Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:22][CH2:21][C:16]4(OCC[O:17]4)[CH2:15][CH2:14]3)=[N:8][O:9][C:5]=2[CH:4]=1.O.Cl.[OH-].[Na+]>C(O)C>[F:2][C:3]1[CH:24]=[CH:23][C:6]2[C:7]([CH2:10][CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][C:16](=[O:17])[CH2:21][CH2:22]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(CCCN3CCC4(CC3)OCCO4)noc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C1CCN(CCCc2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of 51 g of 8-[3-(6-fluoro-1,2-benzisoxazol-3-yl)propyl]-1,4-dioxa-8-azaspiro[4.5]decane hydrochloride, 100 ml of water, 100 ml of ethanol and 150 ml of 3N hydrochloric acid was heated at 75°-80° C. for 3 hrs and an ambient temperature overnight, with stirring. The mixture was cooled, basified with 3N sodium hydroxide solution and extracted with ethyl acetate-ether. The organic extracts were washed with water, saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated to give 37 g (96%) of product as an oil.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]OS(C)(=O)=O)[CH2:5][CH2:4]1.FC(F)(F)C(O)=O.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].[CH3:37][NH:38][CH:39]1[CH2:41][CH2:40]1>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27](=[O:28])[N:2]([C@H:3]2[CH2:4][CH2:5][C@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:38]([CH:39]3[CH2:41][CH2:40]3)[CH3:37])[CH2:7][CH2:8]2)[CH3:1])=[CH:31][CH:32]=1
Reactant: CNC1CC1
Reactant: CN[C@H]1CC[C@H](CCCCCOS(C)(=O)=O)CC1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCCC[C@H]1CC[C@H](N(C)C(=O)Oc2ccc(Cl)cc2)CC1)C1CC1

Procedure:
In analogy to examples 29.10 and 29.11, trans-Methansulfonic acid 5-(4-methyl amino-cyclohexyl)-pentyl ester.trifluoroacetic acid salt and 4-chlorophenyl chloroformate were reacted, followed by treatment with N-methyl-N-cyclopropyl-amine to give trans {4-[5-(Cyclopropyl-methyl-amino)-pentyl]-cyclohexyl}-methyl-carbamic acid 4-chloro-phenyl ester, MS: 407 (MH+, 1Cl).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][N:14]=[C:13]([S:22][CH3:23])[N:12]=2)[N:7]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].Cl>C(O)C.C1COCC1.O>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[CH:15][N:14]=[C:13]([S:22][CH3:23])[N:12]=2)[N:7]([C:24]2[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=2[CH3:31])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(SC)nc1Nc1cc(C(C)(C)C)nn1-c1cc(C)ccc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CSc1ncc(C(=O)O)c(Nc2cc(C(C)(C)C)nn2-c2cc(C)ccc2C)n1
Temperature: 40 °C
Yield: 100.2 %

Procedure:
To a solution of ethyl 4-{[3-tert-butyl-1-(2,5-dimethylphenyl)-1H-pyrazol-5-yl]amino}-2-(methylthio)pyrimidine-5-carboxylate (71 mg, 0.16 mmol) in a mixture of ethanol (0.5 mL) and THF (0.5 mL) was added lithium hydroxide monohydrate (68 mg, 1.6 mmol) in water (1 mL), and the mixture was then heated to 40° C. for 1 h. The reaction mixture was cooled to rt, the pH of the solution was adjusted to 5 by addition of 0.5 N hydrochloric acid, and the mixture was concentrated to dryness. The crude mixture was redissolved in methanol and subjected to HPLC purification using a gradient elution from 30% to 90% acetonitrile in water to afford 66 mg (99%) of the desired product. 1H NMR (300 MHz, CD2Cl2) δ 10.50 (s, 1H), 8.65 (s, 1H), 7.17 (dd, 2H), 7.12 (s, 1H), 6.83 (s, 1H), 2.68 (s, 3H), 2.27 (s, 3H), 1.97 (s, 3H), 1.35 (s, 9H); ES-MS m/z 412.2 (MH+); HPLC RT (min) 3.94.
Reaction SMILES: ClS([N:5]=[C:6]=O)(=O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([O:20][CH3:21])[CH:18]=[C:17]([C:22](O)=O)[CH:16]=2)=[CH:11][CH:10]=1.C[N:26](C)C=O>O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([O:20][CH3:21])[CH:18]=[C:17]([C:22]#[N:26])[C:16]=2[C:6]#[N:5])=[CH:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: COn1cc(C(=O)O)cc1-c1ccc(Cl)cc1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Product: COn1cc(C#N)c(C#N)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 18 %

Procedure:
Chlorosulfonyl isocyanate (8.1 g, 0.0572 mol) is added dropwise to a 50° C. stirred mixture of 5-(p-chlorophenyl)-1-methoxypyrrole-3-carboxylic acid (6.0 g, 0.0238 mol) in acetronitrile and dimethylformamide. The reaction mixture is stirred at room temperature for 20 hours, cooled to 0° C., treated with dimethylformamide (9.2 mL), heated to 50° C. for 1 hour, cooled to room temperature for 3 hours, diluted with water and extracted with chloroform. The combined chloroform extracts are washed sequentially with water, saturated sodium bicarbonate solution, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give a gum. The gum is chromatographed using silica gel, and methylene chloride as eluent to give 2 products as a mixture. Crystallization from chloroform gives 2-(p-chlorophenyl)-1-methoxypyrrole-3,4-dicarbonitrile (1.1 g, 18%), as a yellow solid, mp 193°-194° C. The filtrate from the above crystallization is chromatographed using silica gel, and 30% ethyl acetate in heptane as eluent to give the title compound as a yellow solid (0.93 g, 15%), mp 126°-127° C.
Reaction SMILES: [CH2:1]1[O:24][C:23]2[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]3[S:9][CH:10]=[CH:11][C:12]=3[S:13](N3C=CC=C3)(=[O:15])=[O:14])=[CH:4][C:3]=2[O:2]1.[K].S(Cl)([Cl:29])(=O)=O>>[Cl:29][S:13]([C:12]1[CH:11]=[CH:10][S:9][C:8]=1[CH2:7][CH2:6][C:5]1[CH:21]=[CH:22][C:23]2[O:24][CH2:1][O:2][C:3]=2[CH:4]=1)(=[O:15])=[O:14]
Reactant: O=S(=O)(c1ccsc1CCc1ccc2c(c1)OCO2)n1cccc1
Reactant: O=S(=O)(Cl)Cl
Agent: [K]
Product: O=S(=O)(Cl)c1ccsc1CCc1ccc2c(c1)OCO2
Yield: 42 %

Procedure:
3-chlorosulfonyl-2-[3,4-(methylenedioxy)phenethyl]thiophene was prepared in the same manner as described in the Example 15E using N-{2-[3,4-(methylenedioxy)phenethyl]thiophene-3-sulfonyl}pyrrole by conducting basic hydrolysis (iso-propanol and potassium hydroxide) of the sulfonamide to the potassium salt of sulfonic acid (93%) followed by conversion of the salt to the corresponding sulfonyl chloride in a 42% yield.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[N:5]=1)(=[O:3])[CH3:2].[I:11]I.C(O)(C)C.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[I-:11].[Br:10][C:6]1[N:5]=[C:4]([C:1](=[O:3])[CH2:2][N+:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)c1cccc(Br)n1
Reactant: II
Reactant: c1ccncc1
Solvent: CC(C)O
Product: O=C(C[n+]1ccccc1)c1cccc(Br)n1
Product: [I-]

Procedure:
To a stirred solution of 2-acetyl-6-bromopyridine (100 g; 0.5 mole) in 600 mL pyridine was added iodine (127 g; 0.5 mole). The mixture was heated on a steam bath for 45 minutes, and the product crystallized on cooling. The solid was filtered and the light yellow crystalline cake was rinsed twice with methylene chloride. After drying, 183 g (90%) was obtained. MP 176°-178° C.; silica gel TLC system: 95acetone: 5 isopropanol.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])=[CH:5][N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.CCOC(C)=O>CN1C(=O)CCC1>[CH3:12][O:11][N:9]([CH3:10])[C:7]([C:6]1[C:2]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[N:3][N:4]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:5]=1)=[O:8]
Reactant: C1CCNC1
Reactant: COc1ccc(Cn2cc(C(=O)N(C)OC)c(Cl)n2)cc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1ccc(Cn2cc(C(=O)N(C)OC)c(N3CCCC3)n2)cc1
Yield: 89.7 %

Procedure:
According to Scheme 14 Step 1: A solution of 3-chloro-N-methoxy-1-(4-methoxybenzyl)-N-methyl-1H-pyrazole-4-carboxamide (0.97 mmol, 300 mg) and pyrrolidine (14.5 mmol, 1.03 g) in NMP (10 mL) was stirred at 220° C. for 40 minutes under microwave heating. AcOEt was then added and the organic phase was washed with water. The organic layer was dried over MgSO4, was filtered and was concentrated. The crude compound was purified by flash chromatography with silica gel using cyclohexane/AcOEt (100:0 to 50:50) to yield N-methoxy-1-(4-methoxybenzyl)-N-methyl-3-(pyrrolidin-1-yl)-1H-pyrazole-4-carboxamide (0.87 mmol, 300 mg, 90%) as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:17])[NH:4][C:5](=[O:16])[N:6]([CH:15]=1)[C@@H:7]1[O:14][C@H:11]([CH2:12][OH:13])[CH2:10][C@H:8]1[OH:9].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].CO>N1C=CC=CC=1.C(OCC)(=O)C>[Si:18]([O:13][CH2:12][C@H:11]1[O:14][C@@H:7]([N:6]2[CH:15]=[C:2]([CH3:1])[C:3](=[O:17])[NH:4][C:5]2=[O:16])[C@H:8]([OH:9])[CH2:10]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cn([C@@H]2O[C@H](CO)C[C@H]2O)c(=O)[nH]c1=O
Solvent: CO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1cn([C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)C[C@H]2O)c(=O)[nH]c1=O
Reaction time: 4.5 h
Yield: 84.4 %

Procedure:
5-Methyl-3'-deoxyuridine, from Step 1, was dissolved in 150 mL of dry pyridine and 3.6 g (24 mmol) of t-butyldimethylsilyl chloride was added in 4 portions at 4 times (t): t=0 h, t=2 h, t=3 h and at t=3.75 h. After 4.5 h, 8 mL of methanol was added to the reaction mixture and the reaction mixture was stirred for 0.5 h, then concentrated under reduced pressure to approximately 25% of volume. The concentrated reaction mixture was diluted with ethyl acetate, washed with dilute aqueous sodium bicarbonate solution and then concentrated under reduced pressure. The residue was purified by column chromatography on a 5 cm×37 cm silica gel column eluted with 90% ethyl acetate in hexane. The fractions containing the desired product were combined and concentrated in vacuo to give 7.27 g (84.4% yield based on 24.19 mmol of 2',5'-bis(O-(4"-chloro)benzoyl)-5-methyl-3'-deoxyuridine) of 5'-O-(t-butyldimethylsilyl)-5-methyl-3'-deoxyuridine, [α]D23 =-19.6° (c, 1.42, MeOH). Analysis calculated for C16H28N2O5Si: C, 53.98; H, 7.91; N, 7.87. Found: C, 54.01; H, 7.85; N, 7.79.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15].C(N(CC)CC)C.O>CN(C)C=O>[C:14]([CH2:13][CH2:12][NH:11][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])([OH:16])=[O:15]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: NCCC(=O)O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)CCNc1ccccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 10 h
Yield: 47.6 %

Procedure:
A mixture of 5.0 g (36 mmol) 2-fluoronitrobenzen, 6.3 g (71 mmol) β-alanin, 20 ml triethylamine, 50 ml water and 100 ml dimethylformamide was stirred at 80° C. for 10 h After cooling to 25° C. the reaction mixture was evaporated in vacuo. The residue was stirred with 1N hydrochloric acid, and the precipitate was filtered off and washed with water to give 3.6 g (48%) N- carboxyethyl-2-nitroaniline. M.p. 145° C., 1H-NMR (DMSO-d6): 8.2-6.2 (5H, m), 3.4 (2H, q), 2.5 (2H, t).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH2:5][C:6]1[C:7](Cl)=[N:8][C:9](Cl)=[N:10][CH:11]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[CH:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][CH3:21])[CH2:5][C:6]1[C:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:8][C:9]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:10][CH:11]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1ccccc1OC
Product: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1ccccc1OC
Temperature: 120 °C

Procedure:
A mixture of 3-(2,4-dichloro-pyrimidin-5-yl)-2-(2-methoxy-phenyl)-propionic acid methyl ester (0.34 g, 1.0 mmol) (from Example 7a supra) and aniline (2.0 mL) (Aldrich) was heated at 120° C. for 1 hour. The reaction mixture was washed with hexanes (50 mL×3) and the supernatant was decanted off after each time. The residue was dissolved in ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (30 mL), water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was triturated with ethyl acetate-hexanes. The resulting solid was collected by filtration and washed with diethyl ether to give 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(2-methoxy-phenyl) propionic acid methyl ester as a yellow solid which was used in the next step without further purification. (Yield 340.0 mg, 74.9%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]1[O:10][CH2:9][C:8]([CH3:15])([C:11]([O:13]C)=[O:12])[CH2:7][O:6]1.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][O:2][CH2:3][CH2:4][CH:5]1[O:6][CH2:7][C:8]([CH3:15])([C:11]([OH:13])=[O:12])[CH2:9][O:10]1
Reactant: COCCC1OCC(C)(C(=O)OC)CO1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCCC1OCC(C)(C(=O)O)CO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
478 mg of methyl 2-(2-methoxyethyl)-5-methyl-1,3-dioxane-5-carboxylate (Va-9) are dissolved in 8 ml of tetrahydrofuran, and 92 mg of lithium hydroxide in 2 ml of water are added. The mixture is stirred at room temperature for 16 hours, 92 mg of lithium hydroxide, dissolved in 2 ml of water, are added, and the mixture is stirred for 24 hours. The mixture is acidified with 1N hydrochloric acid and extracted with ethyl acetate, and the solvent of the organic phase is removed under reduced pressure. Water is added to the residue, and the mixture is made basic using 1N aqueous sodium hydroxide solution and extracted with ethyl acetate. The aqueous phase is acidified with 1N hydrochloric acid and extracted with ethyl acetate, the organic phase is separated off and dried over sodium sulphate and the solvent is removed under reduced pressure. This gives 261 mg of 2-(2-methoxyethyl)-5-methyl-1,3-dioxane-5-carboxylic acid as a mixture of two isomeric forms in a purity of about 78% (LCMS).
Reaction SMILES: [CH2:1]=[O:2].C1C=CC=CC=1.[CH3:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[CH2:13][CH2:12][N:11]=1.C[CH2:25][O-:26].[Na+]>>[OH:2][CH2:1][CH:9]([CH2:25][OH:26])[C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[CH2:13][CH2:12][N:11]=1
Reactant: CC[O-]
Reactant: C=O
Reactant: COc1cc2c(cc1OC)C(C)=NCC2
Agent: [Na+]
Solvent: c1ccccc1
Product: COc1cc2c(cc1OC)C(C(CO)CO)=NCC2

Procedure:
To a solution of 2.5 moles of paraformaldehyde in 500 ml. of benzene 1 mole (205.3 g) of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline and subsequently freshly prepared sodium ethylate (1 g sodium+50 ml ethanol) are added at room temperature, with stirring. The reaction mixture is refluxed for 4 hours. The mixture is then evaporated under reduced pressure, and the obtained crystalline material is recrystallized from a mixture of acetone and ether. The aimed compound is obtained which has the same melting point as the product prepared in Example 1.
Reaction SMILES: [N+](C1C=CC(S([N:13]([C@H:20]2[CH2:24][CH2:23][N:22]([C:25]3[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=3)[CH2:21]2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)(=O)=O)=CC=1)([O-])=O.[OH-].[Li+].C(O)(=O)CS>CN(C=O)C>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[NH:13][C@H:20]1[CH2:24][CH2:23][N:22]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])=[CH:27][CH:26]=2)[CH2:21]1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](N(c3ccccn3)S(=O)(=O)c3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=C(O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](Nc3ccccn3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
To a solution of compound 12 (1.41 g, 2.68 mmol) in DMF (13 mL), were successively added lithium hydroxide (382 mg, 9.09 mmol) and thioglycolic acid (274 μL, 3.94 mmol). The mixture was stirred for 18 h at r.t., the solvent was removed in vacuo at 80° C. and the residue was partitioned between EtOAc and H2O. The organic layer was collected, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc/Hexanes (40:60) as an eluent, to afford the title compound 13 (511 mg, 47% yield) as a light yellow oil. 1H NMR: (DMSO-d6) d (ppm): 7.98 (dd, J=5.5, 1.6 Hz, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.35 (td, J=7.0, 2.0 Hz, 1H), 6.80 (d, J=6.3 Hz, 1H), 6.52 (d, J=9.0 Hz, 2H), 6.49-6.46 (m, 2H), 4.52-4.49 (m, 1H), 3.64 (dd, J=10.5, 6.5 Hz, 1H), 3.48-3.44 (m, 1H), 3.39-3.33 (m, 1H), 3.16 (dd, J=10.0, 4.5 Hz, 1H), 2.30-2.24 (m, 1H), 2.00-2.19 (m, 1H), 1.48 (s, 9H). LRMS (ESI): (calc.) 339.19; (found) 340.1 (MH)+
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=2[F:13])[C:7](O)=[O:8])[CH2:3][CH2:2]1.[NH3:14].C1COCC1>C1COCC1>[CH:1]1([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=2[F:13])[C:7]([NH2:14])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(F)c(C2CC2)c1
Reactant: N
Solvent: C1CCOC1
Product: NC(=O)c1ccc(F)c(C2CC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
To a solution of compound 3-cyclopropyl-4-fluoro-benzoic acid (Preparation 56, 74 g, 0.41 mol, 1 eq) in THF (800 mL) was added N,N′-carbonyldiimidazole (88 g, 0.53 mol, 1.29 eq) at room temperature. The suspension was stirred at room temperature for 3 h, and turned into a brown solution. Ammonia/THF (1 L) was added to the mixture and the resulting mixture was stirred at room temperature overnight. THF was removed in vacuum and the residue was taken up with water (300 mL). The mixture was filtrated and the solid was washed with water (100 mL) and ether (200 mL). The solid was dissolved in DCM (500 mL), dried over sodium sulfate and concentrated in vacuum to title compound as a white solid (66 g, 0.368 mol, 89.7%).
Reaction SMILES: Br[C:2]1[S:27][C:5]2=[N:6][C:7]([CH3:26])=[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[CH3:28].O(C([N:36]1[CH:40]=[C:39](B(O)O)[CH:38]=[N:37]1)=O)C(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)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>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[C:8]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:7]([CH3:26])[N:6]=[C:5]3[S:27][C:2]([C:39]4[CH:40]=[N:36][NH:37][CH:38]=4)=[C:3]([CH3:28])[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)n1cc(B(O)O)cn1
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(C)c2c1NS(=O)(=O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc2sc(-c3cn[nH]c3)c(C)c2c1NS(=O)(=O)c1cccc(Cl)c1
Temperature: 100 °C

Procedure:
A mixture of ethyl 2-bromo-4-{[(3-chlorophenyl)sulfonyl]amino}-3,6-dimethylthieno[2,3-b]pyridine-5-carboxylate (Description 63) (350 mg, 0.695 mmol), 1-tert-butoxylcarbonyl-1H-pyrazole-4-boronic acid, pinacol ester (221 mg, 0.751 mmol), tetrakis(triphenylphosphine)palladium(0) (40.1 mg, 0.035 mmol) and potassium carbonate (288 mg, 2.084 mmol) in 1,4-dioxane (1.5 mL), DMF (1.5 mL) and water (0.5 mL) was heated at 100° C. overnight (ca. 16 h). The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated. The residue was purified by normal phase chromatography, eluting with a gradient of 0-100% ethyl acetate in cyclohexane, to give the title compound (150 mg). LCMS (A) m/z: 491 [M+1]+, Rt 1.20 min (acidic).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16]Cl.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:11][O:12][CH2:13][CH2:14][O:15][CH2:16][O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1
Reactant: OCc1ccc(CCl)cc1
Reactant: COCCOCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
A 5 liter round bottom flask, fitted with a reflux condenser, dropping funnel and mechanical stirrer, was charged with p-hydroxymethylbenzyl chloride (255 g, 1.91 moles) in dichloromethane (2 liters). The flask was charged with 2-methoxyethoxymethyl chloride (300 g, 2.41 moles) and stirred at 20°-25° C. while N,N-diisopropylethylamine (500 mL, 2.86 moles) was slowly added. The reaction became exothermic and caused the dichloromethane solvent to reflux vigorously for 20 minutes. The contents were then stirred for 24 hours at room temperature. The dichloromethane extract was washed with water and brine. The remaining organics were dried over anhydrous magnesium sulfate. After removal of the solvent by rotary evaporation, the residue was passed through a plug of silica gel to provide 310 g (67% yield) of the desired product. 1H NMR spectral data were as follows: (CDCl3, 300 MHz): δ 7.35 (m, 4H), 4.80 (s, 2H), 4.62 (s, 2H), 4.58 (s, 2H), 3.72 (m, 2H), 3.58 (m, 2H), 3.4 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:24]2[CH2:25][C:26]([CH3:33])([CH3:32])[CH2:27][C:28]([CH3:31])([CH3:30])[CH2:29]2)[C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(/C=C/C(=O)OC(C)(C)C)cc2)CC(C)(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC(=C(c2ccc(F)cc2)c2ccc(/C=C/C(=O)O)cc2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 26 (˜700 mg, a mixture obtained from the above) and CH2Cl2 (8 mL) was treated with CF3CO2H (2 mL) at RT. The reaction mixture stirred at RT under N2 for 1.5 h and then concentrated under reduced pressure to afford the crude product. The crude material was purified by column chromatography to afford 165 mg of the desired product 27 as a white solid. A portion (350 mg) of the starting triflate 25 was also recovered. Data for 27: 1H NMR (400 MHz, CD3OD): δ 7.64 (d, J=16.0 Hz, 1H), 7.52 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 7.18 (d, J=5.6 Hz, 1H), 7.16 (d, J=5.6 Hz, 1H), 7.00 (t, J=8.8 Hz, 2H), 6.44 (d, J=16.00 Hz, 1H), 1.99 (s, 2H), 1.97 (s, 2H), 1.31 (s, 2H), 0.93 (s, 12H). LCMS (APCI): m/z 391 (M−H)−.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:9]=2[NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19](OCC)(=[O:25])[C:20](OCC)=[O:21]>>[CH:1]1([N:7]2[C:8]3[C:9](=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=3)[NH:10][C:20](=[O:21])[C:19]2=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(C(F)(F)F)ccc1NC1CCCCC1
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n(C2CCCCC2)c1=O

Procedure:
28 g (0.11 mol) of 2-cyclohexylamino-5-trifluoromethylaniline and 322 g (2.2 mol) of diethyl oxalate were refluxed for 2 hours. The reaction mixture was then concentrated, and the crude product was recrystallized from ethanol.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1)#[N:2].[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:21]=[C:13]1[C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[S:16][C:11]([C:9]2[N:10]=[C:5]([CH2:4][CH2:3][C:1]#[N:2])[CH:6]=[CH:7][CH:8]=2)=[N:12]1
Reactant: N#CCCc1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: N#CCCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 53 %

Procedure:
6-(2-Cyanoethyl)-2-pyridinecarbonitrile (0.28 g, 1.8 mmol) and methyl thiosalicylate (0.36 g, 2.1 mmol) were dissolved in toluene (2 ml), and triethylamine (0.37 ml, 2.7 mmol) was added thereto. The reaction mixture was refluxed for 6 hrs and kept at room temperature. The precipitated crystals were collected, washed with toluene and recrystallized from ethanol to give the titled compound (0.28 g, 54%) as white crystals.