Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CCC3CCCCC3)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: BrCCC1CCCCC1
Agent: CC(C)(C)OC(=O)N1CCc2nn(CCC3CCCCC3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(CCC3CCCCC3)c3c2CCNCC3)cc1

Procedure:
The title compound (0.056 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using 1-bromo-2-cyclohexylethane (0.053 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-(2-cyclohexyl-ethyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C21H28ClN3, 357.20; found, m/z 358.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.46-7.34 (m, 4H), 4.08 (t, J=7.6 Hz, 2H), 3.37-3.35 (m, 2H), 3.27-3.25 (m, 2H), 3.13-3.11 (m, 2H), 2.94-2.92 (m, 2H), 1.68-1.20 (m, 7H), 1.18-1.05 (m, 4H), 0.93-0.86 (m, 2H).
Reaction SMILES: [CH:1]1[CH:20]=[CH:19][C:17](=[O:18])/[C:3](=[CH:4]/[NH:5][CH2:6][CH2:7][NH:8]/[CH:9]=[C:10]2/[CH:11]=[CH:12][CH:13]=[CH:14][C:15]/2=[O:16])/[CH:2]=1.CC([O-])=O.CC([O-])=O.[Cu+2:29]>C(O)C>[CH:12]1[CH:11]=[C:10]([CH:9]=[N:8][CH2:7][CH2:6][N:5]=[CH:4][C:3]2[C:17]([O-:18])=[CH:19][CH:20]=[CH:1][CH:2]=2)[C:15]([O-:16])=[CH:14][CH:13]=1.[Cu+2:29]
Reactant: O=C1C=CC=C/C1=C/NCCN/C=C1\C=CC=CC1=O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCO
Product: [O-]c1ccccc1C=NCCN=Cc1ccccc1[O-]
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Anhydrous ethanol was added to a mixture of Salen and Cu(OAc)2 under argon via a syringe. The reaction mixture was stirred at 80° C. for 24 hours. The solvent was removed under reduced pressure, yielding a dark green powder Salen-Cu.
Reaction SMILES: [C:1]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl.[CH2:17]([NH:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](Cl)=[O:38])=[CH:35][CH:34]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31]>COCCOC>[CH2:17]([NH:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])=[O:38])=[CH:40][CH:41]=1)[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH2:31]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: C=CCCCCCCCCC=CCCCNc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C=CCCCCCCCCC=CCCCNc1ccc(C(=O)C(C(=O)OCC)C(=O)OC(C)(C)C)cc1

Procedure:
A solution of 28.0 g. of tert-butyl ethyl malonate in 10 ml. of 1,2-dimethoxyethane is added to a suspension of 4.0 g. of sodium hydride in 1,2-dimethoxyethane under argon. A solution of 17.3 g. of 4-(1-pentadeca-4,14-dienylamino) benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is refluxed for 5 hours, cooled, poured on ice and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated to dryness. The residue is then recrystallized from ether to yield tert-butyl ethyl 4-(1-pentadeca-4,14-dienylamino)benzoylmalonate.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[N+:25]([O-])=O)[CH:10]=1>ClCCl.CO.[Pd]>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][NH:7][C:8](=[O:28])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:25])[CH:10]=1
Reactant: CC(C)Oc1ccc([N+](=O)[O-])c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CC(C)Oc1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(5-isopropoxy-2-nitrophenyl)isonicotinamide (270 mg, 0.53 mmol, 1.00 equiv, 90%) in dichloromethane/methanol (3/6 mL). The solution was treated with Pd/C (270 mg), and stirred under an atmosphere of hydrogen for 2 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum to yield 230 mg (91%) of product as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[N:15]([C@@H:30]2[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:31]2)[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:48](C=O)C>C([O-])(=O)C.[NH4+].C(O)(=O)C.CC(=O)OCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:37])[CH2:31]3)[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]([F:27])([F:29])[F:28])[CH:20]=3)[N:48]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)N(CC(=O)c2ccc(F)c(C(F)(F)F)c2)[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2[C@@H]2CCCN(C(=O)OCc3ccccc3)C2)CC1
Yield: 75 %

Procedure:
Heat a solution of 4-{((R)-1-benzyloxycarbonyl-piperidin-3-yl)-[2-(4-fluoro-3-trifluoromethyl-phenyl)-2-oxo-ethyl]-carbamoyl}-piperidine-1-carboxylic acid tert-butyl ester (4.40 mmol; 2.86 g) in DMF (2.5 mL) and ammonium acetate saturated in acetic acid (15 mL) at 90° C. for 8 h. Dilute with EA, wash the organic phase 3× with water, saturated sodium bicarbonate, brine, dry over MgSO4 and filter. Purify the residue on 80 g silica gel with 5-20% EA/DCM to provide the title compound (2.08 g; 3.30 mmol; 75%). MS (ES+): m/z=631 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)(=[O:8])=[O:7])[N:3]=[N:2]1.[C:22]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:22][N:1]1[CH:5]=[C:4]([S:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)(=[O:8])=[O:7])[N:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c[nH]nn2)CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(S(=O)(=O)N2CCN(C(=O)OC(C)(C)C)CC2)nn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution tert-butyl 4-(1H-1,2,3-triazol-4-ylsulfonyl)piperazine-1-carboxylate (0.54 g, 1.15 mmol) in DMF (10 mL) at 0° C. was added K2CO3 (0.32 g, 2.30 mmol) followed by MeI (0.09 mL, 1.49 mmol) drop wise. Then the reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture was concentrated under reduced pressure and dissolved in CH2Cl2 (20 mL), washed with H2O (20 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Companion unit, 12 g Redisep column, 9:1 mixture of CH2Cl2/CH3OH) to give tert-butyl 4-(1-methyl-1H-1,2,3-triazol-4-ylsulfonyl)piperazine-1-carboxylate as a white foam (32, 0.30 g, 57%): MS (ESI+) m/z 332.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=2[C:23]([F:26])([F:25])[F:24])[CH:9]=[CH:8][C:4]=1[C:5](O)=[O:6].[OH:28][C:29]1[CH:44]=[CH:43][C:32]([CH2:33][NH:34][CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[OH:28][C:29]1[CH:44]=[CH:43][C:32]([CH2:33][N:34]([CH2:35][C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])[C:5](=[O:6])[C:4]2[CH:8]=[CH:9][C:10]([NH:12][C:13](=[O:27])[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[C:23]([F:26])([F:25])[F:24])=[CH:11][C:3]=2[O:2][CH3:1])=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(O)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)c(OC)c2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(O)cc3)c(OC)c2)c(C(F)(F)F)c1
Yield: 99 %

Procedure:
Prepared using General Procedure 6: To a stirred solution of 2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-23 (404 mg, 1.05 mmol), tert-butyl 2-((4-hydroxybenzyl)amino)acetate INT-22 (250 mg, 1.05 mmol) and TEA (367 μL, 2.63 mmol) in DMF (5 mL) was added HATU (421 mg, 1.11 mmol). After 2 h the reaction mixture was diluted with EA (100 mL) and washed with brine (2×150 mL). The organics were pre-absorbed onto silica gel and then purified by chromatography (EA/isohexanes) to afford 633 mg (99%) of tert-butyl 2-(N-(4-hydroxybenzyl)-2-methoxy-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-24 as a waxy solid. LCMS-ESI (m/z) calculated for C31H33F3N2O7: 602 found 601 [M−H]−, tR=2.29 min (Method 10). 1H NMR (400 MHz, DMSO 100° C.) δ 10.25 (s, 1H), 9.28 (s, 1H), 7.52-7.41 (m, 2H), 7.27-7.04 (m, 5H), 6.95 (d, J=8.0 Hz, 1H), 6.72 (dd, J=20.5, 7.9 Hz, 2H), 4.52 (br s, 1H), 4.22 (s, 1H), 3.81 (m, 9H), 3.62 (s, 1H), 1.40 (d, J=2.1 Hz, 4.5H), 1.30 (d, J=2.1 Hz, 4.5H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[C:9]([Si:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:12])([CH3:11])[CH3:10].S(Cl)(C)(=O)=O.[N-:32]=[N+]=[N-].[Li+].[N-]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>N1C=CC=CC=1.CN(C=O)C>[Si:13]([CH:6]([OH:7])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH2:32])([C:9]([CH3:12])([CH3:11])[CH3:10])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCCCCCO
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)CCCCCN

Procedure:
1,6-Hexanediol is monosilylated with tert-butylchloro-diphenylsilane (1 equivalent) in dry pyridine. It is then mesylated with mesyl chloride in pyridine and subsequently treated with lithium azide in DMF solvent. The resulting azide derivative is reduced with triphenyl phosphine to give the title compound.
Reaction SMILES: Br[CH:2]1[C:8]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:10][O:11][C:7]=2[CH2:6][CH:5]([C:19]([O:21][CH3:22])=[O:20])[CH2:4][CH2:3]1.[CH3:23][S-:24].[Na+]>CN(C)C=O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[C@H:2]([S:24][CH3:23])[CH2:3][CH2:4][C@H:5]([C:19]([O:21][CH3:22])=[O:20])[CH2:6][C:7]=3[O:11][N:10]=2)=[CH:13][CH:14]=1.[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[C:8]3[C@H:2]([S:24][CH3:23])[CH2:3][CH2:4][C@@H:5]([C:19]([O:21][CH3:22])=[O:20])[CH2:6][C:7]=3[O:11][N:10]=2)=[CH:13][CH:14]=1
Reactant: C[S-]
Reactant: COC(=O)C1CCC(Br)c2c(-c3ccc(Cl)cc3)noc2C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CC[C@@H](SC)c2c(-c3ccc(Cl)cc3)noc2C1
Product: COC(=O)[C@H]1CC[C@@H](SC)c2c(-c3ccc(Cl)cc3)noc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.5 g (1.3 mmol) of a cis/trans mixture of methyl 4-bromo-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4H-cyclohept[d]isoxazole-7-carboxylate (prepared as described in Example 9) in 5 ml of dry dimethylformamide was stirred, cooled in ice and treated with 0.15 g (2.1 mmol) of sodium methanethiolate. The mixture was stirred at room temperature for 24 hours and then evaporated. The residue was partitioned between water and dichloromethane and the organic phase was dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel using dichloromethane for the elution and there were obtained 0.028 g of methyl cis-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methylthio-4H-cyclohept[d]isoxazole-7-carboxylate of melting point 110°-112° C. and 0.041 g of methyl trans-3-(4-chlorophenyl)-5,6,7,8-tetrahydro-4-methylthio-4H-cyclohept[d]isoxazole-7-carboxylate of melting point 127°-128° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[C@H:3]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5].[C:27](Cl)(=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31].N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.C(OC(=O)C)C>[CH3:1][CH:2]([CH3:26])[C@H:3]([N:7]([C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:22][N:23]=[N:24][N:25]=2)=[CH:13][CH:14]=1)[C:4]([OH:6])=[O:5]
Reactant: CC(C)[C@H](NCc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C(=O)O
Reactant: CCCCC(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)[C@H](C(=O)O)C(C)C
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A suspension of (S)-3-methyl-2-((2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl)-amino)-butyric acid (17.6 g; 50.0 mmol) in 1,2-dimethoxyethan (116 g) is cooled to −5° C., and valeroyl-chloride (9.9 ml; 80 mmol) is added, followed by slow addition of pyridine (6.0 ml; 75 mmol) diluted with 1,2-dimethoxyethane (60 ml). [1] After completion of the reaction, the reaction mixture is quenched with methanol (18 ml). Finally water (50 ml) is added at room temperature, and after stirring for 1 h, the mixture is adjusted to pH 7.5 by addition of aqueous sodium carbonate solution 10% (˜116 ml, 120 mmol) at 0° C. The organic solvents are stripped off at 50° C. in vacuo. Ethylacetate (125 ml) is added to the remaining aqueous concentrate, and the two-phase system is adjusted to pH 2 at 0-5° C. by addition of 2.0 M HCl (˜98 ml). The organic phase is separated and concentrated at 45° C. in vacuo (water is azeotropically removed). The crystallization of the product is initiated at 45° C. and—after addition of cyclohexan (102 ml)—completed by cooling to −5° C. The solid is collected by filtration, and after drying at 50° C., (S)-3-methyl-2-{pentanoyl-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid is received as a white powder.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[Br:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>CN(C=O)C>[Br:31][C:32]1[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:33]=1[C:34]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:35]
Reactant: O=C(Cl)c1ccc(Cl)cc1Br
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccc(Cl)cc1Br

Procedure:
1-(2-Bromo-4-chlorobenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 2-bromo-4-chlorobenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:8]=[CH:7][NH:6][N:5]=1.C1C(=O)N([Cl:16])C(=O)C1>C(Cl)(Cl)Cl>[Cl:16][C:8]1[C:4]([CH2:3][O:2][CH3:1])=[N:5][NH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COCc1cc[nH]n1
Solvent: ClC(Cl)Cl
Product: COCc1n[nH]cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.3 %

Procedure:
To a solution of 3-(methoxymethyl)-1H-pyrazole (compound 281.1, 200 mg, 1.78 mmol) in chloroform (20 mL) was added NCS (237 mg, 1.77 mmol). The reaction mixture was stirred overnight at room temperature, then quenched with 20 mL of H2O. The aqueous phase was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with EtOAc:PE (1:2) as the eluent to furnish 50 mg (19%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][NH2:18])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2.C(O)(=O)C.[S:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH:30]=O)[CH2:25][CH2:24]1.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:30]([CH2:29][CH:26]3[CH2:27][CH2:28][S:23][CH2:24][CH2:25]3)=[N:18][N:17]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([CH3:16])[CH:6]=2
Reactant: O=CCC1CCSCC1
Reactant: COC(=O)c1cc2nc(Cl)c(NN)nc2cc1C
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1cc2nc(Cl)c3nnc(CC4CCSCC4)n3c2cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.2 %

Procedure:
To a mixed liquid of 1.40 g of methyl 3-chloro-2-hydrazino-7-methylquinoxaline-6-carboxylate and 28.0 mL of acetic acid was added 820 mg of tetrahydro-2H-thiopyran-4-ylacetaldehyde, followed by stirring at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and to the residue was added 28.0 mL of N,N-dimethylformamide, followed by replacement with argon. Then, a mixed liquid of 706 mg of copper(II) chloride and 28.0 mL of N,N-dimethylformamide was added thereto, followed by stirring at 50° C. for 20 minutes and at 100° C. for 1 hour. To the reaction liquid were added water and chloroform, followed by extraction with chloroform, the organic layer was washed with 1 M hydrochloric acid, water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine and, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 600 mg of methyl 4-chloro-8-methyl-1-(tetrahydro-2H-thiopyran-4-ylmethyl)[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate as a brown solid.
Reaction SMILES: [OH:1][C@@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:18])=[C:13]([CH2:15][O:16][CH3:17])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:3]1[OH:25].CS(O)(=O)=O.ClCCl>COCCO>[OH:25][C@H:3]1[C@@H:2]([O:1][CH2:13][CH2:15][O:16][CH3:17])[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:18])=[C:13]([CH2:15][O:16][CH3:17])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1.[OH:25][C@H:3]1[C@H:2]([O:1][CH2:13][CH2:15][O:16][CH3:17])[C:11]2[CH:10]=[CH:9][N:8]3[C:12]([CH3:18])=[C:13]([CH2:15][O:16][CH3:17])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COCc1nc2c3c(ccn2c1C)[C@@H](O)[C@H](O)[C@@H](c1ccccc1)N3
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: COCCO
Product: COCCO[C@@H]1c2ccn3c(C)c(COC)nc3c2N[C@H](c2ccccc2)[C@H]1O
Product: COCCO[C@H]1c2ccn3c(C)c(COC)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 55 °C
Yield: 36 %
Yield: 17 %

Procedure:
2.0 g of (7R,8R,9R)-7,8-dihydroxy-2-methoxymethyl-3-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine are dissolved in 50 ml 2-methoxyethanol and 1 ml of methane sulfonic acid is slowly added. The reaction is heated at 55° C. for 3 h and subsequently poured onto 80 ml icewater and 100 ml dichloromethane. The organic layer is separated and the aqueous phase extracted three times with dichloromethane. The combined organic phases are dried over anhydrous sodium sulfate and the solvent removed in vacuo. The two diastereomers are separated by column chromatography on silica gel (eluent: diethyl ether) to afford 850 mg (36%) of (7S,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-methoxymethyl-3-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine (28a, m.p. 63-65° C.) and 400 mg (17%) of (7R,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2-methoxymethyl-3-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine (28b, m.p. 5-53° C.).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1[Cl:8].[C:10]([N:14]=[C:15]=[S:16])([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C>CCOC(C)=O.O>[C:10]([NH:14][C:15]1[S:16][C:3]2[N:4]=[CH:5][N:6]=[C:7]([Cl:8])[C:2]=2[N:1]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)N=C=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)Nc1nc2c(Cl)ncnc2s1
Temperature: 50 °C
Reaction time: 16 h
Yield: 48.3 %

Procedure:
A mixture of 5-Amino-4,6-dichloropyrimidine (9.0 g, 55 mmol), tert-butylisothiocyanate (7.02 g, 61.0 mmol), Cesium Carbonate (39.7 g, 122 mmol) and acetonitrile (200 mL) was stirred at 50° C. for 16 hours. The mixture was allowed to cool to rt. To the mixture, were added water and EtOAc. After being stirred for 30 min, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Column chromatography was performed to yield the title compound (6.45 g, 48%) as a white solid. LCMS: (AA) ES+ 243, 245. 1H NMR (400 MHz, d6-DMSO) δ: 8.71 (bs, 1H), 8.49 (s, 1H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[N+:7]([O-])=O.[H][H].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(N(CC)CC)C.[Pt]=O>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[NH:7][C:12](=[O:14])[CH3:13]
Reactant: Cn1cccc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccn1C

Procedure:
1-Methyl-2-nitropyrrole (15.0 g, 0.1189 mol) in acetic anhydride (60 ml) and triethylamine (150 ml) was hydrogenated over platinum oxide (1.50 g) at room temperature and pressure. The reaction was halted when 3.3 equivalents of hydrogen had been taken up. The catalyst was filtered off and the filtrate evaporated in vacuo to leave a dark oil (18.1 g). This was chromatographed on a silica column using 10% ethyl acetate/ether as solvent to give a clear oil (8.7 g) which discoloured rapidly on exposure to light and/or air. This was then distilled under vacuum to give a colourless oil (7.20 g) (44%). b.p. (airbath) 130° C/0.15 mm. The mass spectrum showed a mass ion at 138 and infra-red and proton magnetic resonance spectra also supported the structure.