Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N+:21]([O-:23])=[O:22])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Reactant: O=Cc1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)ccc1Oc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a stirred solution of 5-chlorosalicylaldehyde (8.56 g) in N,N-dimethylformamide (90 mL) under nitrogen was added, in portions, sodium hydride (1.37 g). To the resulting solution was added 2,5-dichloro-1-nitrobenzene (10.0 g) and N,N-dimethylformamide (10 mL), and the reaction was heated at 100° C. under nitrogen for 6 hours. The reaction was evaporated under vacuum, and the residue was partitioned between chloroform and 1 N NaOH. The layers were separated, and the aqueous layer was extracted once more with chloroform. The combined chloroform extracts were washed with 1 N NaOH, water, 1 N HCl, water, and brine, dried over magnesium sulfate, and evaporated under vacuum. Crystallization from methanol yielded the title compound as a yellow solid. Mp: 128°-130° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[N:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[S:10][CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:22]I.O>CN(C)C=O>[C:16]([O:15][C:13]([N:12]([CH3:22])[C:9](=[N:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[S:10][CH3:11])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSC(=NC(=O)OC(C)(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1,3-Di-(tert-butoxycarbonyl)-2-methyl-isothiourea (Japanese Patent Unexamined Publication No. 2-3661) (2.00 g) was dissolved in N,N-dimethylformamide (20 ml), followed by adding thereto 60% sodium hydride (331 mg), and the resulting mixture was stirred at 50° C. for 2 hours. After the mixture was cooled to 0° C., methyl iodide (1.96 g) was added and the resulting mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate, and the extract solution was washed with water and dried. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography to obtain the desired compound (2.07 g).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:42])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]2[N:25]([CH2:26][CH3:27])[C:24]([C@H:28]([NH:30][S:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=3)(=[O:33])=[O:32])[CH3:29])=[N:23][N:22]=2)[CH:15]=1)(C)(C)C>C(Cl)(Cl)Cl>[Cl:41][C:36]1[CH:35]=[C:34]([S:31]([NH:30][C@@H:28]([C:24]2[N:25]([CH2:26][CH3:27])[C:21]([O:20][C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[C:13]([OH:42])=[O:12])=[N:22][N:23]=2)[CH3:29])(=[O:33])=[O:32])[CH:39]=[CH:38][C:37]=1[Cl:40]
Reactant: CCn1c(Oc2cccc(C(=O)OC(C)(C)C)c2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCn1c(Oc2cccc(C(=O)O)c2)nnc1[C@@H](C)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 43.3 %

Procedure:
Trifluoroacetic acid (0.12 ml) was added to a solution of the compound (260 mg) of Example 18 in chloroform (12.0 ml), and the mixture was stirred at room temperature for five days. The mixture was evaporated to remove the solvent, and the resulting crude product was purified by column chromatography (neutral OH SiO2, ethyl acetate/hexane=50-99%, methanol/chloroform=0-20%) and then recrystallized (methanol/chloroform/hexane) to give the titled compound (Compound 113) (101 mg, colorless powder).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]([C:25]1([CH3:39])[CH2:30][CH2:29][C:28]2[C:31]([CH3:38])=[C:32]([OH:37])[C:33]([CH3:36])=[C:34]([CH3:35])[C:27]=2[O:26]1)#[CH:24].C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:24]#[C:23][C:25]3([CH3:39])[CH2:30][CH2:29][C:28]4[C:31]([CH3:38])=[C:32]([OH:37])[C:33]([CH3:36])=[C:34]([CH3:35])[C:27]=4[O:26]3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Solvent: CCO
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cc3c(s1)-n1c(C)nnc1CN=C3c1ccccc1Cl)O2

Procedure:
The title compound was obtained by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno-[3,2-f][1,2,4]triazolo[4,3-a][4,1]diazepine with rac-2-ethynyl-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol under the conditions described in Example 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of rac-2-{[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][4,1]diazepin-2-yl]ethynyl}-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol with m.p. 155°-160° with foaming. These crystals contained 1.5 molar amounts of water on the basis of the analytical and spectral data.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]2[CH:15]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[Cl:16])=[CH:9][CH:10]=1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 4-(5-bromo-2-chlorobenzyl)phenol (6 g, 20.16 mmol, prepared as described in WO2006120208) in dry DMF (25 mL), was added Cs2CO3 (18.2 g, 60.6 mmol) and allyl bromide (4.2 mL, 50.6 mmol) at 0° C. and the reaction mixture was stirred at r.t. for 2 h. After the completion of the reaction as monitored by TLC, the reaction mixture was diluted with ethyl acetate (200 mL) and washed with water (3×30 mL). The combined organic layers were dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 0.4:9.6 Ethyl acetate:Pet. Ether) to afford the title compound (6.1 g, 89.6%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH2:15][C:14]([C:17]([O:19]C(C)(C)C)=[O:18])=[CH:13][C:12]=3[CH:24]=2)=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>CCCCCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:16][CH2:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:12]=3[CH:24]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)OC(C)(C)C)CO3)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CO3)cc1
Reaction time: 16 h
Yield: 86.4 %

Procedure:
To tert-butyl 6-(4-methylphenyl)-2H-1-benzopyran-3-carboxylate (3.00 g) was added 4N hydrochloric acid-ethyl acetate (10 ml) at room temperature, and the mixture was stirred for 16 hours. To the reaction mixture was added hexane, and crystal was collected by filtration and washed with hexane to give 6-(4-methylphenyl)-2H-1-benzopyran-3-carboxylic acid (2.14 g) as pale yellow crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:11]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=2)[C@@H:10]([O:19][Si:20]([CH:27]([CH3:29])[CH3:28])([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])[C:9]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:31][C:32]1[CH:37]=[CH:36][C:35]([SH:38])=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OC(C)C)(C)C>[C:1]([O:5][C:6]([NH:8][C@@H:11]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][N:13]=1)[C@@H:10]([O:19][Si:20]([CH:24]([CH3:25])[CH3:26])([CH:21]([CH3:22])[CH3:23])[CH:27]([CH3:29])[CH3:28])[C:9](=[O:30])[S:38][C:35]1[CH:36]=[CH:37][C:32]([Br:31])=[CH:33][CH:34]=1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Sc1ccc(Br)cc1
Reactant: CC(C)[Si](O[C@H]1C(=O)N(C(=O)OC(C)(C)C)[C@H]1c1ncccc1F)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)OC(C)C
Product: CC(C)[Si](O[C@@H](C(=O)Sc1ccc(Br)cc1)[C@@H](NC(=O)OC(C)(C)C)c1ncccc1F)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A concentrated residue of (3R,4S)-1-(tert-butoxycarbonyl)-4-(3-fluoro-2-pyridyl)-3-triisopropylsilyloxy-2-azetidinone (92.7 mmol) was dissolved in diisopropyl ether (410 mL), and 4-bromothiophenol (18.4 g, 97.3 mmol) and potassium carbonate (14.7 g) were added thereto and stirred at room temperature for about 30 minutes. The disappearance of (3R,4S)-1-(tert-butoxycarbonyl)-4-(3-fluoro-2-pyridyl)-3-triisopropylsilyloxy-2-azetidinone was confirmed, and water (290 mL) was added to it for liquid-liquid separation. The organic layer was separated, washed with saturated saline water (290 mL), and dried over magnesium sulfate. The insoluble matter was removed through filtration, and the filtrate was concentrated under reduced pressure to obtain a residue of S-(4-bromophenyl) (2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanethioate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([CH2:11][C:10](=[O:12])[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7]2)[CH2:2]1.S(O[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:26][CH:25]=1)(=O)(=O)C.C(=O)(O)[O-].[Na+].[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42]>C(O)C>[C:40]([OH:45])(=[O:44])[C:41]([OH:43])=[O:42].[CH3:34][S:31]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][N:1]2[CH2:6][CH2:5][CH2:4][C:3]3([CH2:11][C:10](=[O:12])[C:9]4[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=4[O:7]3)[CH2:2]2)=[CH:25][CH:26]=1)(=[O:33])=[O:32]
Reactant: O=C1CC2(CCCNC2)Oc2ccccc21
Reactant: CS(=O)(=O)Nc1ccc(CCOS(C)(=O)=O)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(CCN2CCCC3(CC(=O)c4ccccc4O3)C2)cc1
Temperature: 25 °C

Procedure:
A solution of 560 mg (258 mmole) of 3,4-dihydrospiro-[(2H)-1-benzopyran-2,3'-piperidine]4-one in 20 mL ethanol was treated with 880 mg (3 mmoles) of 2-(4-methanesulfonamidophenyl)ethyl mesylate and 0.5 g sodium bicarbonate and heated to reflux for 48 hours. The reaction was cooled to room temperature, poured into saturated sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was treated with 1 eq. oxalic acid and the salt was recrystallized from acetone to give product with mp=204°-210° C. Elemental analysis for C22H26N2O4S·C2H2O4 · 1/2H2O Calcd: N, 5.45; C, 56.12; H, 5.69. Found: N, 5.52; C, 56.35; H, 5.54.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][CH:7]([NH2:14])[CH2:6]2.C(=O)(O)[O-].[Na+].Cl[CH2:21][C:22]([NH2:24])=[O:23]>C(O)C>[CH3:13][O:12][C:11]1[CH:10]=[C:9]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[CH2:6][CH:7]([NH:14][CH2:21][C:22]([NH2:24])=[O:23])[CH2:8]2
Reactant: COc1cc2c(cc1OC)CC(N)C2
Reactant: NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc2c(cc1OC)CC(NCC(N)=O)C2

Procedure:
5,6-Dimethoxy-2-indanylamine (0.024 moles, 4.6 g) and sodium bicarbonate (0.026 moles, 2.2 g) are added to a solution of chloroacetamide (0.024 moles, 2.2 g) in absolute ethanol (100 ml) and refluxed for 10 hours. The mixture is filtered at r.t. and the solution is evaporated to dryness. The resulting oil is chromatographed under medium pressure through silica gel (eluent: methylene chloride/methanol=90/10) Yield: 1.95 g (32.7%)--m.p.=135-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH3:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[CH3:26][O:27][C:28](=[O:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]([C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9])[CH3:36]
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CNc1ccccc1C(=O)OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1N(C)C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (100 mg, 0.24 mmol), 2-methylamino-benzoic acid methyl ester (119 mg, 0.722 mmol), BOP (137 mg, 0.312 mmol), DIEA (265 L, 1.08 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 2-{[5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carbonyl]-methyl-amino}-benzoic acid methyl ester: MS m/z: (M+H) 562.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[OH:32][C:33]1([C:36](O)=[O:37])[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=4)[C@@H:19]([NH:21][C:36]([C:33]4([OH:32])[CH2:35][CH2:34]4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1
Reactant: O=C(O)C1(O)CC1
Product: C[C@H](NC(=O)C1(O)CC1)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(C(F)(F)F)cc1

Procedure:
Prepared as described in Example 105 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(trifluoromethyl)phenyl]propan-2-amine (59a, 21 mg, 50 μmol) and 1-hydroxycyclopropanecarboxylic acid (14 mg, 150 μmol). Yield 10 mg (42%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1.O>CN(C=O)C>[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([O:12][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:6]=2[C:7]([O:9][CH3:10])=[O:8])[CH:21]=1
Reactant: COC(=O)c1cc(Cl)ccc1O
Reactant: BrC1C=CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)ccc1OC1C=CCCC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 18.6 g of methyl 5-chlorosalicylate, 28 g of K2CO3 and 20 g of 3-bromocyclohexene in 200 ml of DMF is stirred at 90° C. overnight. The mixture is then Poured into water, extracted with ethyl acetate, washed with water, dried over magnesium sulfate and evaporated to dryness to obtain crude product. This is purified by flash chromatography using hexane as the eluent to give pure methyl 2-(cyclohexen-3-yloxy)-5-chlorobenzoate as the first fraction which is used directly in the next step.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)=[O:6].[C:23](Cl)(=[O:31])[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:3]([NH:2][C:23]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:31])=[C:4]([CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)=[O:6]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2)Oc1ccccc1
Yield: 88 %

Procedure:
2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide hydrochloride (100 mg) was reacted with 50 μl of phenyl chlorocarbonate in 5 ml of tetrahydrofuran in the presence of 150 μl of diisopropylethylamine. The reaction mixture was subjected to extraction with ethyl acetate and water and recrystallization from ethyl acetate/hexane to give 110 mg of 5-chloro-N-(3,4-methylenedioxybenzyl)-2-phenoxycarbonylaminobenzamide (yield: 88%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]C)=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+].O>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Yield: 89.9 %

Procedure:
To a stirred solution of methyl 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylate (24 g, 77.4 mmol) in ethanol (400 mL) was added sodium hydroxide (4.02 g, 100.6 mmol), water (11 mL) and the mixture was stirred at reflux condition for 6 h. Ethanol was distilled off and residue was diluted with water, extracted with ethylacetate (40 mL) adjusted aqueous layer to PH-3 with 1N HCl and extracted with ethyl acetate (3×250 mL), finally organic layer was washed with brine solution, dried over anhydrous Na2SO4 and concentrated. The crude was washed with pet ether, filtered the solid and dried to afford desired product 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (20.6 g, 89.8%).
Reaction SMILES: C([O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])=[CH:11][C:10]=1[C:20]([NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=1)=[O:21])C1C=CC=CC=1.C(O)C>[Pd].C(OCC)(=O)C>[F:30][C:29]([F:31])([F:32])[C:27]1[CH:28]=[C:23]([NH:22][C:20](=[O:21])[C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][C:9]=2[OH:8])[C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[CH:24]=[C:25]([C:33]([F:35])([F:34])[F:36])[CH:26]=1
Reactant: CN(C)C(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
A solution of 4-benzyloxy-N3-[3,5-bis(trifluoromethyl)phenyl]-N1,N1-dimethyl-isophthalamide (141 mg, 0.28 mmol) and 5% Pd—C (14 mg) in the mixture of ethanol (5 ml) and ethyl acetate (5 ml) was stirred at room temperature for 1 hour under hydrogen atmosphere. The reaction mixture was filtered and the filtrate was evaporated under reduced pressure to give the title compound (106 mg, 91.2%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8]C=CC=2.[CH3:16][Al](C)C>O1CCOCC1>[CH3:8][C:9]1[CH:4]=[N:3][CH:16]=[C:2]([CH3:1])[C:10]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1c(C)[nH]c2ccccc12
Reactant: C[Al](C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)cncc1C
Yield: 78 %

Procedure:
To a solution of ethyl 2-methyl-1H-indole-3-carboxylate (2 g, 6.15 mmol), Pd(PPh3)-4(0.36 g, 0.31 mmol) in dioxane (20 mL) was added Me3Al (2 M in THF, 7.69 ml, 15.37 mmol) under N2. The mixture was stirred at reflux overnight. After the complete of the reaction, the reaction was quenched by addition of 5 mL of water and extracted with EtOAc. The extractions were combined, washed with H2O, dried over Na2SO4, and concentrated under vacuum. The residue was purified by flash column (Eluent: PE/EtOAc=15:1) to give ethyl 3,5-dimethylisonicotinate as a yellow solid. (0.9 g, yield 78%). LRMS (M+H+) m/z: calcd 180.2. found 179.01.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH:15]=[CH:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11][C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1.C(O)(=[O:23])C.OO>O>[NH:1]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[CH:15]=[CH:14][C:13]4[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=4[S:11](=[O:23])[C:10]=3[CH:20]=2)=[N:4][N:3]=[N:2]1
Reactant: CC(=O)O
Reactant: C1=Cc2ccc(-c3nnn[nH]3)cc2Sc2ccccc21
Agent: OO
Solvent: O
Product: O=S1c2ccccc2C=Cc2ccc(-c3nnn[nH]3)cc21
Temperature: 65 °C

Procedure:
To a solution of 2.03 g. (7.3 millimoles) of 3-(5-tetrazolyl)dibenzo[b,f]thiepin in 100 cc. glacial acetic acid is added 15 cc. 30% aqueous hydrogen peroxide. The mixture is heated to 65° C. for 10 minutes; the sulfoxide separates from the hot solution. After cooling and diluting with water, the crystalline product is filtered and washed with water. It is then heated on a steam bath in 25 cc. DMF and filtered hot. The solid is washed with methanol and dried. The yield of sulfoxide is 1.55 g. (72%) as a white solid decomposing at 277° C.-279° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5](Cl)[N:4]([CH3:12])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:19]([SH:22])([CH3:21])[CH3:20].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([S:22][CH:19]([CH3:21])[CH3:20])[N:4]([CH3:12])[N:3]=1
Reactant: COC(=O)c1c(Cl)nn(C)c1Cl
Reactant: CC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(Cl)nn(C)c1SC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30 g of methyl 3,5-dichloro-1-methylpyrazol-4-ylcarboxylate and 25.5 g of potassium carbonate are suspended in 150 ml of DMSO and to this suspension are slowly added 16.1 ml of isopropylmercaptan at a temperature of 25° to 35° C. After stirring for 3 hours at room temperature, the reaction mixture is poured into 200 ml of ice-water and then 300 ml of ethyl acetate are added. After phase separation, the organic phase is washed with 100 ml of water and 100 ml of a saturated aqueous solution of sodium chloride, dried over MgSO4 and concentrated to dryness under vacuum. Distillation of the residue (113°-114° C., 2×10-3 bar) gives 31.5 g of 3-chloro-4-(methoxycarbonyl)-1-methyl-5-isopropylthiopyrazole in the form of a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][O:39][Si](C(C)(C)C)(C)C)[C@@H:28]([O:29][Si](C(C)(C)C)(C)C)[C@H:19]2[O:20][Si](C(C)(C)C)(C)C)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[N:12]=[C:13]([NH2:50])[C:14]3[N:15]=[CH:16][N:17]([C:48]=3[N:49]=2)[C@@H:18]2[O:47][C@H:37]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:19]2[OH:20])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2cnc3c(N)nc(OCCc4ccc(Cl)cc4)nc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1nc(OCCc2ccc(Cl)cc2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 46.4 %

Procedure:
To a solution of 2-[2-(4-chlorophenyl)ethoxy]-2′,3′,5′-tri-O-(TERT-butyldimethylsilyl)-adenosine (Example 1, 500 mg, 0.654 mmol) in 7 mL of anhydrous methanol flushed with nitrogen was added 3.27 mL of a 1.0 M solution of TBAF in THF (5 equiv). The reaction was heated to 50° C. for 48 hours. Upon disappearance of the starting material as indicated by LC/MS analysis, the reaction mixture was allowed to cool to room temperature and was concentrated to dryness. Ethyl acetate (20 ml) and water (20 ml) were added and stirred for 5 minutes. The layers were separated and the aqueous layer reextracted with ethyl acetate (2×20 ml). The organic phases were combined, dried over MgSO4 and concentrated to give an oil. The crude material was then purified on silica gel, eluting with a gradient of 0%-10% methanol in CH2Cl2, affording 128 mg (46%) of the desired product as a white solid.