Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH2:15][OH:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([CH:15]=[O:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1
Reactant: NC(=O)c1ccc(Br)c2c1[nH]c1cc(CO)ccc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: NC(=O)c1ccc(Br)c2c1[nH]c1cc(C=O)ccc12
Reaction time: 0.75 h

Procedure:
Step 1 A partial solution of 4-bromo-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 30-2, 1.00 g, 3.13 mmol) in THF (75 mL) was stirred at rt and treated with 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1 H)-one (Dess-Martin periodinane, 1.993 g, 4.70 mmol). After 45 min, the solution was diluted with EtOAc and washed with 5% aqueous sodium sulfite, NaHCO3 (aq), and brine, then was dried and concentrated. The residue was triturated with methanol, and the precipitate was collected by filtration, washed with methanol and dried to provide 4-bromo-7-formyl-9H-carbazole-1-carboxamide as a tan powder (ca. 85% purity, 948 mg, 81%) used without purification. 1H NMR (400 MHz, DMSO-d6) δ 12.13 (1 H, s), 10.14 (1 H, s), 8.80 (1 H, d, J=8.1 Hz), 8.38 (1 H, d, J=0.9 Hz), 8.28 (1 H, br. s.), 7.97 (1 H, d, J=8.1 Hz), 7.83 (1 H, dd, J=8.3, 1.4 Hz), 7.64 (1 H, br. s.), 7.54 (1 H, d, J=8.1 Hz). Mass spectrum m/z 317, 319 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17](=[NH:20])[NH:18]O)=[N:9]1)([CH3:4])([CH3:3])[CH3:2].CC(OC(C)=O)=O>[Pd].CC(O)=O>[C:1]([O:5][C:6](=[O:21])[CH2:7][N:8]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C:10]([C:17](=[NH:18])[NH2:20])=[N:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Cn1nc(C(=N)NO)c2cccnc21
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)Cn1nc(C(=N)N)c2cccnc21

Procedure:
[3-(N-Hydroxycarbamimidoyl)-pyrazolo[3,4-b]pyridin-1-yl]-acetic acid tert-butyl ester (6.17 g) in a 100 mL vial was charged with AcOH (45 mL) and Ac2O (4.3 mL). The resultant mixture was stirred at room temperature for 1 h at this time the initial suspension became a clear solution. To this solution was added Pd/C (10%, 900 mg) and stirred under 1 atm H2 balloon, and resultant mixture was stirred over night at room temperature. The reaction mixture was filtered through a pad of celite washed with DCM/MeOH. Evaporation of the solvent gave (3-amidino-pyrazolo[3,4-b]pyridin-1-yl)-acetic acid tert-butyl ester which was used without further purification.
Reaction SMILES: Cl[C:2]([N:14]=[C:15]=[O:16])([C:10](F)([F:12])[F:11])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[Cl:5]>CCOCC.[Zn]>[F:11][C:10]([F:12])=[C:2]([N:14]=[C:15]=[O:16])[C:3]([F:8])([F:9])[C:4]([F:6])([F:7])[Cl:5]
Reactant: O=C=NC(Cl)(C(F)(F)F)C(F)(F)C(F)(F)Cl
Agent: [Zn]
Solvent: CCOCC
Product: O=C=NC(=C(F)F)C(F)(F)C(F)(F)Cl

Procedure:
By the procedure of Example 2, adding 1,3-dichloro-1 -(trifluoromethyl)tetrafluoropropyl isocyanate to a suspension of powdered zinc in ether will yield 2,2-difluoro-1-(2-chlorotetrafluoroethyl)vinyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.ON1C2C=CC=CC=2N=N1.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH2:47])=[C:41]([Cl:48])[CH:40]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[Br:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH2:46][NH:47][C:17]([C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[CH:10]=[C:9]4[C:4]([CH:5]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:6][CH2:7][O:8]4)=[CH:3][C:2]=3[Cl:1])=[CH:21][CH:20]=2)=[O:19])=[C:41]([Cl:48])[CH:40]=1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Br)cc4Cl)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 17 h
Yield: 60.8 %

Procedure:
To a stirred solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (1.15 g. 3.05 mmol), 1-hydroxybenzotriazole hydrate (0.51 g, 3.4 mmol) and 2-(4-bromo-2-chlorophenyl)ethanamine (0.75 g, 3.2 mmol) in N,N-dimethylformamide (10 mL) at ambient temperature was added solid 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.70 g, 3.7 mmol). The resulting solution was stirred at ambient temperature for 17 hours, then diluted with water (100 mL) and extracted with ethyl acetate (100 mL). Addition of 1M hydrochloric acid (20 mL) enabled layer separation. The organic layer was dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel, eluting with 75/25 hexanes/ethyl acetate, to afford ethyl 7-(4-(4-bromo-2-chlorophenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate as an off-white solid (1.10 g, 60% yield).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][NH:5][C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.[H-].[Na+].[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1.O>[CH2:26]([O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([N:5]2[C:6]([C:7]3[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=3)=[C:2]([F:1])[C:3]([CH2:14][N:15]([CH3:23])[C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[CH:4]2)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1cn(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 102.2 %

Procedure:
To a solution of tert-butyl {[4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (200 mg) in tetrahydrofuran (10 mL) was added sodium hydride (60% in oil, 50 mg), and the mixture was stirred at room temperature for 10 min. 4-(Benzyloxy)benzenesulfonyl chloride (210 mg) was added and the mixture was further stirred for 30 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:3→1:1) to give the title compound as a colorless oil (yield 360 mg, quantitative).
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[CH3:20][O:21][NH2:22]>C(O)C>[CH3:20][O:21][N:22]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11](=[O:19])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1ccccc1F
Reactant: CON
Solvent: CCO
Product: CCOC(=O)c1cn(OC)c2ccccc2c1=O
Temperature: 25 °C
Yield: 25.6 %

Procedure:
Ethyl 3-ethoxy-2-(2-fluorobenzoyl)-2-propenoate (4.0 g, prepared from ethyl 3-(2-fluorophenyl)-3-oxopropanoate as in Preparation No. 59) and O-methylhydroxylamine (16 mmol, prepared by mixing 1 eq of sodium ethoxide with 1 eq of O-methylhydroxylamine hydrochloride in ethanol) are stirred in ethanol (20 mL) for 1 hour at rt. The mixture is concentrated, diluted with dioxane (75 mL) and re-concentrated to remove any remaining ethanol. The resulting enamine is diluted in dioxane (70 mL) and sodium hydride (60% dispersion, 0.64 g) is added. The mixture is heated to reflux for 2.5 hours, cooled to rt and concentrated in vacuo. The remaining residue is partially dissolved in ethanol (100 mL) and filtered. The filtrate is concentrated in vacuo and chromatographed (7% MeOH/CH2Cl2). The combined fractions are concentrated, leaving a residue which is recrystallized in a 1:1 ether/hexanes mixture to afford 0.95 g of ethyl 1-methoxy-4-oxo-1,4-dihydro-3-quinolinecarboxylate (Mp 120-121° C.) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14]CCCCC.[Si](C=[N+]=[N-])(C)(C)C>CO.C1C=CC=CC=1>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: CCCCCC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a stirred solution of 4-hydroxy-3-nitrobenzoic acid (3.00 g, 0.0164 mol) in MeOH-benzene (1:4, v/v) was added dropwise 2.0 M-n-hexane solution of TMSCHN2 (8.2 mL, 0.0164 mol) at room temp. After the resulting solution was stirred for 4 hr at room temp, the mixture was evaporated off in vacuo. The oily residue was chromatographed on silica-gel with CHCl3 as eluent to afford 4.23 g (79%) methyl 4-hydroxy-3-nitrobenzoate as a pale yellow crystalline material.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:27]2[C:22]1=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6](=[O:34])[C@@H:7]([NH:16][C:17]([O:19][CH2:20][CH:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=2[C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:18])[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=2)=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: OCc1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCc2ccccn2)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
The product from Example G ((S)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)-propionic acid tert-butyl ester) (4.00 g, 8.64 mmol), 2-pyridylcarbinol (0.92 mL, 9.50 mmol) and triphenylphosphine (2.24 g, 8.64 mmol) were dissolved in 50 mL of dry THF. The solution was cooled in an ice bath under an argon atmosphere and diethyl azidocarboxylate (1.36 mL, 8.64 mmol) was added dropwise over 20 minutes. The ice bath was removed and the solution allowed to stir overnight at room temperature. The solution was concentrated under reduced pressure and partitioned between ethyl acetate and water (100 mL each) and separated. The organic layer was washed with 10% aqueous HCl (2×50 mL), 10% sodium bicarbonate (2×50 mL), brine (2×50 mL), dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a foam (4.80 g). The foam was purified by chromatography (silica gel, 1:1.5 ethyl acetate/hexane) to give the product as a white foam (3.90 g, 82%).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[O:5][C:6]2[C:11]([C:12](=[O:21])[C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:3].C(N(CC)C(C)C)(C)C.Br[C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[NH:34][CH:35]=[N:36]2>C(O)(C)(C)C>[N:40]1[C:32]([NH:1][C@@H:2]([C:4]2[O:5][C:6]3[C:11]([C:12](=[O:21])[C:13]=2[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH3:3])=[C:33]2[C:37]([NH:36][CH:35]=[N:34]2)=[N:38][CH:39]=1
Reactant: Brc1ncnc2nc[nH]c12
Reactant: C[C@@H](N)c1oc2ccccc2c(=O)c1-c1cccc(F)c1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1ncnc2[nH]cnc12)c1oc2ccccc2c(=O)c1-c1cccc(F)c1

Procedure:
This example is also described in Example 56 of WO 2011/055215. To a solution of (R)-2-(1-Amino-ethyl)-3-(3-fluoro-phenyl)-chromen-4-one (0.41 g, 1.52 mmoles) in tert-butanol (7 ml), N,N-diisopropylethylamine (0.53 ml, 3.04 mmoles) and 6-bromopurine (0.242 g, 1.21 mmoles) are added and refluxed for 24 h. The reaction mixture is concentrated, diluted with water, and extracted with ethyl acetate. The organic layer is dried over sodium sulphate and concentrated under reduced pressure. The crude product is purified by column chromatography with methanol:ethyl acetate to afford the title compound as an off-white solid. MP: 274-276° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 12.96 (s, 1H), 8.14-8.01 (m, 4H), 8.11 (s, 1H), 7.81 (dt, J=8.5, 1.5 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.49 (m, 2H), 7.25-7.19 (m, 3H), 5.18 (br m, 1H), 1.56 (d, J=7.0 Hz, 3H). Mass: 402.04 (M++1).
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][CH2:22][C:21]([CH3:26])([CH3:25])[CH2:20][C:19]=4[N:18]([CH3:27])[N:17]=3)[N:14]=2)[N:9](COCC[Si](C)(C)C)[CH:8]=1)=[O:6])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>ClCCl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]3[C:24]4[CH2:23][CH2:22][C:21]([CH3:25])([CH3:26])[CH2:20][C:19]=4[N:18]([CH3:27])[N:17]=3)[N:14]=2)[NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4c3CCC(C)(C)C4)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4c3CCC(C)(C)C4)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of N-isopropyl-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (90 mg, 181 μmol) in dichloromethane (3 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol). The reaction mixture was stirred at 25° C. overnight then concentrated. The residue was re-dissolved in 5 mL of a mixture of dichloromethane/MeOH/ammonium hydroxide (60:10:1) and stirred at 25° C. for 3 h, then evaporated to a yellow solid, dissolved in dichloromethane (containing a few drops of MeOH) and purified by chromatography (40 g, 50 μm particle size, Analogix, 0 to 5% MeOH containing 10% ammonium hydroxide in dichloromethane). The pure product was suspended in dichloromethane and cyclohexane added to promote solid formation. The solid was separated by decanting the mother liquors and then dried to give N-isopropyl-2-(1,6,6-trimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (54 mg, 147 μmol, 81%) as a white solid. MS (M+H)+=461; 1H NMR (DMSO-d6) δ: 9.11 (s, 1H), 8.37 (s, 1H), 8.17 (d, J=1.9 Hz, 1H), 7.90 (s, 1H), 7.87 (s, 1H), 7.27-7.38 (m, 2H), 7.06-7.15 (m, 1H), 6.91 (t, J=2.1 Hz, 1H), 6.80-6.89 (m, 1H), 4.20 (s, 3H), 4.11 (dq, J=13.9, 6.8 Hz, 1H), 1.06 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:13])=[CH:5][C:6]=1[CH:7]1[CH2:12][NH:11][CH2:10][CH2:9][NH:8]1.Cl[C:15]1[CH:24]=[C:23]2[C:18]([C:19](=[O:30])[C:20]([C:27]([OH:29])=[O:28])=[CH:21][N:22]2[CH2:25][CH3:26])=[CH:17][C:16]=1[F:31]>N1C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([Cl:13])=[CH:5][C:6]=1[CH:7]1[NH:8][CH2:9][CH2:10][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([C:19](=[O:30])[C:20]([C:27]([OH:29])=[O:28])=[CH:21][N:22]3[CH2:25][CH3:26])=[CH:17][C:16]=2[F:31])[CH2:12]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: Clc1cc(C2CNCCN2)c(Cl)s1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(c4cc(Cl)sc4Cl)C3)cc21

Procedure:
A 3.1 g portion of 2-(2,5-dichloro-3-thienyl)piperazine was dissolved in 8 ml of pyridine, 880 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added and the mixture was heated, under argon, in a pressure bottle, at 120°-130° C. for 18 hours. After cooling, the solid was collected, washed with ethanol, dried and recrystallized from dimethylformamide, giving 171 mg of the desired product, mp 254°-256° C. (dec.).
Reaction SMILES: [C:1]1(=[O:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10](OC(C)=C)(=[O:12])[CH3:11]>C(=O)([O-])[O-].[Na+].[Na+]>[C:10]([O:9][C:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)(=[O:12])[CH3:11]
Reactant: O=C1CCCCCCC1
Reactant: C=C(C)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)OC1=CCCCCCC1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
In the presence of 0.6 g of paratoluenesulfonic acid, 50 g (0.4 mol) of cyclooctanone and 100 ml (0.9 mol) of isopropenyl acetate were refluxed for 11 hours. The reaction mixture was cooled, stirred with 0.6 g of anhydrous sodium carbonate at room temperature for one hour, left standing overnight, and filtered. The filtrate was distilled under reduced pressure to afford 60 g (91% yield) of 1-cyclooctenyl acetate having a boiling point of 71° to 73° C./3 mmHg.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]([O:11]C)=[O:10])[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[N:5]=[N:6][S:7][C:8]=2[C:9]([OH:11])=[O:10])[CH2:2][CH2:3]1
Reactant: COC(=O)c1snnc1C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1snnc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Methyl 4-cyclopropyl-1,2,3-thiadiazole-5-carboxylate (35 g; 190 mmols) was dissolved in methanol (150 ml), and an aqueous solution (150 ml) of sodium hydroxide (15 g; 360 mmols) was added dropwise thereto over 30 minutes under cooling in an ice-bath. After completion of the dropwise addition, the mixture was stirred for 2 hours at room temperature, and methanol was evaporated under reduced pressure, followed by washing with ethyl acetate. The aqueous layer was acidified by using concentrated hydrochloric acid, and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was washed with a mixed solvent of hexane-ethyl acetate to thereby obtain 28 g of 4-cyclopropyl-1,2,3-thiadiazole-5-carboxylic acid.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][C@H:40]1[CH2:44][OH:45])=[O:38])([CH3:35])([CH3:34])[CH3:33].[CH3:46][C:47]1[N:52]=[CH:51][C:50](O)=[CH:49][CH:48]=1>C1COCC1>[CH3:46][C:47]1[N:52]=[CH:51][C:50]([O:45][CH2:44][C@@H:40]2[CH2:41][CH2:42][CH2:43][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])=[CH:49][CH:48]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: Cc1ccc(O)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
To a solution of triphenylphosphine (3.83 g, 14.60 mmol) in 40 mL of anhydrous THF at 0° C. was added diethyl azodicarboxylate (2.3 mL, 14.60 mmol) dropwise. The mixture was stirred at 0° C. for 30 minutes, then brought to room temperature. (S)-1-t-Butoxycarbonyl-2-pyrrolidinemethanol (1.96 g, 9.75 mmol, Aldrich Chemical Co.) and 6-methyl-3-pyridinol (Aldrich Chemical Co., 1.60 g, 14.60 mmol) were added to the reaction vessel, and the mixture was stirred for 16 hours. Solvent was removed in vacuo, and the residue was diluted with hexane and sonicated for 30 minutes. The resulting precipitate was filtered and washed with hexane. The hexane was removed in vacuo. The residue was purified by silica gel flash chromatography using a gradient from 100% hexane to a 1:1 solution of ethyl acetatelh exane (100%Hex, 10% EtOAc/Hex, 20%EtOAc/Hex, 1:1EtOAc/Hex) to give 1.61 g (57% ) of the title compound as a pale yellow oil. TLC Rf=0.42 (1:1 EtOAc/Hex). MS (DCI/NH3) m/e: 293 (M+H)+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH2:19])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][C:10]=1[CH2:17][CH:18]=[CH2:19]
Reactant: C=CCc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCc1cc(CO)ccc1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 793.1 %

Procedure:
To a solution of approximately 7.26 g (2.6 mmol) of the crude product of Step D, dissolved in 50 mL of anhydrous THF was added 26 mL (2.6 mmol) of tetra-n-butylammonium fluoride and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then evaporated in vacuo and the residual oil was purified on a silica gel flash chromatography column eluted with 5% methanol/chloroform to afford 3.386 g (79%) of the title compound as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[I:11](Cl)Cl)([O-:3])=[O:2].[OH-:14].[Na+]>>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[I:11]=[O:14])([O-:3])=[O:2]
Reactant: [OH-]
Reactant: Cc1ccc(I(Cl)Cl)c([N+](=O)[O-])c1
Agent: [Na+]
Product: Cc1ccc(I=O)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
2-Nitro-4-methyl(dichloroiodo)benzene (2.0 g, 6.0 mmol) was added portion-wise, over a period of 15 min, to a cold (5° C.), stirred solution of 20 percent aqueous sodium hydroxide (100 mL). Five min after the addition, the desired product, an orange solid, insoluble in the reaction medium, was isolated by filtration; yield, 1.51. g.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(Nc2ccccc2)n1

Procedure:
Into 800 g of blocks of ice, a solution of 36.9 g of cyanuric chloride in 320 ml of acetone was added dropwise with stirring to prepare a dispersion. 18.6 g of aniline was added dropwise at temperature of 5° C. or lower into the dispersion. At the same time of the addition of aniline, 210 mL of 5% sodium carbonate aqueous solution was added dropwise at temperature of 5° C. or lower with keeping the same dropping rate as in the addition of aniline to the dispersion, to precipitate crystal, whereby 2,4-dichloro-6-phenylamino-1,3,5-triazine was obtained.
Reaction SMILES: COC1C=CC(C[NH:8][CH2:9][C:10]2[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]([F:30])([F:29])[F:28])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:20])=CC=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CC#N.O>[CH3:20][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]=[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]([F:30])([F:28])[F:29])[C:10]([CH2:9][NH2:8])=[CH:19]2
Reactant: COc1ccc(CNCc2cc3cccc(C)c3nc2-c2ccccc2C(F)(F)F)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: Cc1cccc2cc(CN)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure G using N-(4-methoxybenzyl)(8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methanamine (1.1427 g, 2.62 mmol, 1 eq) and ammonium cerium(iv) nitrate (3.59 g, 6.55 mmol, 2.5 eq) in CH3CN—H2O (2:1, 12 mL). After purification, (8-methyl-2-(2-(trifluoromethyl)phenyl)quino-lin-3-yl)methanamine was obtained as brown syrup. 1H NMR (DMSO-d6) δ ppm 8.47 (1 H, s), 7.91 (1 H, d, J=7.4 Hz), 7.84 (1 H, d, J=7.4 Hz), 7.67-7.81 (2 H, m), 7.47-7.62 (3 H, m), 3.46-3.70 (2 H, m), 2.61 (3 H, s), 1.86 (2 H, br. s.).