Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:11][C@H:12]([C:23]([OH:25])=[O:24])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O.CC(=C)C.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(=O)=O.C(OCC)(=O)C>[N+:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@@H:12]([C:23]([OH:25])=[O:24])[NH2:11])=[CH:19][CH:18]=1)([O-:22])=[O:21]
Reactant: O=C(N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O)OCc1ccccc1
Agent: C=C(C)C
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 25 °C

Procedure:
The Cbz-4-nitrophenylalanine (75 g, 0.22 m) is dissolved in dioxane (300 ml). The resulted stirred solution is cooled in Dry Ice bath to −20° C. (internal). The liquefied isobutylene (approx. 290 ml) is added followed by conc. sulfuric acid (35 ml) added in three equal portions, 30 min apart. The addition of acid is a very exothermic process, accompanied by substantial degree of polymerization. Efficient mechanical stirring is essential at this stage. Resulted mixture is stirred for 20 hr, allowing to warm up to ambient temperature then is cautiously poured into sat. aq. sodium carbonate solution (2 L) and diluted with ethyl acetate (600 ml). Organic layer is separated and aqueous layer is extracted with ethyl acetate (2×200 ml). Combined extracts are washed with water and dried with sodium sulfate. The solution is filtered and evaporated to dryness. The residue is taken up in ethyl acetate/hexane mixture (500 ml; 1:1) and filtered through plug of silica gel (ca. 2×2 in). The silica is rinsed with an additional amount of the same solvent (2 L total) and the filtrates are evaporated to give fully protected 4-nitrophenylalanine as a viscous oil, 73 g (83% after two steps). 1H-NMR, CDCl3, (δ): 8.12 (d, 2H, J=8.4 Hz), 7.36 (m, 7H), 5.35 (m, 1H), 5.10 (m, 2H), 4.57 (m, 1H), 3.31 (m, 2H), 1.43 (s, 9H). 13C-NMR, CDCl3, (δ): 169.7, 155.3, 146.9, 143.9, 136.0, 130.2, 128.4, 128.2, 128.0, 123.3, 82.9, 66.9, 54.7, 38.2, 31.4, 27.8, 13.9. MS (m/z): 423.1 [M+23].
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:10]([O:22][C:23]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@@H:9]([CH2:37][O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[O:8][C@H:5]1[S:6][CH3:7])=[N+]=[N-]>C(S)CCS>[NH2:1][C@@H:4]1[C@@H:11]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:10]([O:22][C:23]([C:25]2[C:26]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@@H:9]([CH2:37][O:38][Si:39]([C:52]([CH3:55])([CH3:54])[CH3:53])([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[O:8][C@H:5]1[S:6][CH3:7]
Reactant: COc1ccc(CO[C@@H]2[C@@H](N=[N+]=[N-])[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Agent: SCCCS
Product: COc1ccc(CO[C@@H]2[C@@H](N)[C@H](SC)O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H]2OC(=O)c2ccccc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A mixture of methyl 2-azido-4-O-biphenylcarbonyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (11) (150 mg, 0.19 mmol) and TEA (3 drops) in 1,3-propanedithiol (1 mL) was stirred at room temperature overnight. The reaction mixture was chromatographed using EtOAc—hexane 15:85 then EtOAc—hexane 1:1 solvent systems as mobile phases to give methyl 2-amino-4-O-biphenylcarbonyl-6-O-tert-butyldiphenylsilyl-2-deoxy-3-O-(4-methoxybenzyl)-1-thio-β-D-glucopyranoside (42) (130 mg, 91%).
Reaction SMILES: [C:1](=[N:9][OH:10])([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].[O:17]=[C:18]1[CH2:23][CH:22]([C:24](OC)=O)[CH2:21][CH2:20][NH:19]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[C:2]1([C:1]2[N:8]=[C:24]([CH:22]3[CH2:21][CH2:20][NH:19][C:18](=[O:17])[CH2:23]3)[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccccc1
Reactant: COC(=O)C1CCNC(=O)C1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1CC(c2nc(-c3ccccc3)no2)CCN1
Yield: 53.6 %

Procedure:
Add benzamidoxime (5.63 g, 41.36 mmol) to a 1M solution of potassium t-butoxide (31 mL, 31 mmol) in tetrahydrofuran and anhydrous tetrahydrofuran (442 mL). Add methyl 2-oxopiperidine-4-carboxylate (5 g, 31.8 mmol) and stir overnight at room temperature. Pour reaction over saturated aqueous sodium bicarbonate and extract into chloroform. Separate layers and extract the aqueous phase with additional chloroform. Dry the combined organic layers over anhydrous magnesium sulfate, filter, and concentrate to dryness under reduced pressure. Purify the resulting residue by flash chromatography (silica gel), eluting with 1-5% 7 N ammoniated methanol in dichloromethane to afford the title compound (4.15 g). 1H NMR (CDCl3) δ 2.19 (m, 1H), 2.34 (m, 1H), 2.8-2.95 (m, 2H), 3.44-3.52 (m, 2H), 3.57 (m, 1H), 6.13 (bs, 1H), 7.45-7.54 (m, 3H), 8.0-8.11 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[C:6]([O:16][CH2:17][CH3:18])[CH:5]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[NH2:1][C:4]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:7]([CH2:8][CH2:9][NH2:10])=[C:6]([O:16][CH2:17][CH3:18])[CH:5]=1
Reactant: CCOc1cc([N+](=O)[O-])c(OCC)cc1CCN
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(CCN)c(OCC)cc1N
Yield: 102 %

Procedure:
3.05 g (12.0 mmol) 4-nitro-2,5-diethoxyphenethylamine N6 was dissolved in 50 ml ethanol, and 1.5 g 10% palladium on carbon black was added. This suspension was hydrogenated at 2.2 atm. for 18 hours, till no more hydrogen uptake was observed. The catalyst was filtered off and the solvent was evaporated to afford 2.75 g light yellow oil (yield: 102%).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH:15]2[CH:11]1[CH2:12][N:13]([C:16]1[N:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][N:17]=1)[CH2:14]2)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH2:9][CH:10]1[CH:15]2[CH:11]1[CH2:12][N:13]([C:16]1[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][N:21]=1)[CH2:14]2
Reactant: CCOC(=O)c1cnc(N2CC3C(CNC(=O)OC(C)(C)C)C3C2)nc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N2CC3C(CN)C3C2)nc1
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
Ethyl 2-(6-{[(tert-butoxycarbonyl)amino]methyl}-3-azabicyclo[3.1.0]hex-3-yl)pyrimidine-5-carboxylate (1.7 g, 4.7 mmol) was stirred in DCM (20 ml) at r.t. under N2. 4M HCl in dioxane (2.35 ml, 9.4 mmol) was added, immediately causing a solid to precipitate. The reaction was left to stir for 30 min and then the solvent was removed in vacuo. The residue was dissolved in DCM (100 ml) and washed with sat. aq. NaHCO3 (100 ml). The organic layer was then dried (Na2SO4) and the solvent removed in vacuo to give the title compound as an orange solid (1.2 g, 97%). LCMS purity 97%, m/z 263 [M+H]+, 1H NMR (300 MHz, d6-DMSO) δ: 0.64 (1H, m), 1.29 (3H, t, J=7.2 Hz), 1.58 (2H, m), 3.33 (4H, m), 3.55 (2H, d, J=11.7 Hz), 3.82 (2H, d, J=11.7 Hz), 4.26 (2H, q, J=7.2 Hz), 8.76 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:15]([N:22]1[CH2:27][CH2:26][CH:25]([NH:14][C:9]2[C:10]([CH3:13])=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1noc(-c2ccc(Br)cc2)c1NC1CCN(Cc2ccccc2)CC1
Temperature: 0 °C

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-ylamine (0.500 g, 1.73 mmol) and 1-benzyl-piperidin-4-one were mixed with acetic acid (0.200 mL) in MeOH (8 mL). The reaction was cooled to 0° C. and stirred for one hour before sodium cyanoborohydride (0.108 g, 1.74 mmol) was added. The reaction was allowed to warm to room temperature and was monitored by analytical LCMS. When complete, the reaction was quenched with aqueous sodium bicarbonate then submitted to standard workup procedures. The crude material was purified by silica gel chromatography (0-100% EtOAc in hexanes) to afford the title compound
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Br[CH2:12][C:13]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)=O>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[S:9][CH:12]=[C:13]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[N:10]=1
Reactant: NC(=S)Nc1ccccn1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(Nc3ccccn3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Pyridin-2-yl-thiourea (2.06 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.06 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=298.0 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: [NH:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][NH2:11])[CH2:3][CH2:2]1.[CH:12](OCC)=[O:13]>>[NH:1]1[C:8]2[N:4]([N:5]=[CH:6][C:7]=2[CH2:9][CH2:10][NH:11][CH:12]=[O:13])[CH2:3][CH2:2]1
Reactant: CCOC=O
Reactant: NCCc1cnn2c1NCC2
Product: O=CNCCc1cnn2c1NCC2

Procedure:
A suspension of 2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)ethylamine (155 mg) in ethyl formate (3 ml) was refluxed for 4.5 hours. After evaporation of the solvent in vacuo, the residue was triturated with ethyl acetate and dried in vacuo to give 2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazol-7-yl)ethylformamide (165 mg) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH2:4][CH2:3]1.[Br:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=1I.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][C:23]=1[C:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH:6]=1
Reactant: FC(F)(F)c1ccc(Br)c(I)c1
Reactant: CN1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CN1CC=C(c2cc(C(F)(F)F)ccc2Br)CC1

Procedure:
A solution of Pd(Ph3P)4 (0.986 g, 0.854 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine (2.000 g, 8.96 mmol), 1-bromo-2-iodo-4-(trifluoromethyl)benzene (1.377 ml, 8.54 mmol), and potassium phosphate (5.44 g, 25.6 mmol) in 20 mL dioxane 10 mL water was heated to 90° C. for one hour. LC/MS showed mostly product, so the reaction mixture was poured into water and extracted with DCM. The organics were dried over MgSO4 and concentrated. Purification of the crude residue by silica gel column chromatography (0 to 97% EtOAc/heptane, 3% MeOH) gave 4-(2-bromo-5-(trifluoromethyl)phenyl)-1-methyl-1,2,3,6-tetrahydropyridine. m/z (ESI) 320.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]=[C:6](Cl)[C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH3:2].[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[NH:41][CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([CH2:33][CH2:34][O:35][C:36]3[CH:37]=[C:38]4[C:42](=[CH:43][CH:44]=3)[N:41]([C:6]([C:7]3[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=3)=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH:40]=[CH:39]4)[N:31]=2)[CH2:26][CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C=C(Cl)c1cccc(C)c1
Product: CCOC(=O)C=C(c1cccc(C)c1)n1ccc2cc(OCCc3ccc4c(n3)N(C(=O)OC(C)(C)C)CCC4)ccc21
Yield: 40 %

Procedure:
The title compound was synthesized from 3-chloro-3-m-tolyl-acrylic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure outlined in Example 18, step (d), in a 40% yield as an E/Z isomeric mixture. 1H NMR (CDCl3) δ 7.19 (m, 2.2H), 7.04 (m, 2.6H), 6.96 (m, 1.6H), 6.86 (m, 1.6H), 6.66 (m, 2H), 6.48 (d, 0.8H, J=0.8 Hz), 6.40 (d, 0.2H, J=0.8 Hz), 6.11 (s, 0.8H), 6.04 (s, 0.2H), 4.30 (m, 2H), 3.93 (m, 2H), 3.68 (m, 2H), 3.13 (t, 2H, J=6.4), 2.65 (t, 2H, J=6.4 Hz), 2.24 (s, 3H), 1.85 (m, 2H), 1.43 (s, 9H), 0.94 (t, 3H, J=6.8 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10][N:9]([C:16]3[CH:17]=[C:18]([NH:22]C(=O)C)[CH:19]=[CH:20][CH:21]=3)[C:8]2=[O:26])=[CH:4][CH:3]=1.Cl>C1COCC1>[NH2:22][C:18]1[CH:17]=[C:16]([N:9]2[C:8](=[O:26])[N:7]([CH2:6][C:5]3[CH:27]=[CH:28][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12](=[O:13])[C:11]([O:14][CH3:15])=[N:10]2)[CH:21]=[CH:20][CH:19]=1
Reactant: COc1nn(-c2cccc(NC(C)=O)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1nn(-c2cccc(N)c2)c(=O)n(Cc2ccc(Cl)cc2)c1=O
Yield: 95.1 %

Procedure:
According to Scheme 9 Step 1: A mixture of N-(3-(4-(4-chlorobenzyl)-6-methoxy-3,5-dioxo-4,5-dihydro-1,2,4-triazin-2(3H) yl)phenyl)acetamide (500 mg, 1.24 mmol) in a solution 6N of HCl (10 mL) and THF (10 mL) was stirred at reflux for 3 hours. The THF was evaporated and the aqueous layer was basified with saturated solution of NaHCO3 until neutral pH. The aqueous layer was then extracted with ethyl acetate (×3). The organic layers were combined to be successively washed with water then with brine, dried over MgSO4, filtered and concentrated. The crude product was azeotroped with acetonitrile to afford 2-(3-aminophenyl)-4-(4-chlorobenzyl)-6-methoxy-1,2,4-triazine-3,5(2H,4H)-dione as a beige solid (423 mg, 94.5%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6](O)[N:5]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=[C:4]2[N:3]=1.P(Cl)(Cl)([Cl:18])=O.Cl>>[Cl:18][C:6]1[N:5]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[N:11]=[C:4]2[N:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(C(F)(F)F)nc2n1
Agent: Cl
Product: Cc1cc(Cl)n2nc(C(F)(F)F)nc2n1

Procedure:
A mixture of 0.750 g (3.44 mmol) 5-methyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-ol and 1.35 mL (14.46 mmol) of phosphorus oxychloride was heated under reflux for 60 minutes, during which time the pinkish solid dissolved gradually with the evolution of hydrogen chloride gas. The resultant dark red solution was distilled under reduced pressure to remove excess phosphorus oxychloride and the residue triturated with ice-water. The resultant aqueous solution was extracted with methylene chloride, the organic layer thus obtained was dried and the solvent was removed to give the desired product. Further washes of the crude residue with methylene chloride gave 0.547 g of 7-chloro-5-methyl-2-(trifluoromethyl)-[1,2,4]triazolo[1,5-a]pyrimidine. Yield 67.4%. The washed crude was used without purification in the next step.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]([CH2:14]O)[S:12][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.C(=O)([O-])O.[Na+].[I-:29].[Na+]>O1CCCC1.CC(C)=O.O>[I:29][CH2:14][C:11]1[S:12][CH:13]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=2)[N:10]=1
Reactant: [I-]
Reactant: OCc1nc(-c2cccc(C(F)(F)F)c2)cs1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: FC(F)(F)c1cccc(-c2csc(CI)n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.2 %

Procedure:
To a solution (5 mL) of the compound (1.2 g, 4.6 mmol) obtained in Example 190b in tetrahydrofuran was added oxalyl chloride (0.68 mL, 9.3 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. To a solution (20 mL) of the residue in acetone was added sodium iodide (2.1 g, 14 mmol), and the mixture was stirred at 70° C. for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=90/10) to give the title compound (530 mg, 31% in 2 steps) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1[Cl:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][CH:25](C(O)=O)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(#N)C.O.[N+]([O-])([O-])=O.[Ag+]>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:2]3[C:3](=[O:14])[C:4]4[C:9]([C:10](=[O:13])[C:11]=3[Cl:12])=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:24][CH2:23]2)=[CH:18][CH:17]=1
Reactant: O=C(O)C1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: O
Solvent: CC#N
Product: O=C1C(Cl)=C([C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)C(=O)c2ccccc21

Procedure:
A mixture of 2,3-dichloro-1,4-naphthoquinone (57.0 gm), 4-(4-chlorophenyl)-cyclohexane-1-carboxylic acid (60.0 gm) and silver nitrate (42.7 gm) is taken in acetonitrile (600 ml) and then a solution of ammonium persulphate (180.12 gm) in water (780 ml) is added. The mixture is heated to reflux, maintaining good stirring. The mixture was refluxed for 4 hrs. Then cooled in ice for about 1 hr after which it is filtered. The filtrate is kept aside for acetonitrile recovery. The solid is extracted with hot methylene chloride (100 ml×3). The inorganic salt is collected separately for recovery of silver. The organic layer is dried over anhydrous sodium sulphate and concentrated to get light brownish yellow solid (38.5 gm).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH2:33]1[C:36]2([CH2:39][NH:38][CH2:37]2)[CH2:35][N:34]1C(OC(C)(C)C)=O>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:34]3[CH2:35][C:36]4([CH2:39][NH:38][CH2:37]4)[CH2:33]3)=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC3(CNC3)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate to afford a white powder. HPLC (Condition 4) tR=4.17 min, UPLC-MS (Condition 3) tR=0.77 min, m/z=461 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.30 (br. s, 2H) 3.63 (s, 4H) 3.75-3.92 (m, 4H) 6.41 (d, J=2.35 Hz, 1H) 7.26-7.35 (m, 2H) 7.77 (br. s, 1H) 7.81-7.89 (m, 2H) 8.05 (d, J=2.35 Hz, 1H) 8.71 (d, J=2.35 Hz, 1H) 10.22 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([Br:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Br:9][C:5]1[N:6]=[C:7]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[Cl:16])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Nc1ncc(Br)nc1-c1ccccc1Cl
Reaction time: 0.5 h
Yield: 54 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0.24 g) is added at room temperature to a solution of 2-amino-3,5-dibromopyrazine (0.51 g) in dimethoxyethane (12 mL). The mixture is stirred for 30 min and sodium carbonate (0.53 g), water (6 mL) and 2-chlorophenylboronic acid (0.32 g) are added and the mixture is stirred for 18 h at 100° C. The mixture is cooled, citric acid (10%, 20 mL) is added and the mixture is extracted with ethyl acetate (3×50 mL). Organic phases were pooled, washed with sodium bicarbonate and brine, dried with Na2SO4 and the solvent was evaporated. The residue was purified by chromatography on silica gel with dichloromethane to yield 0.31 g of the title compound as a white solid, mp 138.5-139.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH2:9][NH:8][C:7](=O)[C:6]=2[CH:14]=1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:14]=1
Reactant: O=C1CNC(=O)c2cc(Br)ccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)CNCCN2
Temperature: 63 °C
Reaction time: 19 h

Procedure:
7-bromo-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (11.8 g, 46.2 mmol) was transferred to a round bottom flask. THF (0.57M) was added to the flask to make a slurry. Lithium aluminum hydride in 1M solution of THF (138.8 mmol) was added dropwise. When the addition was completed, the reaction mixture was heated to 63° C. After 19 hours, the reaction mixture was cooled to room temperature and then to 0° C. Water (3 mL) was added to the cooled reaction mixture, and the reaction mixture was stirred for 1 hour. After the 1 hour, 9 mL of 15% NaOH was added and the reaction mixture was stirred for another hour. Water was then added and the resulting precipitate was filtered off. The precipitate was then washed with ethyl acetate several times. The solvent was removed from the filtrate and the filtrate was transferred to a separatory funnel with ethyl acetate. The filtrate was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine (1×), dried with magnesium sulfate, filtered and concentrated to give a yellow solid. Further purification (1% TEA/Ethyl acetate to start, then switched to 20% ammonia (2M solution in methanol/ethyl acetate, then 100% methylene chloride) yielded the desired product.