Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:20][C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36]CC)=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[OH-].[Na+]>CN(C)C=O.C(O)C.O1CCCC1.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([N:31]([CH3:30])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:26])=[CH:28][CH:29]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:10][C:9]=2[CH3:19])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1sc(-c2ccccc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 77.4 %

Procedure:
To a mixture of 4-{[cyclohexyl(2-methyl-5-phenylthiophen-3-yl)methyl]amino}benzoic acid (300 mg) synthesized in Example 278 (7), ethyl 3-(methylamino)propanoate (117 mg), 1-hydroxybenzotriazole monohydrate (136 mg) and triethylamine (124 μL) in N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (170 mg), and the mixture was stirred at room temperature for 1.5 days. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give colorless oil. To a mixture of the obtained oil, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 2 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (281 mg, 77%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([OH:12])=O.Cl.CN.[CH2:16]([N:18](CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[CH3:16][NH:18][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:12]
Reactant: O=C(O)c1cc2ccccc2o1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2ccccc2o1
Reaction time: 8 h
Yield: 109.8 %

Procedure:
To a solution of 2-benzofurancarboxylic acid (1.62 9,10 mmole), methylamine hydrochloride (0.79 g. 11 mmole), triethylamine (3.1 mL, 22 mmole), and HOBt 1H2O (1.5 g, 11 mmole) in DMF (30 mL) was added EDC (2.1 g, 11 mmole). The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with 5% NaHCO3 and extracted with CH2Cl2. The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. Flash chromatography on silica gel (3% MeOIVCH2Cl2) gave the title compound (1.75 g, 100%) as white solid: MS (ES) m/e 176 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10](=[O:20])[N:11]([CH3:19])[C:12]=2[C:16](O)=[O:17])[C:7]1=[O:23].C(Cl)(=O)C(Cl)=O.[CH3:34][NH:35][CH3:36].C1COCC1>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:21][CH3:22])[C:10](=[O:20])[N:11]([CH3:19])[C:12]=2[C:16]([N:35]([CH3:36])[CH3:34])=[O:17])[C:7]1=[O:23]
Reactant: COc1c2c(c(C(=O)O)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CNC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1c2c(c(C(=O)N(C)C)n(C)c1=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 6-(3-chloro-4-fluorobenzyl)-4-methoxy-2-methyl-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylic acid (8.50 g, 22 mmol) in methylene chloride (300 mL) at 0° C. was added oxalyl chloride (2.25 mL, 26 mmol) and 1 drop of anhydrous DMF. The reaction was stirred at 0° C. for 15 minutes during which time no bubbling was observed. The reaction was then allowed to warm to room temperature and stirred for 40 minutes. At this time bubbling had ceased, and all material was in solution. An aliquot of the solution was quenched with dimethylamine and checked by LCMS to confirm completion. To the solution of the acid chloride starting material at 0° C. was added dimethylamine in THF (43.56 mL, 87 mmol, 2.0 M). The green/yellow reaction was allowed to stir at room temperature overnight although the reaction appeared to proceed immediately by LCMS. The solvent was removed in vacuo, and the resulting residue was dissolved in chloroform. The solution was washed with water and 5% aqueous HCl solution and back extracted to recover the product. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting iridescent green/yellow residue was examined in several TLC solvent systems (95:5 CH2Cl2:MeOH, 2:1 acetone:hexanes, 1:1 EtOAc:hexanes) with the most efficient separation of some early running impurities achieved in the CH2Cl2:MeOH system. The material was purified by silica gel flash column chromatography, loaded as a solution in methylene chloride onto a 330 g RediSep column. Gradient elution consisted of 1.5 L each of neat CH2Cl2, 1% MeOH:CH2Cl2, 2% MeOH:CH2Cl2, 3% MeOH:CH2Cl2, 4% MeOH:CH2Cl2, and 5% MeOH:CH2Cl2, in sequential order. The desired material began to elute with 3% and was pushed off the column with 4% and 5%, yielding two sets of fraction. The earlier set afforded of the desired product plus a fluorescent green contaminant. The later set afforded clean material.
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([CH3:25])=[C:13]([CH:15]3[C:21](=[O:22])[CH:20]4[CH2:23][CH:17]([CH2:18][CH2:19]4)[C:16]3=[O:24])[CH:14]=2)=[CH:6][CH:5]=1.[OH-].[Li+].Cl>CO>[O:24]=[C:16]1[CH:15]([C:13]2[CH:14]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:26])=[O:2])=[CH:5][CH:6]=3)[S:11][C:12]=2[CH3:25])[C:21](=[O:22])[CH:20]2[CH2:23][CH:17]1[CH2:18][CH2:19]2
Reactant: COC(=O)c1ccc(-c2cc(C3C(=O)C4CCC(C4)C3=O)c(C)s2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1sc(-c2ccc(C(=O)O)cc2)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.6 %

Procedure:
To a solution of 4-[4-(2,4-dioxobicyclo[3.2.1]oct-3-yl)-5-methylthiophen-2-yl]benzoic acid methyl ester (60 mg, 0.16 mmol) in methanol (2 ml) is added 1N aqueous lithium hydroxide solution (2 ml) and the reaction stirred at room temperature for 72 hours. The reaction is acidified with 2N aqueous hydrochloric acid (25 ml) and extracted with dichloromethane (25 ml). The organic layer is washed with brine, dried over magnesium sulphate, filtered and the filtrate is concentrated in vacuo to give 4-[4-(2,4-dioxobicyclo[3.2.1]oct-3-yl)-5-methylthiophen-2-yl]benzoic acid (44 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C1([N:18](C)N)C=CC=CC=1>>[OH:1][C:2]1[C:11]([NH2:18])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CN(N)c1ccccc1
Reactant: Oc1ccc2cccnc2c1
Product: Nc1c(O)ccc2cccnc12
Temperature: 130 °C
Yield: 30.8 %

Procedure:
7-Hydroxyquinoline (1.1 g, 7.5 mmol) and 1-phenyl-1-methylhydrazine (0.92 g, 7.5 mmol) were combined and heated at 130° C. under nitrogen for 16 h. After cooling the solvent was partially evaporated, the crude product was purified by column chromatography with heptane/EtOAc (1:1) as the eluent to give the title compound (370 mg, 31%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.Br[C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:16][C:10]([O:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)([CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: Oc1ccc(Cl)cn1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(Cl)cn1
Temperature: 50 °C

Procedure:
A mixture of 5-chloro-2-hydroxypyridine (5.0 g, 39 mmol), ethyl 2-bromoisobutyrate (5.7 mL, 39 mmol) and cesium carbonate (25 g, 77 mmol) in 50 mL of acetonitrile was heated at 50° C. overnight. The volatile materials were removed by concentrating on a rotary evaporator, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to dryness, and the residue was purified by flash column chromatography on silica gel eluted with 5% ethyl acetate in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.99 (d, m), 7.67 (dd, 1H), 6.68 (d, 1H), 4.13 (q, 2H), 1.64 (s, 6H), 1.14 (t, 3H). LC-MS: m/e 244 (M+H)+ (3.41 min).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[N:6][CH:7]=1.[NH:16]1[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[O:22])[CH2:17]1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:19][CH:18]([NH:20][C:21]([CH2:23][NH:24][C:25](=[O:36])[C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=4)=[O:22])[CH2:17]3)[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(OC2CCC(=O)CC2)nc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1ccc(OC2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)nc1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(5-methyl-pyridin-2-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>CN(C)C=O>[Si:14]([O:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[N:7][CH:6]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: Oc1cnc(Cl)nc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cnc(Cl)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.8 %

Procedure:
To a solution of 20.2 g (0.154 mol) of 2-chloro-5-hydroxypyrimidine in 150 ml of N,N-dimethylformamide, 15.8 g (0.232 mol) of imidazole and 26.8 g (0.178 mol) of tert-butyldimethylsilyl chloride were added, and the reaction mixture was stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction solution was poured into water and extracted with n-heptane three times. The obtained organic phases were combined, washed with 0.01 N sodium hydroxide aqueous solution, water and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to provide 39.5 g of the title compound as a white solid (yield: 100%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:9]1([CH3:26])[CH2:12][N:11]([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10]1)#[N:8].O1CC[CH2:29][CH2:28]1>>[C:14]1([CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:11]2[CH2:10][C:9]([CH2:7][NH:8][CH2:28][CH3:29])([CH3:26])[CH2:12]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1CCOC1
Reactant: CC1(C#N)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCNCC1(C)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
6.1 g (161 mmol) of lithium aluminium hydride are suspended in 250 ml of tetrahydrofuran, and a solution of 21.1 g (80.5 mmol) of 3-cyano-1-diphenylmethyl-3-methylazetidine in 150 ml of tetrahydrofuran are added dropwise during 1 hour. The temperature is maintained during the addition at between 30° and 35° C. and the mixture is then stirred for 12 hours at room temperature. The excess lithium aluminium hydride is destroyed with ethanol, the insoluble inorganic fraction is filtered off, the tetrahydrofuran is removed, the residue is dissolved with chloroform, the organic phase is washed with water, dried with anhydrous sodium sulphate and evaporated to dryness and 16.1 g (75%) of 3-aminomethyl-1-diphenylmethyl-3-methylazetidine, melting point 46°-8° C., are obtained.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:26]=[C:18]3[C:19]4[C:24]([CH2:25][N:17]3[N:16]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(Cl)Cl>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:26]=[C:18]3[C:19]4[C:24]([CH2:25][N:17]3[N:16]=2)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=[CH:13][CH:14]=1
Reactant: c1ccc(COc2cccc(-c3nc4n(n3)Cc3ccccc3-4)c2)cc1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: Oc1cccc(-c2nc3n(n2)Cc2ccccc2-3)c1

Procedure:
2-(3-Benzyloxyphenyl)-5H-s-triazolo[5,1-a] isoindole (17 g) is suspended in 500 ml of ethanol and hydrogenated at atmospheric pressure and room temperature in the presence of 3 g of 10% Pd on charcoal. After addition of 500 ml of methylene chloride, the catalyst is filtered off and the solution is concentrated to dryness. The title product is purified by crystallization from dioxane. Yield 10.68 g (85.7%); m.p. 251-2°C.
Reaction SMILES: CC1CCCN(C)C1(C)C.C([Li])CCC.CCCCCC.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24].[CH:27]([O:30][C:31]([C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([C:43]([O:45][CH:46]([CH3:48])[CH3:47])=[O:44])=[CH:35][CH:34]=1)=[O:32])([CH3:29])[CH3:28].[Cl-].[NH4+]>C1COCC1>[CH:46]([O:45][C:43]([C:36]1[C:37]2[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]([C:31]([O:30][CH:27]([CH3:29])[CH3:28])=[O:32])=[CH:34][C:35]=1[Si:23]([CH3:26])([CH3:25])[CH3:24])=[O:44])([CH3:48])[CH3:47]
Reactant: C[Si](C)(C)Cl
Reactant: CC(C)OC(=O)c1ccc(C(=O)OC(C)C)c2ccccc12
Agent: CC1CCCN(C)C1(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1cc([Si](C)(C)C)c(C(=O)OC(C)C)c2ccccc12
Temperature: -78 °C
Yield: 34.2 %

Procedure:
Under a nitrogen stream, to a solution of tetramethylpiperidine (0.39 mL, 2.311 mmol) in THF (1.8 mL) was added a solution of n-butyllithium in n-hexane (2.67 M, 0.87 mL, 2.323 mmol) under ice cooling, and the resultant solution was stirred for 10 minutes at the same temperature. The solution was cooled to −78° C., and then chlorotrimethylsilane (2.47 mL, 19.325 mmol) and a solution of naphthalene-1,4-dicarboxylic acid diisopropyl ester (0.58 g, 1.931 mmol) in THF (2 mL) were added thereto. The temperature of the solution was raised over 1 hour to room temperature, and then to the solution was added saturated aqueous ammonium chloride to stop the reaction. The resultant mixture was twice extracted with dichloromethane. After drying the organic layer over anhydrous magnesium sulfate, solvent was removed by distillation under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:9)), to thereby obtain the titled compound (246 mg, 34%).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][C:4]=1[CH3:13])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].C(O)(=O)C>O>[C:14]([O:12][C:6]1[CH:5]=[C:4]([CH3:13])[C:3]([CH2:1][CH3:2])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])(=[O:16])[CH3:15]
Reactant: CCc1cc(C(=O)O)c(O)cc1C
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(C(=O)O)c(OC(C)=O)cc1C
Reaction time: 8 h

Procedure:
A mixture of 5-ethyl-4-methylsalicylic acid (15.00 g), acetic anhydride (80 ml) and acetic acid (80 ml) was heated under reflux for 1.5 hours, poured into water (1 l) and allowed to stand overnight. The solid formed was filtered off and recrystallised from benzene to give 2-acetoxy-5-ethyl-4-methylbenzoic acid, m.p. 132°-134° C. (Found; C, 64.71; H, 6.46; C12H14O4 requires; C, 64.85; H, 6.35).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11](O)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:20]1[O:22][C@@H:21]1[CH2:23]OS(C1C=C([N+]([O-])=O)C=CC=1)(=O)=O>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:23][C@@H:21]2[O:22][CH2:20]2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cnn(Cc2ccccc2)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(Cn2cc(C[C@H]3CO3)cn2)cc1
Yield: 73.1 %

Procedure:
1-Benzyl-4-hydroxypyrazole (2 g, 11.5 mmol), potassium carbonate(3.2 g, 23 mmol), and (2s)-glycidyl-3-nitrobenzenesulfonate (2.98 g, 11.5 mmol) were slurried in actone (300 ml) at reflux for 17 hours. The acetone was removed in vacuo, the residue extracted from brine with chloroform, and dried over sodium sulfate. The solvent was removed again and the residue purified by column chromatography (silica gel, chloroform→1% methanol/chloroform) to yield product (1.8 g, 68%). MS, NMR.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:19])[N:14]([CH:16]1[CH2:18][CH2:17]1)C)=O)(C)(C)C.[C:20](O)(C(F)(F)F)=O>C(Cl)Cl>[CH:18]1([CH2:16][NH:14][C:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:19])[CH2:17][CH2:20]1
Reactant: CN(C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C1CC1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCC1CC1)[C@@H]1CCCN1

Procedure:
A solution of (S)-2-(cyclopropyl-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester in 50% TFA in DCM was stirred at rt for 4 hours. The reaction was concentrated and purified to give (S)-pyrrolidine-2-carboxylic acid cyclopropylmethyl-amide.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:16])[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17]1([SH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1CCCCC1>O1CCOCC1>[OH:1][NH:2][C:3](=[O:16])[CH2:4][CH:5]([S:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Sc1ccccc1
Reactant: O=C(C=CCCCCc1ccccc1)NO
Solvent: C1COCCO1
Solvent: C1CCNCC1
Product: O=C(CC(CCCCc1ccccc1)Sc1ccccc1)NO
Temperature: 85 °C

Procedure:
7-Phenyl-hept-2-enoic acid hydroxyamide (0.3 g; 1.4 mmol) is combined with thiophenol (0.26 g; 2.4 mmol) and piperidine (0.04 g; 0.5 mmol) in 1,4-dioxane (6 mL) and heated to 85° C. for 4 hours. After cooling, the reaction is concentrated in vacuo and purified by column chromatography using 5% MeOH/CH2Cl2 to obtain 7-phenyl-3-phenylsulfanylheptanoic acid hydroxyamide.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2)C=N1.[I:19]I>>[I:19][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: c1ccc2[nH]ccc2c1
Agent: c1ccc2[nH]ncc2c1
Product: Ic1c[nH]c2ccccc12

Procedure:
Compounds of formula VIII may also be prepared directly from an indole or indazole of formula XVII by reacting the formula XVII substrate with iodine to give the 3-iodoindole or -indazole of formula XVIII; coupling the formula XVIII compound with an appropriate thiol of formula XIX to give the 3-thioindole or-indazole of formula XX and oxidizing said formula XX compound with a conventional oxidizing agent such as H2O2, m-chloroperbenzoic acid, or the like to afford the desired formula VIII intermediate. The reaction is shown in flow diagram IV.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH2:10][C:11]1[N:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1)=[N+]=[N-].O.[OH-].[Na+]>CCOCC>[NH2:7][CH2:10][C:11]1[N:16]=[C:15]([CH3:17])[C:14]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:13][CH:12]=1
Reactant: Cc1nc(CN=[N+]=[N-])ccc1OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1nc(CN)ccc1OCc1ccccc1
Reaction time: 0.75 h

Procedure:
A solution of 3-benzyloxy-6-chloromethyl-2-methylpyridine (8.02 g) and sodium azide (5.98 g) in 400 ml of ethanol is heated at 80° for 4 hours. The reaction mixture is cooled, filtered and evaporated to yield a residue which is partitioned between ice-cold 0.5N NaOH (150 ml) and ether (150 ml). The organic phase is dried over sodium sulfate and evaporated to yield 6-azidomethyl-3-benzyloxy-2-methylpyridine, NMR: (CDCl3) 2.47 (3H), 4.27 (2H), 4.95 (2H). Lithium aluminum hydride (1.27 g) is added to a solution of 6-azidomethyl-3-benzyloxy-2-methylpyridine (7.18 g) in 120 ml of dry ether at room temperature. After stirring for 45 minutes, 1.3 ml of water, 1.3 ml of 15% sodium hydroxide and 3.8 ml of water are added sequentially. The salts are filtered off and the filtrate is evaporated to yield 6-aminomethyl-3-benzyloxy-2-methylpyridine; NMR: (CDCl3) 1.67 (2H), 2.47 (3H), 3.8 (2H), 4.95 (2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C@H:11]([OH:14])[CH2:12]Cl.[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[CH2:10][C@H:11]1[CH2:12][O:14]1
Reactant: O[C@H](CCl)Cc1cc(F)c(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Fc1cc(F)c(C[C@H]2CO2)cc1F
Reaction time: 1 h
Yield: 85 %

Procedure:
(2S)-3-(2,4,5-trifluorophenyl)-1-chloro-2-propanol obtained in step 1 was dissolved in 50 ml of methanol, and NaOH (2.3 g) was added dropwise thereto. A mixture was stirred for 1 hour, and methanol was removed therefrom under a reduced pressure. Water (50 ml) and ethyl acetate (50 ml) were added thereto, and the organic layer formed thereafter was separated. The separated organic layer was washed with satuated saline, dried over MgSO4, and filtered to remove MgSO4. The organic solvent was removed from the filtrate under a reduced pressure to obtain the title compound (7.6 g; yield: 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH2:11][OH:12]>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[CH:11]=[O:12]
Reactant: OCc1n[nH]c2ccc(Cl)cc12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: O=Cc1n[nH]c2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.5 %

Procedure:
A solution of (5-chloro-1H-indazol-3-yl)methanol (0.208 g, 1.14 mmol) in ethyl acetate (10 mL) was added with manganese dioxide (0.991 g, 11.4 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered through Celite, then the filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain 5-chloro-1H-indazole-3-carbaldehyde (0.106 g, 51%).
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]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH:23]([O:26][CH2:27][CH2:28]O)([CH3:25])[CH3:24].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:28][CH2:27][O:26][CH:23]([CH3:25])[CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Reactant: CC(C)OCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
A mixture of 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine (0.33 mmol), 2-isopropoxyethanol (0.65 mmol), diethyl azodicarboxylate (114 mg, 0.65 mmol) and triphenylphosphine (171 mg, 0.65 mmol) in 1,4-dioxane (2 mL) was heated using microwave irradiation to a temperature between 85 and 120° C. for a 30 to 90 min period. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC to provide Compound 7.