Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]([OH:10])=[O:9].OS(O)(=O)=O.[CH2:16](O)[CH3:17]>>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][C:8]([O:10][CH2:16][CH3:17])=[O:9]
Reactant: CCO
Reactant: O=C(O)CC1CCCC1=O
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC1CCCC1=O

Procedure:
To a solution of 2-(2-oxocyclopentyl)acetic acid (23.6 g, 166 mmol) in absolute ethanol (400 mL) was added H2SO4 (16.28 g, 166 mmol). The resultant solution was heated under reflux overnight. The reaction mixture was concentrated and the liquid residue was added into ice-water (200 mL). The aqueous mixture was extracted with DCM (3×200 mL). The combined organic layers were washed with H2O (300 mL), brine (300 mL), dried over Na2SO4, decanted, concentrated and dried under vacuum to afford the title compound as a light yellow liquid (27.2 g). LCMS m/z=171.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 1.19 (t, J=7.14 Hz, 3 H), 1.50-1.62 (m, 1 H), 1.65-1.80 (m, 1 H), 1.92-2.02 (m, 1 H), 2.12 (dd, J=16.7, 8.86 Hz, 1 H), 2.19-2.29 (m, 2 H), 2.30-2.44 (m, 2 H), 2.65 (dd, J=15.12, 2.6 Hz, 1H), 4.07 (q, J=7.14 Hz, 2H).
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](Cl)=[O:12])([O-:7])=[O:6].Cl>ClC1C=CC=CC=1>[Cl:1][C:8]1[CH:9]=[CH:10][C:14]([C:11](=[O:12])[C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([N+:5]([O-:7])=[O:6])[CH:9]=2)=[CH:15][CH:16]=1
Reactant: [Cl-]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=C(c1ccc(Cl)cc1)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 147.2 %

Procedure:
30.5 g (0.27 mol) of chlorobenzene and 36 g (0.27 mol) of aluminium chloride are introduced into a 250 cm3 flask and 25 g (0.135 mol) of m-nitrobenzoyl chloride dissolved in 15 cm3 of chlorobenzene are added dropwise. The mixture is heated for 5 hours at between 50° and 60° C. and is then allowed to cool and is hydrolysed with 500 g of ice + 20 cm3 of concentrated HCl (d = 1.18); the batch is extracted with ether and the extract is washed with aqueous sodium hydroxide solution (strength 30 g/l) and then with water; the ether phase is dried, decolorised and then evaporated in vacuo; 26 g of the expected ketone are obtained. Melting point 97° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:38])[NH:6][C:7]2[CH:36]=[CH:35][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH2:26][CH2:25][N:24]([C:27](=[O:34])[CH2:28][CH2:29][C:30]([O:32]C)=[O:31])[CH2:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:37])[CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([NH:4][C:5](=[O:38])[NH:6][C:7]2[CH:36]=[CH:35][C:10]([O:11][C:12]3[CH:17]=[CH:16][N:15]=[C:14]4[CH:18]=[C:19]([C:21]5[CH2:26][CH2:25][N:24]([C:27](=[O:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH2:23][CH:22]=5)[S:20][C:13]=34)=[C:9]([F:37])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)CCC(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC(=O)N1CC=C(c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.5 %

Procedure:
To a stirred suspension of 272 (120 mg, 0.223 mmol) in THF/MeOH (5/5 mL) was added NaOH 1M (3 mL, 3.00 mmol). The reaction mixture was stirred at RT for 16 h and concentrated. The residue was then diluted with water and extracted with DCM/MeOH. The organic layer was successively washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 15/85 over 20 CV) to afford a material that upon trituration with AcOEt afforded the title compound 273 (10 mg, 0.019 mmol, 9% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.90-8.79 (bs, 1H), 8.35 (d, =5.6 Hz, 1H), 7.64-7.56 (m, 1H), 7.32-7.29 (m, 1H), 7.27-6.96″(m, 4H), 6.68-6.60 (m, 1H), 6.48-6.40 (m, 1H), 5.14-5.01 (m, 1H), 3.94-3.88 (m, 1H), 3.68-3.48 (m, 2H), 2.63-2.56 (m, 2H), 2.50-2.30 (m, 3H), 2.20-2.08 (m, 1H), 1.92-1.79 (m, 1H), 0.57-0.52 (m, 2H), 0.34-0.30 (m, 2H). MS (m/z): 525.39 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3].[C:51]([NH:61][CH2:62][C:63](O)=[O:64])([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]>>[C:51]([NH:61][CH2:62][C:63]([NH:1][C@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:50])[N:16]([CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:17](=[O:35])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:5])[CH3:3])=[O:64])([O:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:52]
Reactant: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)N
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: CCCCCCCCCCCCCCCCCC(=O)N(CCCCCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@H](C)NC(=O)CNC(=O)OCc1ccccc1

Procedure:
from N-(2-L-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-octadecanamide and N-carbobenzoxy-glycine.
Reaction SMILES: [C:1]([C:6]1[N:7]=[C:8]([CH2:13][CH2:14][CH3:15])[NH:9][C:10]=1[C:11]#[N:12])(=[O:5])[CH2:2][CH2:3][CH3:4].Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:20][CH:19]=1.[H-].[Na+]>CN(C)C(=O)C>[C:33]([O:32][C:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:9]2[C:10]([C:11]#[N:12])=[C:6]([C:1](=[O:5])[CH2:2][CH2:3][CH3:4])[N:7]=[C:8]2[CH2:13][CH2:14][CH3:15])=[CH:19][CH:20]=1)=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: CCCC(=O)c1nc(CCC)[nH]c1C#N
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCC(=O)c1nc(CCC)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c1C#N
Yield: 72.1 %

Procedure:
Following a procedure similar to that described in Example 45(a), but using 1.026 g of 4-butyryl-2-propylimidazole-5-carbonitrile (prepared as described in Preparation 28), 1.91 g of t-butyl 4'-(bromomethyl)biphenyl-2-carboxylate and 0.209 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 20 ml of N,N-dimethylacetamide, 1.70 g of the title compound were obtained as a viscous oil.
Reaction SMILES: [CH2:1]([C:14]1[S:15][C:16]([CH3:19])=[N:17][N:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:20][N:21]1[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=[C:22]1[CH:29]=O.C(OC(=O)C)(=O)C>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:14]1[S:15][C:16]([CH:19]=[CH:29][C:22]2[N:21]([CH3:20])[C:25]([N+:26]([O-:28])=[O:27])=[CH:24][N:23]=2)=[N:17][N:18]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCCCc1nnc(C)s1
Reactant: Cn1c([N+](=O)[O-])cnc1C=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCCCCCCc1nnc(C=Cc2ncc([N+](=O)[O-])n2C)s1
Yield: 56.6 %

Procedure:
8.45 g of 2-tridecyl-5-methyl-1,3,4-thiadiazole, 4.65 g of 1-methyl-5-nitroimidazole-2-carboxaldehyde and 0.5 g of zinc chloride are heated in 40 ml of acetic acid and 15 ml of acetic anhydride for 24 hours at reflux temperature. After the solvent has been removed, the residue is recrystallized from alcohol. 7.1 g of product is obtained, corresponding to 61% of the theory. The melting point is 91° C.
Reaction SMILES: [CH:1]1([N:5]([C@H:18]2[CH2:22][CH2:21][CH2:20][C@@H:19]2[NH:23]C(=O)OC(C)(C)C)[C:6](=[O:17])[C:7]2[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:8]=2[O:15][CH3:16])[CH2:4][CH2:3][CH2:2]1.[ClH:31].O1CCOCC1>CO>[ClH:31].[NH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][C@@H:18]1[N:5]([CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:6](=[O:17])[C:7]1[C:8]([O:15][CH3:16])=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cccc(OC)c1C(=O)N(C1CCC1)[C@H]1CCC[C@@H]1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-(N-cyclobutyl2,6-dimethoxybenzamido)cyclopentyl]carbamate (1.34 g, 3.20 mmol) in methanol (11 ml) was added HCl in 1,4-dioxane (4 M, 8.00 ml, 32.0 mmol). The reaction was stirred at room temperature for 17 hours (overnight) and then was concentrated in vacuo, azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)=[C:21]([Cl:36])[CH:20]=3)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=[CH:10]1)(=O)C.[OH-].[Na+].Cl.O>O1CCCC1>[Cl:36][C:21]1[CH:20]=[C:19]([NH:18][C:16]2[C:17]3[N:9]([CH2:8][CH2:7][CH2:6][CH2:5][OH:4])[CH:10]=[CH:11][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:24]=[CH:23][C:22]=1[O:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1
Reactant: CC(=O)OCCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: OCCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 82.9 %

Procedure:
To a solution of 4-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]butyl acetate (281 mg) in tetrahydrofuran (4.0 mL) was added 1N aqueous sodium hydroxide solution (2.8 mL), and the mixture was stirred at room temperature for 4.5 hrs. 1N Aqueous hydrochloric acid solution (2.8 mL) was added, and the mixture was stirred for 15 min. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer washed successively with 5% aqueous sodium hydrogen carbonate solution, water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:hexane/ethyl acetate=95/5→0/100). The object fraction was concentrated under reduced pressure and dried. Ethanol/diisopropyl ether (5/95) was added to the residue, and the mixture was stirred with heating to 80° C., allowed to cool to room temperature, and stood still. The resultant precipitate was collected by filtration. The obtained precipitate washed with diisopropyl ether and dried under reduced pressure to give the title compound (214 mg) as white powder crystals.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15]CC)=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[OH-].[K+]>C(O)C>[CH3:1][NH:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)c1ccc2c(NC)nccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNc1nccc2cc(C(=O)O)ccc12
Temperature: 65 °C
Yield: 72.3 %

Procedure:
To a suspension of ethyl 1-(methylamino)isoquinoline-6-carboxylate (150 mg, 0.65 mmol) in ethanol (2.5 mL) was added 1 N aqueous potassium hydroxide (6.5 mL, 6.5 mmol). The reaction was heated to 65° C. for 1.5 hours. The reaction was cooled to room temperature and concentrated to dryness. The solid was dissolved in water and the solution was acidified with 1 N HCl. The mixture was concentrated. The solid was dissolved in water (50 mL) and extracted twice with 2-butanol (50 mL). The combined organics were washed with brine (20 mL), dried over magnesium sulfate, filtered, and concentrated to give the title compound (95 mg, 72%) as a white solid. +ESI (M+H) 203.2; 1H NMR (400 MHz, DMSO-d6, δ): 13.07 (br. s., 1H), 10.25 (d, J=4.9 Hz, 1H), 8.74 (d, J=8.8 Hz, 1H), 8.51 (s, 1H), 8.15 (dd, J=8.6, 1.8 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.35 (d, J=7.0 Hz, 1H), 3.15 (d, J=4.7 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[CH:15]=[C:14]([C:16]4[N:20]([C:21]5[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=5[F:28])[N:19]=[CH:18][N:17]=4)[S:13][C:10]=3[C:11]=2[N:12]=1.C([O-])(=O)C.[K+].[CH3:34][C:35]1[C:40](B(O)O)=[CH:39][CH:38]=[CH:37][N:36]=1>C(#N)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:34][C:35]1[C:40]([C:2]2[CH:3]=[CH:4][C:5]3[O:6][CH2:7][CH2:8][C:9]4[CH:15]=[C:14]([C:16]5[N:20]([C:21]6[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=6[F:28])[N:19]=[CH:18][N:17]=5)[S:13][C:10]=4[C:11]=3[N:12]=2)=[CH:39][CH:38]=[CH:37][N:36]=1
Reactant: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Reactant: Cc1ncccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ncccc1-c1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Temperature: 25 °C
Yield: 70 %

Procedure:
5-(2-(Chloro)-6,7-dihydropyrido[3,2-b]thieno[2,3-d]oxepin-9-yl)-1-(2,4-difluorophenyl)-1H-1,2,4-triazole (50 mg, 0.1 mmol) was dissolved in 1 ml acetonitrile and 1 ml water, with potassium acetate (39.9 mg, 0.406 mmol). The solution was degassed by bubbling with nitrogen for 5 min. 2-Methylpyridin-3-ylboronic acid (21.4 mg, 0.156 mmol) was added, then tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol). The reaction was microwaved at 300 watts, 140° C. for 20 minutes, cooled to room temperature, and extracted with ethyl acetate. The combined organics were concentrated and purified by reverse phase HPLC to give 474 (70% yield). MS: (ESI+)=474.0
Reaction SMILES: [C:1]([N:8]1[CH2:11][CH:10]([NH2:12])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:14]1[S:15][CH:16]=[CH:17][N:18]=1.ClCCCl>C(Cl)(Cl)Cl>[C:1]([N:8]1[CH2:11][CH:10]([NH:12][C:14]2[S:15][CH:16]=[CH:17][N:18]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC(N)C1
Reactant: Brc1nccs1
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC(Nc2nccs2)C1
Temperature: 140 °C
Reaction time: 2 h
Yield: 10.8 %

Procedure:
A mixture of 5.0 g (29.1 mmol) of 1-Boc-3-aminoazetidine and 2.62 ml (29.1 mmol) of 2-bromothiazole was heated to 140° C. with stirring for 2 h. After cooling to RT, 800 mg (3.14 mmol, 11%) of 1-Boc-3-(thiazol-2-ylamino)azetidine were obtained from the mixture by CC (SiO2, 1 st DCE, 2nd chloroform).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:5][CH:4]=1.[CH2:18]([C:20]1[C:21]([OH:30])=[C:22]([C:27](=[O:29])[CH3:28])[CH:23]=[CH:24][C:25]=1O)[CH3:19]>>[C:27]([C:22]1[CH:23]=[CH:24][C:25]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[N:11]=[CH:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])=[CH:7][CH:8]=2)=[C:20]([CH2:18][CH3:19])[C:21]=1[OH:30])(=[O:29])[CH3:28]
Reactant: N#Cc1ccnc(Sc2ccc(CO)cc2)c1
Reactant: CCc1c(O)ccc(C(C)=O)c1O
Product: CCc1c(OCc2ccc(Sc3cc(C#N)ccn3)cc2)ccc(C(C)=O)c1O
Yield: 100.2 %

Procedure:
Using the method of Preparation 166 using 6-(4-(hydroxymethyl)phenylthio) isonicotinonitrile (1.10 g, 4.54 mmol) and 1-(3-ethyl-2,4-dihydroxyphenyl)ethanone (818 mg, 4.54 mmol) affords the title compound (1.84 g, quant.). MS (APCI-neg) m/z (rel intensity): 403 (M−H, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1>CCOC(C)=O.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]=1[NH2:15]
Reactant: Cc1cccc(Nc2ccccc2)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cccc(Nc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.3 %

Procedure:
A mixture of (3-methyl-2-nitrophenyl)phenylamine (931 mg, 4.08 mmol) and 10% Pd/C (465 mg) in EtOAc (20 mL) was degassed with a stream of nitrogen and stirred at RT under a hydrogen atmosphere for 4 h. The suspension was then filtered through a PTFE frit and the filtrate was concentrated in vacuo affording 3-Methyl-N1-phenylbenzene-1,2-diamine as an off-white solid (763 mg, 94%). LCMS: RT 3.37 min [M+H]+ 199.0.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH3:6][N:7]1[C:11]([CH3:12])=[N:10][N:9]=[C:8]1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[Cl:4][CH2:12][C:11]1[N:7]([CH3:6])[C:8]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:9][N:10]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1nnc(-c2ccncc2)n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(CCl)nnc1-c1ccncc1
Reaction time: 2 h
Yield: 22.8 %

Procedure:
Sulfuryl dichloride (0.58 ml, 8.34 mmol) in DCM (8 ml) was slowly added to a cooled (−10° C.) solution of 4-(4,5-dimethyl-4H-1,2,4-triazol-3-yl)pyridine (454 mg, 2.61 mmol) in DCM (25 ml) and DMF (8 ml) and then the solution was stirred for 2 h. NaHCO3 (sat.) was added and the mixture was extracted with EA. The organic phase was dried and concentrated. Recrystallization from EA afforded 124 mg (23%) of the title compound. 1H NMR: 3.83 (s, 3 H) 4.84 (s, 2 H) 7.62 (d, 2 H) 8.82 (d, 2 H).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[CH:31][C:32](=[O:36])[N:33]([CH3:35])[CH:34]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)(C(C)(C)C)(C)C.Cl>CO>[OH:8][CH2:9][C:10]1([CH3:37])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:29]5[CH:30]=[CH:31][C:32](=[O:36])[N:33]([CH3:35])[CH:34]=5)=[CH:25][CH:24]=4)[CH2:21][CH2:22]3)=[N:18][N:19]=[C:12]2[CH2:11]1
Reactant: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)ccc1=O
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO)C5)CC3)cc2)ccc1=O
Yield: 97.2 %

Procedure:
A solution of the compound (402 mg, 0.75 mmol) obtained in Example 55-1) and 4 M hydrochloric acid (1,4-dioxane solution, 1 mL) in methanol (4 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate was added to the residue, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 12 g, methanol:ethyl acetate=0:100 to 40:60, gradient) to obtain the title compound (308 mg, 97%) as a colorless solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH:13]1([N:16]=[C:17]=S)[CH2:15][CH2:14]1>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:17]([NH:16][CH:13]3[CH2:15][CH2:14]3)[NH:2][C:3]=2[CH:7]=1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: S=C=NC1CC1
Agent: Cl
Product: O=S1(=O)N=C(NC2CC2)Nc2cc(Cl)sc21

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and cyclopropyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 272°-273° C.; 1H-NMR (DMSO-d6 ): δ 0.55 (m, 2H), 0.78 (m, 2H), 2.6 (m, 1H), 7.10 (s, 1H), 7.88 (br. s, 1H), 10.95 (br. s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[CH2:20][CH2:19][CH2:18][C:12]=3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)=[O:4].[Mg]>CO.C1COCC1>[CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:11]3[CH2:20][CH2:19][CH2:18][CH:12]3[C:13](=[O:17])[NH:14][C:15]=2[CH:16]=1)=[O:4]
Reactant: COC(=O)CCc1ccc2c3c(c(=O)[nH]c2c1)CCC3
Agent: [Mg]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCc1ccc2c(c1)NC(=O)C1CCCC21
Temperature: 25 °C
Reaction time: 24 h
Yield: 22 %

Procedure:
A solution of 550 mg (2.0 mmol) of 7-(methoxycarbonylethyl)-1,2,3,5-tetrahydrocyclopenta[c]-quinolin-4-one in 130 ml of methanol-THF 3:1 is mixed with 972 mg (40.0 mmol) of magnesium and stirred for 24 hours at room temperature. The reaction mixture is filtered over glass fibers, the filter residue is washed with dichloromethane-methanol, and the combined filtrates are concentrated by evaporation in a vacuum. Purification of the residue on silica gel yields 120 mg of product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:6]=[CH:5]2.C([Li])CCC.CON(C)[C:28]([C:30]1[CH:35]=[C:34]([Cl:36])[N:33]=[CH:32][N:31]=1)=[O:29]>C1COCC1>[Cl:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]([C:28]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=2)[N:7]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:6]=[CH:5]3)=[O:29])[CH:35]=1
Reactant: CON(C)C(=O)c1cc(Cl)ncn1
Reactant: Cc1cc(Br)cc2cnn(COCC[Si](C)(C)C)c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2cnn(COCC[Si](C)(C)C)c12
Temperature: -75 °C
Reaction time: 1 h

Procedure:
Under an argon atmosphere 0.34 g (1.00 mmol) 5-bromo-7-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole in 10 mL THF were cooled to −75° C., mixed with 0.70 mL (1.1 mmol) of a 1.6 molar n-butyllithium solution and stirred for 1 h at −75° C. Then 0.25 g (1.1 mmol) 6-chloro-pyrimidine-4-carboxylic acidmethoxy-methyl-amide, dissolved in a little THF, were added dropwise. The cooling bath was removed and the mixture was heated to 0° C. and stirred for a further hour in the ice bath. The mixture was stirred with saturated sodium hydrogen carbonate solution, extracted with EtOAc, the organic phase was dried and evaporated down. The residue was purified by flash chromatography.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([SH:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:1](=[O:12])([S:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCS
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)SCCCCCCCCCC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and 1-decanethiol as starting materials to give the aimed compound.
Reaction SMILES: [Br:1][C:2]1[C:6]2[CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[C:15]([O:18][C@@H:19]([CH3:23])[C:20](Cl)=[O:21])(=[O:17])[CH3:16]>CN(C)C(=O)C.C(OCC)(=O)C>[C:15]([O:18][C@@H:19]([CH3:23])[C:20]([NH:14][NH:13][C:11]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][CH:3]=[C:2]([Br:1])[C:6]=2[CH:7]=1)=[O:12])=[O:21])(=[O:17])[CH3:16]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: NNC(=O)c1ccc2occ(Br)c2c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H](C)C(=O)NNC(=O)c1ccc2occ(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a solution of 3-bromo-1-benzofuran-5-carbohydrazide (2.64 g, 10.35 mmol) in N,N-dimethylacetamide (10 mL) was added dropwise (1S)-2-chloro-1-methyl-2-oxoethyl acetate (1.44 mL, 11.38 mmol) at 0° C., and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from hexane/ethyl acetate to give the title compound (3.41 g, yield 89%) as colorless crystals.