Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[C:4]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[N:3]1.[C:16]([O:20][C:21]([N:23]([CH2:49][C:50]([F:53])([F:52])[F:51])[C:24]1[CH:29]=[C:28]([C:30]2[O:31][CH:32]=[C:33]([C:35](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:36])[N:34]=2)[CH:27]=[CH:26][N:25]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(CC)CC)C>CO.[C].[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:35]([C:33]2[N:34]=[C:30]([C:28]3[CH:27]=[CH:26][N:25]=[C:24]([N:23]([CH2:49][C:50]([F:52])([F:51])[F:53])[C:21](=[O:22])[O:20][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:29]=3)[O:31][CH:32]=2)=[O:36])[C:4]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])=[N:3]1
Reactant: Cn1cc([N+](=O)[O-])c(N2CCOC2=O)n1
Reactant: CC(C)(C)OC(=O)N(CC(F)(F)F)c1cc(-c2nc(C(=O)Oc3c(F)c(F)c(F)c(F)c3F)co2)ccn1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: Cn1cc(NC(=O)c2coc(-c3ccnc(N(CC(F)(F)F)C(=O)OC(C)(C)C)c3)n2)c(N2CCOC2=O)n1
Yield: 18.6 %

Procedure:
A solution of 3-(1-methyl-4-nitro-1H-pyrazol-3-yl)-1,3-oxazolidin-2-one (58 mg), pentafluorophenyl 2-(2-((tert-butoxycarbonyl) (2,2,2-trifluoroethyl)amino)pyridin-4-yl)-1,3-oxazole-4-carboxylate (197 mg), 10% palladium-carbon (29 mg) and triethylamine (76 μL) in methanol (1.4 mL) was stirred overnight at room temperature under hydrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (28 mg).
Reaction SMILES: CCN=C=NCCCN(C)C.ON1C2C=CC=CC=2N=N1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]([OH:30])=O.Cl.[CH3:32][NH:33][O:34][CH3:35]>CN(C)C=O.C(N(CC)CC)C>[CH3:35][O:34][N:33]([CH3:32])[C:28](=[O:30])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=1
Reactant: O=C(O)c1ccccn1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccn1
Reaction time: 0.25 h

Procedure:
EDCI (2.30 g, 0.012 mol) and 1-hydroxy benztriazole (1.36 g, 0.009 mol) were added o a stirred solution of pyridine-2-carboxylic acid (1.0 g, 0.008 mol) in N,N-dimethyl formamide (16 mL) at 0° C. The reaction mixture was allowed to stir for 15 min then triethyl amine was added followed by addition of N,O-dimethyl hydroxyl amine hydrochloride at 0° C. The resulting mixture was stirred at RT overnight. The reaction mixture was partitioned between water (30 mL) and ethyl acetate (2×30 mL). The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography using 100-200 mesh silica gel and 0-20% EtOAc: Hexane as eluant to obtain product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[CH:11]([C:13]1[O:17][C:16](B(O)O)=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[N+:8]([C:4]1[CH:3]=[C:2]([C:16]2[O:17][C:13]([CH:11]=[O:12])=[CH:14][CH:15]=2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2cccc([N+](=O)[O-])c2)o1
Temperature: 25 °C

Procedure:
To a mixture of 1.5 g of 1-bromo-3-nitrobenzene (7.42 mmol), 1 g of 5-formyl-2-furanboronic acid (7.42 mmol), and 35 mL of a solution of saturated sodium carbonate (Na2CO3) in 0.2 M tetrahydrofuran was added 0.2 g of tetrakis triphenylphosphine palladium [Pd(PPh3)4] (0.2 mmol) at room temperature with stirring. After completion of the addition, the resulting mixture was heated for an additional 12 hrs, cooled to room temperature, and concentrated in vacuo. The concentrate was extracted with methylene chloride, and the organic layer thus formed was added, washed with saturated brine, dried over magnesium sulfate, and concentrated in a vacuum. Purification by silica gel column chromatography afforded the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33](B(O)O)=[CH:32][N:31]=1>>[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:36][CH3:37])[C:33]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:32][N:31]=1
Reactant: CS(=O)(=O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: COc1ncc(B(O)O)c(OC)n1
Product: COc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(S(C)(=O)=O)CC4)cc3n2)c(OC)n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperidin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared following Example 46, was reacted with 2,4-dimethoxypyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 131. NMR (CDCl3): 1.96-2.04 (2H, m), 2.18-2.26 (4H, m), 2.84-2.91 (1H, m), 2.86 (3H, s, Me), 3.12-3.20 (2H, m), 3.82 (2H, s, CH2), 3.84-3.90 (4H, m, CH2), 3.98-4.02 (4H, m, CH2), 4.04 (3H, s, Me), 4.08 (3H, s, Me), 7.32 (1H, s, Ar) and 8.94 (1H, s, Ar). MS: (ESI+): MH+=535.39
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:11]1[CH:20]=[N:19][C:18]2[C:13](=[C:14]([Cl:21])[CH:15]=[CH:16][CH:17]=2)[N:12]=1>C1COCC1>[Cl:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:20]=[N:19]2
Reactant: Clc1cnc2cccc(Cl)c2n1
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1cccc2ncc(Nc3ccccc3)nc12
Temperature: 50 °C
Reaction time: 16 h
Yield: 43 %

Procedure:
Aniline (0.810 ml, 8.89 mmol) was added to a mixture of NaH (60% w/w in mineral oil; 0.356 g, 8.89 mmol) in THF (59.3 ml) at 0° C.; the resulting mixture was stirred for 15 min before 2,8-dichloroquinoxaline (177a, 1.18 g, 5.93 mmol, Pharmabridge, Inc., Doylestown, Pa.) was added; the reaction mixture was stirred at 50° C. for 16 h. Purification by silica gel (100% hexanes to 40% EtOAc/hexanes) provided 8-chloro-N-phenylquinoxalin-2-amine (180a, 43% yield) as a yellow solid. MS (ESI, pos. ion) m/z: 256.2 (M+1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:27][C@H:26]([CH2:28][O:29]C(=O)C2C=CC=CC=2)[C@@H:16]([O:17]C(=O)C2C=CC=CC=2)[C@H:6]1[O:7]C(=O)C1C=CC=CC=1)(=O)[CH3:2].[F:38][C:39]([F:51])([F:50])[C:40]([NH:42][C:43]1[CH:44]=C(O)C=[CH:47][CH:48]=1)=[O:41].B(F)(F)F.ClCCl>O1CCCC1>[O:4]([C:1]1[CH:2]=[CH:47][CH:48]=[C:43]([NH:42][C:40](=[O:41])[C:39]([F:51])([F:38])[F:50])[CH:44]=1)[C@@H:5]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:16]([OH:17])[C@H:6]1[OH:7]
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=C(Nc1cccc(O)c1)C(F)(F)F
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1cccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 168 h
Yield: 49.7 %

Procedure:
A solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (500 mg, 0.99 mmol), 3-trifluoroacetamidophenol (407 mg, 1.98 mmol) from Stage 1 and boron trifluoride diethyletherate (1.41 g, 9.93 mmol, 1.25 ml) in a mixture of dry dichloromethane (10 ml) and dry tetrahydrofuran (30 ml) was stirred at room temperature under argon for 7 days. Work-up as in Stage 1 of Example 1 and purification by flash chromatography on silica gel (2% acetone in toluene as eluant) gave the title compound as a colourless solid (166 mg, 21%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([N:19]4[CH2:23][CH2:22][C@@:21]5([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[C:25](=[O:32])[O:24]5)[CH2:20]4)=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.CO.Cl>O1CCOCC1>[O:1]=[C:2]1[CH2:3][NH:4][CH2:5][CH2:6][N:7]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([N:19]3[CH2:23][CH2:22][C@@:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[C:25](=[O:32])[O:24]4)[CH2:20]3)=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)C(=O)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5=O)cc4)CC3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 3-oxo-4-[4-(1-{[(1R)-3-oxo-1H,3H-spiro[2-benzofuran-1,3′-pyrrolidin]-1′-yl]carbonyl}cyclopropyl)phenyl]piperazine-1-carboxylate (180 mg, 0.00034 mol) in methanol (2 mL, 0.05 mol) was added 4 M of hydrogen chloride in 1,4-dioxane (0.4 mL) and the mixture was stirred at rt for 3 hours and then concentrated. LC/MS: 432.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N:3]=1.[N-:13]=[N+:14]=[N-:15].[Na+].[OH-].[Na+].Cl>C(O)(=O)C>[CH3:1][C:2]1[N:3]([C:4]2[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:7])=[O:8])[N:15]=[N:14][N:13]=1
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1nnnn1-c1ccccc1C(=O)O
Temperature: 27.5 °C

Procedure:
The crude 2-methyl-4-oxo-3,1-benzoxazine was dissolved in acetic acid (1.9 L). Sodium azide (130.0 g) was added to the solution in portions with stirring. The reaction mixture was cooled in an ice bath to maintain the reaction temperature at 25 to 30° C. during the addition. The reaction mixture was allowed to stir at ambient temperature over the weekend. The acetic acid was removed under vacuum to provide a white solid. The solid was combined with 10% sodium hydroxide (1.4 L) then heated on a steam bath for 1 hour. Additional sodium hydroxide (120 g of 50% sodium hydroxide) was added. The mixture was heated on a steam bath for an additional hour then allowed to cool to ambient temperature overnight. Additional sodium hydroxide (120 g of 50% sodium hydroxide) was added. The mixture was heated on a steam bath for 2 hours then allowed to cool. The reaction mixture was poured with rapid stirring into a mixture of concentrated hydrochloric acid (1.0 L) and ice (3 L). The resulting mixture was stirred at ambient temperature overnight. A precipitate was isolated by filtration, rinsed with water then slurried with water (4 L). The solid was isolated by filtration, rinsed with water then oven dried at 50° C. to provide 278.0 g of crude 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid as a tan solid, m.p. 157-160° C. The crude material was dissolved in 10% sodium hydroxide (2.5 L). The resulting solution was heated (95-99° C.) for 2.5 hours, cooled, then poured with vigorous stirring into a mixture of concentrated hydrochloric acid (500 mL) and ice (5 L). The resulting mixture was allowed to stir for 2 hours. The precipitate was isolated by filtration, rinsed with water, then slurried with water (3 L). The solid was isolated by filtration, rinsed with water then dried overnight at ambient temperature to provide 228 g of 2-(5-methyl-1H-tetrazol-1-yl)benzoic acid, m.p. 164-166° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[C:7](=[CH2:13])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1.[OH:14]I(C1C=CC=CC=1)OS(C1C=CC(C)=CC=1)(=O)=O>O.CO>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]2[CH2:13][C:7](=[O:14])[CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Reactant: C=C1CCCc2cc(OC)ncc21
Solvent: O
Solvent: CO
Product: COc1cc2c(cn1)CC(=O)CCC2
Yield: 66.5 %

Procedure:
3-Methoxy-8-methylene-5,6,7,8-tetrahydroisoquinoline (125) (1.27 g, 7.25 mmol) in a mixture of water (5 mL) and MeOH (45 mL) was treated with [hydroxy(tosyloxy)iodo]benzene (2.84 g, 7.25 mmol) in MeOH (7 mL). After about 30 min water (15 mL) was added then the mixture was concentrated under reduced pressure to remove most of the MeOH. The mixture was basified to about pH 10 with sat. aq. NaHCO3 then EtOAc (˜30 mL) was added. Insoluble material was removed by filtration. The filtrate layers were separated then the aqueous layer was extracted with EtOAc (20 mL). The combined organic solutions were washed with brine (˜25 mL) then dried over MgSO4 and filtered. The filtrate was concentrated under reduced pressure then the material was purified on silica gel (40 g) using a gradient from 0-100% EtOAc in heptane. Pure product fractions were combined and concentrated under reduced pressure to yield 3-methoxy-6,7-dihydro-5H-cyclohepta[c]pyridin-8(9H)-one (126) (0.922 g, 67%); LC/MS, method 3, Rt=1.66 min, MS m/z 192 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 6.57 (s, 1H), 3.92 (s, 3H), 3.63 (s, 2H), 2.93-2.85 (m, 2H), 2.61-2.54 (m, 2H), 2.04-1.94 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:7]=2[C:16]2[C:17]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34](O)=[O:35])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:3][CH2:2]1.[NH2:37][C@H:38]1[CH2:43][CH2:42][C@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:40][CH2:39]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:15])[F:14])=[CH:8][C:7]=2[C:16]2[C:17]3[N:24]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([CH3:33])=[C:22]([C:34]([NH:37][C@H:38]4[CH2:43][CH2:42][C@H:41]([NH:44][C:45](=[O:51])[O:46][C:47]([CH3:49])([CH3:48])[CH3:50])[CH2:40][CH2:39]4)=[O:35])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:2][CH2:3]1
Reactant: Cc1c(C(=O)O)c2ncnc(-c3cc(C(F)(F)F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Product: Cc1c(C(=O)N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c2ncnc(-c3cc(C(F)(F)F)ccc3OCC3CC3)c2n1COCC[Si](C)(C)C

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-(trifluoromethyl)phenyl]-6-methyl-5-{[2-(trimethylsilyl)ethoxy]methyl}-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example D.c8) and commercially available tert-butyl trans-(4-amino-cyclohexyl)-carbamate the title compound is obtained as colorless foam.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([S:15]([C:18]2[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=2)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:9]1([S:15]([C:18]2[CH:19]=[CH:20][C:21]([O:27][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:22]([C:24](=[O:26])[CH3:25])[CH:23]=2)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(S(=O)(=O)c2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl bromide (1.443 g; 0.0087 mol) was added to a suspension of 1-(5-benzenesulfonyl-2-hydroxy-phenyl)-ethanone (2.01 g; 0.0073 mol) and potassium carbonate (2.01 g; 0.015 mol) in acetonitrile (5.0 mL). The mixture was heated under reflux for 18 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate, filtered, washed with water and saturated sodium bicarbonate, dried (Na2SO4) and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel (hexane-ethyl acetate; 7:3) to give 1-(5-benzenesulfonyl-2-benzyloxy-phenyl)-ethanone as a white solid (2.17 g; 81%). A sample was recrystallized from diethyl ether-hexane: M. p. 80.5-82.4° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH3:17])[C:3]=12.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26]O)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:26][CH2:25][N:22]3[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]3)[N:15]=[C:16]([CH3:17])[C:3]=12
Reactant: Cc1n[nH]c2nnc(-c3ccccc3)c(Cl)c12
Reactant: CN1CCN(CCO)CC1
Product: Cc1nn(CCN2CCN(C)CC2)c2nnc(-c3ccccc3)c(Cl)c12

Procedure:
Compound Iv was synthesized from 4-chloro-3-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(4-methylpiperazin-1-yl)ethanol following the general procedure for the Mitsunobu reaction described above.
Reaction SMILES: [CH3:1][S:2][C:3]1[NH:4][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[N+](=[CH2:20])=[N-].C(O)(=O)C>CCOCC>[CH3:20][N:7]1[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:4]=[C:3]1[S:2][CH3:1]
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)c1nc(SC)[nH]c1C(=O)OCC
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOC(=O)c1nc(SC)n(C)c1C(=O)OCC
Reaction time: 8 h
Yield: 97 %

Procedure:
The diethyl 2-(methylthio)-4,5-imidazoledicarboxylate (10 g; 0.039 mol) was slowly added in small portions to a solution of diazomethane in ether (containing approximately 3 g of diazomethane). Nitrogen was evolved immediately and the solution was allowed to stand at room temperature overnight. Excess diazomethane was then decomposed by the addition of dilute acetic acid and the reaction mixture was worked up in the usual way. Diethyl 1-methyl-2-(methylthio)-4,5-imidazoledicarboxylate (10.2 g; 97%) was obtained as a thick yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]=[C:10]=[S:11].C1COCC1.[CH2:17]([NH2:20])[CH2:18][NH2:19].Cl>O>[NH2:19][CH2:18][CH2:17][NH:20][C:10]([NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[S:11]
Reactant: S=C=Nc1c(Cl)cccc1Cl
Reactant: NCCN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: NCCNC(=S)Nc1c(Cl)cccc1Cl
Reaction time: 0.5 h

Procedure:
A solution of 2,6-dichlorophenyl isothiocyanate (500 mg) and THF (5 ml) was added dropwise under argon within 20 minutes to a solution of ethylenediamine (3.68 g) and abs. THF (4 ml). After stirring for a further 30 min, the mixture was added to water, acidified with 10% HCl and extracted three times with ethyl acetate. The aqueous phase was made basic using saturated potassium carbonate solution, and extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulfate, the solvent was removed under reduced pressure and the residue was co-evaporated twice with toluene. After drying in high vacuum, the desired product was obtained as a white solid (532 mg).
Reaction SMILES: [K].[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([OH:15])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:20][Cl:21]>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:15][CH2:20][Cl:21])=[O:14])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc(OCc2ccccc2)c1
Reactant: ClCBr
Agent: [K]
Solvent: CN(C)C=O
Product: O=C(OCCl)c1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To the potassium salt of 3-benzyloxybenzoic acid (2.39 g, 8.91 mmol) was added the bromochloromethane (8.7 ml, 15 eq.) and DMF (10.7 mL). The mixture was then stirred at room temperature for 12-18 hours. The mixture was then filtered and the filtrate concentrated. Purification of the crude product via flash chromatography (EtOAc: Hexanes 1:10) yielded 1.2 g of the title compound as a light yellow oil. 1H NMR (300 MHz, CDCl3) δ=5.12 (s, 2H), 5.96 (s, 2H), 7.22-7.25 (m, 1H), 7.26-7.47 (m, 6H), 7.68-7.72 (m, 2H), MS(ESI) 276.
Reaction SMILES: Cl.[CH2:2]1[N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[N:13]=[CH:14][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]3)[CH2:3]1.C(O)C.[BH4-].[Na+]>O>[CH2:2]1[N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[NH:13][CH2:14][C:8]3=[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]3)[CH2:3]1
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1cc2c3c(c1)CNc1ccccc1N3CC2
Reaction time: 1 h

Procedure:
A stirred mixture, under N2, of 18.0 g of 1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine hydrochloride and 100 ml of absolute ethanol is cooled to 0° C., and sodium borohydride is added in small portions and at such a rate as to minimize frothing and to keep the reaction temperature below 5° C. The addition takes about 1 hour and 3 g of NaBH4 is required to discharge the initial maroon color, and another 0.5 g is added to insure complete reduction. An hour later, water is added in portions to decompose excess reagent and maximize precipitation of product. The crystalline solid is filtered, washed well with water and dried to yield 1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 175°-177° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.Cl.[NH:31]1[CH:35]=[C:34]([CH2:36][CH2:37][C:38]([OH:40])=O)[N:33]=[CH:32]1.[NH2:41][C@H:42]([CH2:60][C:61]1[CH:66]=[CH:65][C:64]([O:67][CH3:68])=[CH:63][CH:62]=1)[C:43]([N:45]1[CH2:48][C:47]([CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]2)([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:46]1)=[O:44]>CN(C=O)C>[CH:54]1([C:47]2([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])[CH2:46][N:45]([C:43](=[O:44])[C@H:42]([NH:41][C:38](=[O:40])[CH2:37][CH2:36][C:34]3[N:33]=[CH:32][NH:31][CH:35]=3)[CH2:60][C:61]3[CH:62]=[CH:63][C:64]([O:67][CH3:68])=[CH:65][CH:66]=3)[CH2:48]2)[CH2:59][CH2:58][CH2:57][CH2:56][CH2:55]1
Reactant: CCCCCC1(C2CCCCC2)CN(C(=O)[C@H](N)Cc2ccc(OC)cc2)C1
Reactant: O=C(O)CCc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC1(C2CCCCC2)CN(C(=O)[C@@H](Cc2ccc(OC)cc2)NC(=O)CCc2c[nH]cn2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 55.3 %

Procedure:
100 mg (0.311 mmol) of TBTU and 0.1 ml (0.715 mmol) of triethylamine are added to 55 mg (0.311 mmol) of 3-(1H-imidazol-4-yl)propionic acid hydrochloride in 1 ml of DMF. After 10 minutes, 99 mg (0.256 mmol) of (R)-2-amino-1-(3-cyclohexyl-3-pentylazetidin-1-yl)-3-(4-methoxyphenyl)propan-1-one dissolved in 1 ml of DMF are added. After stirring for 118 hours at ambient temperature, the reaction medium is extracted with a 1/2 heptane/EtOAc mixture and washed with 1N sodium hydroxide and a saturated sodium chloride solution. The organic phase is dried over MgSO4, filtered and concentrated. The residue is purified on a silica column (eluent 9/1 DCM/MeOH). 72 mg of N—[(R)-2-(3-cyclohexyl-3-pentylazetidin-1-yl)-1-(4-methoxybenzyl)-2-oxoethyl]-3-(1H-imidazol-4-yl)propionamide are obtained in the form of a white powder, with a yield of 55%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:26])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:7]=[N:8][N:9]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14](O)=[O:15])[C:10](=[O:12])[CH:11]=1.[CH3:27][C:28]1([CH3:40])[O:32][C@H:31]([CH2:33][N:34]2[CH:38]=[CH:37][C:36]([NH2:39])=[N:35]2)[CH2:30][O:29]1>>[Cl:1][C:2]1[C:3]([F:26])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:7]=[N:8][N:9]([CH:13]([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:14]([NH:39][C:36]2[CH:37]=[CH:38][N:34]([CH2:33][C@@H:31]3[CH2:30][O:29][C:28]([CH3:40])([CH3:27])[O:32]3)[N:35]=2)=[O:15])[C:10](=[O:12])[CH:11]=1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc(Cl)c2F)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4cccc(Cl)c4F)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 2-[4-(3-chloro-2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid (Intermediate 82) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-[4-(3-chloro-2-fluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-propionamide as an off-white solid as a mixture of diastereomers (1.24 g, 84%).
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[C:7]([O:11][CH3:12])(=[O:10])[CH:8]=[CH2:9].[F-].[K+]>C(O)C>[CH3:5][C:4]([N+:1]([O-:3])=[O:2])([CH3:6])[CH2:9][CH2:8][C:7]([O:11][CH3:12])=[O:10]
Reactant: C=CC(=O)OC
Reactant: CC(C)[N+](=O)[O-]
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)CCC(C)(C)[N+](=O)[O-]
Yield: 82.8 %

Procedure:
2-Nitropropane (25 g, 0.28 mol) was dissolved in ethanol (140 ml) and methyl acrylate (25.3 ml, 0.28 mol) and potassium fluoride (1.63 g, 0.028 mol) were added. The mixture was refluxed under heating for 4 h. After cooling, ethanol was evaporated by concentration under reduced pressure, and the residue was extracted with ethyl acetate (100 ml) and water (50 ml). Ethyl acetate was evaporated under reduced pressure to give the objective compound (40.6 g, yield 82.5%).