 4.50 (t, J=8.1 Hz, 1H), 4.39 (t, J=8.4 Hz, 1H), 4.07 (t, J=7.0 Hz, 1H), 3.97 (t, J=7.3 Hz, 1H), 2.42 (s, 3H), 2.21 (s, 3H), 2.21-2.17 (m, 1H), 1.73-1.67 (m, 1H), 1.17 (d, J=6.2 Hz, 3H), 1.12 (d, J=6.2 Hz, 3H), 0.83 (d, J=6.6 Hz, 6H). UPLC (M+H)=401.3.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.O=P(Cl)(Cl)Cl.[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH2:35][C:34]2=[O:42])[CH:30]=[CH:31][CH:32]=1>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([N:33]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35](=[C:9]3[CH2:10][CH2:11][CH2:12][N:8]3[CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:34]2=[O:42])[CH:30]=[CH:31][CH:32]=1
Reactant: O=C1CCCN1Cc1ccccc1
Reactant: O=C1Cc2ccccc2N1c1cccc(Cl)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1C(=C2CCCN2Cc2ccccc2)c2ccccc2N1c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
N-benzyl-2-pyrrolidone (1.58 ml, 9.85 mmoles) was combined with 2 ml toluene under N2 and cooled to 0°-5°. POCl3 (0.5 ml, 5.9 mmoles) was added and the mixture stirred 30 minutes. Toluene (3 ml) and 1-(3-chlorophenyl-2(1H,3H)-indolone (1.2 g, 4.92 mmoles) were added and the stirred reaction mixture warmed to 25° for 30 minutes and then to 70°-75° for 18 hours. The reaction mixture was cooled, diluted with 100 ml CH2Cl2, washed with saturated NaHCO3, H2O and brine, dried and concentrated in vacuo to an oil (2.6 g). The oil was chromatographed on silica gel (45×150 mm) using CH2Cl2 as eluant, yielding title product, initially an oil which was crystallized from ether/pentane, 1.04 g (53%), m.p. 72°-75°.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH:14]=[CH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C>[C:1]([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:16])[CH2:14][CH2:15][N:24]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: C=CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CCN(CCC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)Cc1ccccc1
Yield: 38 %

Procedure:
A solution of 1.0 g (4.44 mmol) (R)-1-acryloyl-pyrrolidine-2-carboxylic acid tert-butyl ester and 0.24 ml (2.22 mmol) benzylamine in 25 ml acetonitrile was stirred for 16 h at 80° C. Concentration in vacuo and flash chromatography (gradient: 0-10% MeOH in EtOAc) afforded 470 mg (34%) of the title compound as a yellow oil. MS m/e (%): 558 (M+H+, 100).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12]3[C:13]([NH2:17])=[N:14][O:15][N:16]=3)[NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:20](I)[CH:21]([CH3:23])[CH3:22]>CN(C=O)C>[CH2:20]([N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[C:12]1[C:13]([NH2:17])=[N:14][O:15][N:16]=1)[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)CI
Reactant: Nc1nonc1-c1nc(-c2ccccc2)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1cc(-c2ccccc2)nc1-c1nonc1N
Yield: 19 %

Procedure:
Synthesis of 4-(4-phenyl-1H-imidazol-2-yl)-1,2,5-oxadiazol-3-amine (50 mg, 0.22 mmol) was dissolved in DMF and NaH (15 mg, 0.7 mmol) was added. The reaction mixture became dark red. Isobutyl iodide (60 mg, 0.33 mmol) was added and the reaction mixture heated to 120 CC in the microwave for 5 minutes. The reaction mixture was concentrated to an oil which was purified by RPHPLC (CH3CN/H2O, 0.1% TFA) to give the product, 12 mg, 0.042 mmol, 19% yield. HPLC Method B Rt 4.50 min, MH+ 284.30. 1H NMR (500 MHz, CDCl3) δ 7.71 (m, 2H), 7.34 (m, 2H), 7.28 (s, 1H), 7.23 (m, 1H), 4.19 (d, J=7.4 Hz, 2H), 2.12 (m, 1H), 0.92 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]([NH2:23])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4].[CH2:24]([N:26]([CH2:29][CH3:30])[CH2:27]C)[CH3:25].ClC(OC1C=CC=CC=1)=[O:33].O>O1CCCC1>[CH3:1][NH:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][C:15]3[C:20]([C:21]#[N:22])=[CH:19][N:18]=[C:17]([NH:23][C:27]([N:26]4[CH2:29][CH2:30][CH2:25][CH2:24]4)=[O:33])[CH:16]=3)=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)=[O:4]
Reactant: CNC(=O)n1ccc2cc(Oc3cc(N)ncc3C#N)ccc21
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)n1ccc2cc(Oc3cc(NC(=O)N4CCCC4)ncc3C#N)ccc21
Yield: 22.8 %

Procedure:
N1-Methyl-5-(2-amino-5-cyano-4-pyridyl)oxy-1H-1-indolecarboxamide (20 mg) synthesized in Example 215 was suspended in tetrahydrofuran (0.5 ml) at room temperature; triethylamine (0.121 ml, 0.868 mmol) and phenyl chloroformate (0.08 ml, 0.633 mmol) was added thereto while stirring; and the reaction mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture; this was subjected to extraction with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. N,N-Dimethylformamide and pyrrolidine (0.013 ml) was added to a portion of the residue (14 mg); and the reaction mixture was stirred overnight. The reaction mixture was partitioned between ethyl acetate and water; and the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Fuji Silysia NH, ethyl acetate-methanol). The resultant was washed with a solvent mixture (ether: hexane=1:1) to yield the title compound as crystals (6 mg).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([OH:34])(=O)=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:17]>CN(C=O)C>[O:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:9]=[C:8]1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([Cl:4])(=[O:34])=[O:32])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)=[O:17]
Reactant: O=C(Nc1ccc(-c2ccc(S(=O)(=O)O)cc2)cc1)c1cc2ccccc2o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)Cl)cc2)cc1)c1cc2ccccc2o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.6 %

Procedure:
To 75 ml of DMF cooled to −20° C., oxalyl chloride (6.7 ml, 76 mmol) was carefully added dropwise. A white suspension was formed and the fumes generated were removed by blowing N2 through the flask. A solution of 4′-[(benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonic acid (15 g, 38 mmol) in 100 ml DMF was added slowly and the temperature was maintained <0° C. After the addition was complete, the reaction mixture was warmed to room temperature and was stirred at room temperature for 3 h. The reaction mixture was poured into 4L ice/water, and the suspension was filtered. The solid was collected and dried under vacuum to provide 7.3 g of 4′-[(benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonyl chloride, obtained as off-white solid.