Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC(C)([O-])C.[K+].Cl[C:17]1[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH3:24])[CH:18]=1.O>CC(N(C)C)=O>[F:9][C:3]1[CH:4]=[C:5]([O:8][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([O:23][CH3:24])[CH:18]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc(O)cc1F
Reactant: COc1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(Oc2ccc(N)c(F)c2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A solution of 4-amino-3-fluorophenol (0.20 g, 1.6 mmol) in 4 mL of anhydrous DMA was treated with potassium tert-butoxide (0.24 g, 1.9 mmol). The resultant dark-red solution was stirred at RT for 1 hour in a capped vial. 4-Chloro-2-methoxypyridine (0.26 g, 1.6 mmol) was added and the reaction mixture was heated overnight at 100° C. Water (50 mL) was added and the solution was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by silica gel column chromatography to obtain 2-fluoro-4-(2-methoxypyridin-4-yloxy)benzenamine (0.20 g, 58% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J=6.0 Hz, 1H), 6.95 (dd, J=2.8, 12.0 Hz, 1H), 6.82 (dd, J=8.4, 8.8 Hz, 1H), 6.73 (dd, J=2.0, 8.4 Hz, 1H), 6.54 (dd, J=2.4, 6.0 Hz, 1H), 6.10 (d, J=2.4 Hz, 1H), 5.17 (s, 1H), 3.81 (s, 3H); MS (ESI) m/z: 235.0 (M+H+).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>O1CCOCC1>[C:1]1([NH:7][C:8]([C:10]2[CH:15]=[C:14]([N:16]3[CH2:17][C:18](=[O:21])[C:19](=[CH:24][N:25]([CH3:27])[CH3:26])[CH2:20]3)[CH:13]=[CH:12][N:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCN(c2ccnc(C(=O)Nc3ccccc3)c2)C1
Reactant: COC(OC)N(C)C
Solvent: C1COCCO1
Product: CN(C)C=C1CN(c2ccnc(C(=O)Nc3ccccc3)c2)CC1=O
Temperature: 100 °C
Yield: 60.9 %

Procedure:
A suspension of 4-(3-oxopyrrolidin-1-yl)-pyridine-2-carboxylic acid phenylamide (130 mg, 0.46 mmol) and dimethylformamide dimethylacetal (0.12 mL, 0.90 mmol) in 1,4-dioxane (2 ml) was heated under nitrogen at 100° C. for 4.5 h. The solvent was removed in vacuo and the residue was purified by chromatography on silica gel (25 g) eluted with dichloromethane:methanol 19:1 and gave the title compound (95 mg, 0.28 mmol, yield 61%).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.CN(C1C=CC=CN=1)C>C(Cl)Cl>[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([N:32]=[C:2]=[O:4])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCOc1ccc(N=C=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8.74 g of triphosgene in 125 ml of methylene chloride cooled to 0° C. is added dropwise a solution of p-(tetradecyloxy)aniline, 7.95 g of triethylamine and 239.93 mg of dimethylaminopyridine in 125 ml of methylene chloride over 30 minutes. Stirring at ambient temperature is continued for 4 hours. The solvent is evaporated and the residue stirred with ether and filtered. The cake is washed with additional ether and the combined filtrates evaporated to give the desired product as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]#N)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[C:14]([NH2:17])(=[S:16])C.Cl>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([CH2:12][C:14](=[S:16])[NH2:17])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: Cc1cnc2c(c1)CCCC2C#N
Reactant: CC(N)=S
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)CCCC2CC(N)=S
Yield: 59.8 %

Procedure:
3-Methyl-8-cyano-5,6,7,8-tetrahydroquinoline (1.7 g., 0.01 m.) and thioacetamide (1.5 g., 0.02 m.) were dissolved in dimethylformamide (50 ml.), and the solution saturated with dry hydrogen chloride gas and then heated on a steam bath for 4 hours. The cooled reaction mixture was poured onto water (200 ml.), washed with ethyl acetate (2 × ml) and the extracts discarded. The aqueous solution was adjusted to pH 10.0 with 46% sodium hydroxide and extracted into methylene chloride (2 × 200 ml.). The combined extracts were dried (sodium sulphate), evaporated i vacuo and the residual oil triturated with isopropanol and filtered. Recrystallization from benzene gave the title compound as pale yellow needles (1.3 g., 63%) m.p. 149°.
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[C:6](Cl)(=[O:8])[CH3:7].[S:10]1[C:14]([NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])=[CH:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2.O>ClCCl>[C:6]([C:13]1[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[S:10][C:14]=1[NH:15][S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])(=[O:8])[CH3:7]
Reactant: CC(=O)Cl
Reactant: CCS(=O)(=O)Nc1cc2ccccc2s1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1sc2ccccc2c1C(C)=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Tin (IV) chloride (173 μL, 1.48 mmol) was added to a solution of acetyl chloride (124 μL, 1.75 mmol) in dichloromethane (10 mL), at 0° C., and the resulting solution was stirred for 5 min. To the resulting mixture was then added a solution of ethanesulfonic acid benzo[b]thiophen-2-ylamide (325 mg, 1.35 mmol) in dichloromethane (2 mL) at 0° C. The resulting solution was allowed to warm to ambient temperature and then stirred overnight. The resulting solution was treated with water (10 mL), the organic layer separated, dried over sodium sulfate, filtered, and the solvent evaporated in vacuo to yield N-(3-acetyl-benzo[b]thiophen-2-yl)-ethanesulfonamide as a colorless solid. 1H-NMR (DMSO-d6): δ 1.25 (t, 3H), 2.71 (s, 3H), 3.39 (q, 2H), 7.34-7.48 (m, 2H), 7.94 (d, 1H), 8.10 (d, 1H); MS: m/z 284.1 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)[C@@H](Cc1ccc(OCC(=O)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1

Procedure:
(R)-N-benzyloxycarbonyl-tyrosine methyl ester was reacted in a manner analogous to that described in Example 3 with t-butyl bromoacetate in the presence of potassium carbonate to give N-benzyloxycarbonyl-3-[p-(tert-butoxycarbonylmethoxy)phenyl]-D-alanine methyl ester. The colorless oil was hydrogenated in methanol, after addition of 5% palladium/carbon, in a shaking apparatus at room temperature under atmospheric pressure, obtaining, after filtration and removal of the solvent, 3-[p-(tert-butoxycarbonylmethoxy)phenyl]-D-alanine methyl ester in the form of a colorless oil.
Reaction SMILES: [C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:20][C:21]1([CH3:30])[CH2:26]C(O)[CH2:24][C:23]([CH3:29])([CH3:28])[NH:22]1>C(O[Sn](CCCC)(CCCC)O[Sn](OC(=O)C)(CCCC)CCCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH:19]1[CH2:24][C:23]([CH3:29])([CH3:28])[NH:22][C:21]([CH3:30])([CH3:26])[CH2:20]1)=[O:17])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCCCCCCC(=O)NCCCCCC(=O)OC
Agent: CCCC[Sn](CCCC)(OC(C)=O)O[Sn](CCCC)(CCCC)OC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)NCCCCCC(=O)OC1CC(C)(C)NC(C)(C)C1
Temperature: 110 °C
Yield: 89.6 %

Procedure:
A 250 mL single-necked reaction flask was equipped with a magnetic stirrer and a Dean-Stark trap fitted with a condenser and nitrogen inlet/outlet. To this flask was charged 6.1 g (22.5 mmol) of compound D, 5.29 g (33.7 mmol) of 2,2,6,6-tetramethyl-4-piperidinol, and 150 mL of toluene. Under a slow nitrogen flow, 8 mL of toluene was distilled off and the trap drained. After lowering the heat source and allowing the mixture to cool to 110° C., 0.17 g (0.28 mmol) of 1,3-diacetoxy-1,1,3,3-tetrabutyldistannoxane was added and the heat source raised. Another 100 mL of toluene was slowly distilled off over 16 hours and the resulting mixture was cooled to room temperature and diluted with methylene chloride. The organic solution was washed with water to remove excess amino alcohol and dried over anhydrous sodium carbonate. Filtration and removal of solvent under reduced pressure followed by further solvent removal in vacuo (<1 mm) at 60° C. gave 8.0 g (90%) of Compound VI as a light brown wax. The structure of the material was confirmed by 1H NMR analysis. 1H NMR (CDCl3): δ 5.60 (m, 1H, NHCO—); 5.18 (m, 1H, R2CHOCO—); 3.25 (dt, 2H, —CH2—NH—); 2.28 (t, 2H, —CH2COO—); 2.16 (t, 2H, —CH2CONH—); 1.95-1.10 (m, 20H, CH2(CH2)3CH2, CH2(CH2)5, CH2CH2C(CH3)2); 1.20 (d, 12H, CH2C(CH3)2; 0.88 (t, 3H, —CH2CH3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N:9]([CH3:14])[C:10](=[O:13])[CH:11]=[CH2:12])=[CH:4][N:3]=1.[NH2:15][CH:16]([CH3:20])[CH2:17][O:18][CH3:19].C(N(CC)CC)C>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4].C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[C:5]([N:9]([CH3:14])[C:10](=[O:13])[CH2:11][CH2:12][N:15]2[CH:16]([CH3:20])[CH2:17][O:18][CH3:19])=[CH:4][N:3]=1
Reactant: C=CC(=O)N(C)c1cnc(Cl)nc1Cl
Reactant: COCC(C)N
Agent: [Ti+4]
Agent: CC[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(C)N1CCC(=O)N(C)c2cnc(Cl)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 13.8 %

Procedure:
N-(2,4-dichloropyrimidin-5-yl)-N-methyl-prop-2-enamide (Intermediate 113; 318 mg, 1.37 mmol), 2-Amino-1-methoxypropane (152 μl, 1.44 mmol), Triethylamine (382 μl, 2.74 mmol), Titanium Tetra-ethoxide (29 μl, 0.137 mmol) and DCM (5 mL) were combined and stirred at room temperature for 1 hr, heated to 40° C. for 3 hrs, cooled to room temperature, washed with water and gravity filtered through a PTFE. The organic solution was purified by chromatographic separation on silica eluting with a shallow gradient (25 column volumes) of 10-50% Ethyl Acetate/iso-hexane. Product containing fractions were combined and evaporated to give the title compound as a clear gum (54 mg, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:18][C:19]1[N:23]([C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[N:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH:15]3[CH2:17][CH2:16]3)[C:28](=[O:29])[C:27]3[CH:26]=[CH:25][C:24]([N:23]4[C:19]([CH3:18])=[N:20][CH:21]=[N:22]4)=[CH:32][CH:31]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: Cc1ncnn1-c1ccc(C(=O)O)cc1
Reactant: Clc1cnc(N2CCC(NC3CC3)CC2)nc1
Product: Cc1ncnn1-c1ccc(C(=O)N(C2CC2)C2CCN(c3ncc(Cl)cn3)CC2)cc1

Procedure:
The title compound is prepared from [1-(5-chloro-pyrimidin-2-yl)-piperidin-4-yl]-cyclopropyl-amine and 4-(5-methyl-[1,2,4]triazol-1-yl)-benzoic acid following a procedure analogous to that described in Example 107. LC (method 19): tR=3.79 min; Mass spectrum (ESI+): m/z=438 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([CH:12]=O)[N:11]=[C:4]2[N:3]=1.[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:30]=3[OH:37])[O:24][C:23](=[O:25])[CH2:22][C:21](=[O:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>CO>[CH:14]1([C:19]2([CH2:27][CH2:28][C:29]3[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[CH:31][C:30]=3[OH:37])[O:24][C:23](=[O:25])[C:22]([CH2:12][C:10]3[N:11]=[C:4]4[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]4[N:9]=3)=[C:21]([OH:26])[CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCc1ccc(O)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)c1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Solvent: CO
Product: CCc1ccc(O)c(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)c1
Reaction time: 0.25 h
Yield: 39.2 %

Procedure:
5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (0.19 g, 1.1 mmol) was added to a solution of 6-cyclopentyl-6-[2-(5-ethyl-2-hydroxy-phenyl)-ethyl]-dihydro-pyran-2,4-dione (0.3 g, 0.91 mmol Example A(169)) in MeOH (8 mL). The reaction mixture was stirred for 15 mins and then treated with borane-dimethylamine complex (47 mg, 0.80 mmoL). After 24 hours the reaction mixture was filtered through a glass frit to remove a fine white ppt. The filtrate was concentrated and purified by prep HPLC to give the product (175 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ: 1.07 (t, J=7.6 Hz, 3H), 1.41-1.72 (br m, 8H), 1.97 (m, 1H), 2.10 (m, 1H), 2.41-2.73 (m, 13H), 3.70 (d, J=16.2 Hz, 1H), 3.79 (d, J=16.2 Hz, 1H), 6.66 (d, J=8.1 Hz, 1H), 6.81 (d, J=8.1 Hz, 1H), 6.84 (s, 1H), 7.02 (s, 1H), 9.02 (s, 1H), 10.88 (s, 1H). MS (ESI): 491.20 (M+H+).
Reaction SMILES: [C:1]1([C:7]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:15][C:14]3[N:13](S(C4C=CC(C)=CC=4)(=O)=O)[N:12]=[C:11]([NH2:26])[C:10]=3[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCOCC1>O1CCCC1>[C:27]1([C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:15][C:14]3[NH:13][N:12]=[C:11]([NH2:26])[C:10]=3[CH:9]=[CH:8]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)n2nc(N)c3c2CC(c2ccccc2)(c2ccccc2)C=C3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: Nc1n[nH]c2c1C=CC(c1ccccc1)(c1ccccc1)C2
Temperature: 50 °C
Yield: 41.9 %

Procedure:
A suspension of 0.22 g of 6,6-diphenyl-1-(4-toluenesulphonyl)-6,7-dihydro-1H-indazol-3-ylamine and 1.5 cm3 of aqueous 1N sodium hydroxide solution in 5 cm3 of tetrahydrofuran is heated at a temperature in the region of 50° C. for about 24 hours. 5 cm3 of dioxane are added to the preceding mixture and the resulting mixture is heated at a temperature in the region of 100° C. for 2 hours. After concentrating the reaction mixture to dryness under reduced pressure (13 kPa), the residue is taken up in 30 cm3 of ethyl acetate and 30 cm3 of water. The aqueous phase is extracted with twice 30 cm3 of ethyl acetate and the combined organic phases are washed with 30 cm3 of saturated aqueous sodium bicarbonate solution, 30 cm3 of water and 30 cm3 of saturated aqueous sodium chloride solution and then dried over magnesium sulphate, filtered and concentrated under reduced pressure (13 kPa). After purification by flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)], the residue is taken up in 5 cm3 of diisopropyl ether, drained by suction, washed with 2 cm3 of diisopropyl ether and dried under reduced pressure (13 kPa) at a temperature in the region of 30° C. 0.06 g of 6,6-diphenyl-6,7-dihydro-1H-indazol-3-ylamine is thus obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][C:24]=3[N:25]=2)=[C:15]([Cl:32])[CH:14]=1)(=[O:11])=[O:10].[N:33]([Si](C)(C)C)=[N+:34]=[N-:35].C([Sn](=O)CCCC)CCC.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:14]=[C:15]([Cl:32])[C:16]([S:20][C:21]2[S:22][C:23]3[CH:29]=[CH:28][C:27]([C:30]4[NH:35][N:34]=[N:33][N:31]=4)=[CH:26][C:24]=3[N:25]=2)=[C:17]([Cl:19])[CH:18]=1)(=[O:11])=[O:10]
Reactant: N#Cc1ccc2sc(Sc3c(Cl)cc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3Cl)nc2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2nc3cc(-c4nnn[nH]4)ccc3s2)c(Cl)c1)c1ccc(Cl)cc1Cl
Temperature: 90 °C
Yield: 76.9 %

Procedure:
To a solution of 2,4-dichloro-N-[3,5-dichloro-4-(5-cyano -benzothiazol-2-ylsulfanyl)-phenyl]-benzenesulfonamide (297) (250 mg, 0.45 mmol) in toluene (5 mL), was added azidotrimethylsilane (Aldrich, 0.12 mL, 0.90 mmol) and dibutyltin oxide (Aldrich, 11 mg, 0.045 mmol). The resulting mixture was heated at 90° C. overnight (15 hours). A 1M aqueous solution of HCl (50 mL) and ice was added and the crude reaction mixture was extracted 3× with EtOAc (50 mL). The organic layers were combined and washed twice with a brine solution (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude solid was chromatographed (20% EtOAc in CH2Cl2, then 10% MeOH in CH2Cl2) to yield 209 mg (77%) of product as a white solid.
Reaction SMILES: [CH3:1][C@@:2]12[C:8](=[CH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C@@H:6]1[CH2:5][CH:4]=[CH:3]2.[C-:17]#[N:18].[K+]>CS(C)=O.C(OCC)(=O)C>[C:17]([C@:8]1([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:7][C@H:6]2[C@:2]1([CH3:1])[CH:3]=[CH:4][CH2:5]2)#[N:18]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)C=C1C[C@@H]2CC=C[C@]12C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)C[C@@]1(C#N)C[C@@H]2CC=C[C@@]21C
Reaction time: 2 h
Yield: 38.1 %

Procedure:
Tert-butyl(±)-[(1S,5R)-5-methyl-bicyclo[3.2.0]hept-3-en-6-ylidene]acetate (300 mg, 1.36 mmol) and potassium cyanide (89 mg, 1.36 mmol) were mixed at room temperature in anhydrous dimethyl sulfoxide (2 mL), and the mixture was stirred for 2 hours and then left overnight. The mixture was further stirred for 10 hours in an oil bath at 100° C. and then left overnight. The reaction solution was diluted with ethyl acetate, then washed with water and saturated saline, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the compound of interest as a colorless oil (128 mg). In this procedure, a by-product tert-butyl(±)-[(1S,5R,6R)-6-cyano-5-methyl-bicyclo[3.2.0]hept-3-en-6-yl]acetate was obtained as a colorless oil (45 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([NH2:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.I[CH2:14][CH3:15]>[Na].C(O)C>[CH2:14]([O:12][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9])[CH3:15]
Reactant: COc1ccc(O)c(C(N)=O)c1
Reactant: CCI
Agent: [Na]
Solvent: CCO
Product: CCOc1ccc(OC)cc1C(N)=O
Temperature: 25 °C
Yield: 70.7 %

Procedure:
5-Methoxysalicylamide (41.8 g., 0.250 mole) was dissolved in a solution of sodium (6.37 g., 0.277 g-atom) in ethanol (250 ml.). To the resulting cooled (ice-water) solution was added iodoethane (38.9 g., 0.250 mole) over a period of 20 minutes. The reaction mixture was allowed to warm to room temperature over 0.75 hour and then was heated under reflux for 19 hours. The mixture was concentrated and the residue triturated with water. The mixture was filtered and collected solid recrystallized from acetonitrile to give 2-ethoxy-5-methoxybenzamide (34.5 g., 70.7%), m.p. 128°-130°.
Reaction SMILES: [N:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[C:7]([CH3:14])[N:8]=[CH:9]2)=[C:2]=[S:3].[OH:15][CH2:16][CH:17]1[NH:22][CH2:21][C:20]2[CH:23]=[CH:24][S:25][C:19]=2[CH2:18]1>C(O)C>[OH:15][CH2:16][CH:17]1[N:22]([C:2](=[S:3])[NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[C:7]([CH3:14])[N:8]=[CH:9]3)[CH2:21][C:20]2[CH:23]=[CH:24][S:25][C:19]=2[CH2:18]1
Reactant: Cc1cc2c(N=C=S)cccc2cn1
Reactant: OCC1Cc2sccc2CN1
Solvent: CCO
Product: Cc1cc2c(NC(=S)N3Cc4ccsc4CC3CO)cccc2cn1
Reaction time: 15 h
Yield: 93 %

Procedure:
5-Isothiocyanato-3-methylisoquinoline (5.1 g) is added to a solution of (RS)-6-hydroxymethyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3.4 g) in absolute ethanol (55 cc). After 15 hours at a temperature of about 20° C., the resulting crystals are filtered off, washed with diisopropyl ether and then dried at 60° C. under reduced pressure (0.1 mm Hg; 0.013 kPa). (RS)-6-Hydroxymethyl-5-[(3-methylisoquinol-5-yl)thiocarbamoyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (6.9 g), melting at 190° C., is thus obtained.
Reaction SMILES: [Br:1]Br.[OH-].[Na+].[N+:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[CH:11]2)([O-:7])=[O:6].S([O-])(O)=O.[Na+]>O1CCOCC1>[Br:1][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)[NH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Reaction time: 3.5 h
Yield: 26.3 %

Procedure:
A solution of bromine (0.75 ml, 14.6 mmol) in a 2N-aqueous sodium hydroxide solution (20 ml) was added dropwise to a mixed solution of 5-nitro-1H-indazole (3.26 g, 20.0 mmol), dioxane (60 ml) and a 2N-aqueous sodium hydroxide solution (30 ml) at 0° C. and stirred at 0° C. for 30 minutes and then at room temperature for 3.5 hours. An aqueous sodium hydrogensulfite solution was added thereto until a solid was precipitated, to terminate the reaction, followed by extraction with ethyl acetate. The extract solution was washed with an aqueous sodium thiosulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was suspended in ethyl acetate and extracted with a 0.1N-aqueous sodium hydroxide solution. After 6 times of the extraction, the combined aqueous layer was acidified with hydrochloric acid and then re-extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby 3-bromo-5-nitro-1H-indazole (0.93 g, 19%) was obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)=[O:36])=[CH:31][C:30]=1[F:43]>ClCCl>[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([N:37]2[CH2:38][CH2:39][N:40]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=3)[CH2:41][CH2:42]2)=[O:36])=[CH:31][C:30]=1[F:43]
Reactant: Nc1ccc(C(=O)N2CCNCC2)cc1F
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Reaction time: 6 h

Procedure:
tert-Butyl 4-(4-amino-3-fluorobenzoyl)piperazine-1-carboxylate (0.649 mmol, 210 mg) was stirred with dichloromethane (˜2 mL) and trifluoroacetic acid (˜0.5 mL) overnight. The mixture was purified by SCX chromatography to give the intermediate (4-amino-3-fluorophenyl)(piperazin-1-yl)methanone. 2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.649 mmol, 219 mg), potassium carbonate (0.649 mmol, 90 mg) and acetonitrile (5 mL) were added to the intermediate (4-amino-3-fluorophenyl)(piperazin-1-yl)methanone and the mixture was stirred for 6 hours. The reaction mixture was concentrated under reduced pressure. The residue obtained was stirred in dichloromethane, filtered and the filtrate was purified by silica chromatography (eluting with dichloromethane increasing to ethyl acetate) to afford the title compound (46 mg).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[CH:16]=[C:15]([N+]([O-])=O)[CH:14]=[CH:13][N:12]=1>>[Cl:10][C:11]1[CH:16]=[C:15]([S:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=[CH:13][N:12]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Sc2ccccc2)ccn1
Yield: 93.9 %

Procedure:
Using the method of Example 3, Step A, thiophenol (1.04 g, 9.46 mmol), 60% sodium hydride in mineral oil (378 mg, 9.46 mmol), and 2-chloro-4-nitropyridine (1.50 g, 9.46 mmol) were reacted to provide 2-chloro-4-(phenylthio)pyridine (1.97 g, 94% yield) as an oil. 1H NMR (CDCl3) δ 8.11 (d, 1H), 7.45-7.58 (m, 5H), 6.90 (s, 1H), 6.85 (d, 1H).