Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:29]1[S:30][CH:31]=[CH:32][N:33]=1)CCC>C1(C)C=CC=CC=1.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>[S:30]1[CH:31]=[CH:32][N:33]=[C:29]1[C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Reactant: O=C(c1ccc(I)cc1)N1Cc2cccn2Cc2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(c1ccc(-c2nccs2)cc1)N1Cc2cccn2Cc2ccccc21
Temperature: 120 °C
Yield: 62.9 %

Procedure:
To a solution of 1.1 g of 10,11-dihydro-10-(4-iodobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 1.49 g of 2-(tributylstannyl)thiazole (Reference Example 48) in 50 ml of toluene under nitrogen is added 0.2 g of tetrakis(triphenylphosphine)palladium and the mixture heated to 120° C. for 16 hours. The toluene is evaporated in vacuo to a residue which is columned on silica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give 0.62 g of the desired product as an amphorous solid; M+H=372.3; M+Na=395.3.
Reaction SMILES: C(O[C:4](=[N:19][NH:20][CH:21]=O)[C:5]1[S:6][C:7]([S:17][CH3:18])=[C:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]=12)C.[CH3:23][NH2:24]>C(O)C>[CH3:15][C:11]1([CH3:16])[CH2:10][C:9]2=[C:5]([C:4]3[N:24]([CH3:23])[CH:21]=[N:20][N:19]=3)[S:6][C:7]([S:17][CH3:18])=[C:8]2[C:13](=[O:14])[CH2:12]1
Reactant: CCOC(=NNC=O)c1sc(SC)c2c1CC(C)(C)CC2=O
Reactant: CN
Solvent: CCO
Product: CSc1sc(-c2nncn2C)c2c1C(=O)CC(C)(C)C2
Temperature: 60 °C

Procedure:
Formic acid[ethoxy-(6,6-dimethyl-3-methylthio-4-oxo-4,5,6,7-tetrahydrobenzo[c]thiophen-1-yl)methylene]hydrazide (150 mg, 0.49 mmol) was dissolved in a solution of methylamine in ethanol (30%, 10 mL) and the mixture heated at 60° C. More methylamine solution (10 mL) was added periodically over 8 h. The solution was evaporated to dryness and the residue purified by chromatographed on silica gel, eluting with methanol:dichloromethane (5:95). The title compound was obtained as a white powder (60 mg, 44%). mp 178-180° C. Found: C, 52.50; H, 5.43; N, 12.73%. C14H17N3OS2.0.8 (H2O) requires: C, 52.25; H, 5.83; N, 13.06%. 1HNMR (360 MHz, CDCl3)δ 1.05 (6H, s), 2.44 (2H, s), 2.62 (3H, s), 2.79 (2H, s), 3.75 (3H, s), 8.28 (1H, s). MS (ES+) 308 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:36])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=2[NH:20][C:21](=[O:35])[C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][C:23]=2[O:30][CH2:31][CH2:32][CH2:33][NH2:34])=[N:6][CH:7]=1.CO.[Li+].[OH-].Cl>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:36])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=2[NH:20][C:21](=[O:35])[C:22]2[CH:27]=[CH:26][C:25]([S:28][CH3:29])=[CH:24][C:23]=2[O:30][CH2:31][CH2:32][CH2:33][NH2:34])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)Nc2ccc(Cl)cn2)c(NC(=O)c2ccc(SC)cc2OCCCN)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CSc1ccc(C(=O)Nc2cc(C(=O)O)ccc2C(=O)Nc2ccc(Cl)cn2)c(OCCCN)c1
Temperature: 65 °C
Yield: 84.9 %

Procedure:
To a mixture of N-(5-chloropyridin-2-yl)-4-methoxycarbonyl-2-[4-methylthio-2-(3-aminopropoxy)benzoylamino]benzamide (480 mg, 0.91 mmol), MeOH (10 mL) and water (7 mL) was added LiOH (109 mg, 4.54 mmol). The reaction mixture was heated to 65° C. for 45 min and then cooled to room temperature. To the mixture was added 5N HCl (1.8 mL, 9 mmol), and the resulting solid was filtered with CH2Cl2 and 20% Et2O/hexanes washes to give the title compound as a white solid (213 mg, 55%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.C[O-].[Na+].Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C=O)C>[N:22]1([CH2:21][CH2:20][O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]3)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Reactant: ClCCN1CCOCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cc(OCCN3CCOCC3)ccc2c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
6.4 g of methyl 6-hydroxy-2-naphthoate and 2.56 g of sodium methoxide are stirred under N2 at 40° C. for 30 min in 100 ml of DMF. 8.04 g of N-(2-chloroethyl)morpholine are then added and the mixture is stirred at 80° C. for 2 h. The reaction mixture is poured onto water, and the precipitate which is deposited is filtered off with suction. 9.2 g of methyl 6-[2-(4-morpholinyl)ethoxy]-2-naphthoate are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:32])[CH2:20][C:21](N3[C@H](C(C)C)COC3=O)=[O:22])=[C:8]2[CH3:33])=[CH:4][CH:3]=1.[OH:36]O.[Li+].[OH-]>C1COCC1>[Br:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:32])[CH2:20][C:21]([OH:22])=[O:36])=[C:8]2[CH3:33])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CC(C)CC(=O)N1C(=O)OC[C@H]1C(C)C)c(C)n2Cc1ccc(Br)cc1
Reactant: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To the oxazolidinone from Step 7, isomer A (295 mg, 0.54 mmol) in THF (10 mL) at -10° C. was added 30% H2O2 (0.5 mL) followed by 1M aqueous LiOH (3 mL). The mixture was stirred at 0° C. for 45 min, and was then cooled to -10° C. to be quenched by careful addition of 1M aqueous Na2S2O5 (10 mL). The mixture was acidified (6M HCl, 1 mL) and the product was extracted with EtOAc. The organic layer was washed with H2O and brine, and was then dried (MgSO4), and filtered. After removal of the solvent, the crude product was purified by flash chromatography (1:5 EtOAc/hexane followed by 1:2 EtOAc/hexane). The resulting off-white solid was stirred vigorously with 1:10 EtOAc/hexane for 2 h to give, after filtration, 188 mg of the title compound. [α]D =+4.6° (c=1, acetone)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7](Cl)(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[Na+]>O.CCOCC>[C:7]([NH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])(=[O:12])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: NCCC(=O)O
Reactant: CCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCCCC(=O)NCCC(=O)O

Procedure:
β-Alanine (20 mmol) was reacted with valeryl chloride (22 mmol) in the presence of NaOH (40 mmol) in a mixture of H2O and ether using the method described in Example 5. The crude crystalline product (2.75 g, 79%) was recrystallized from a mixture of isopropyl ether (150 ml) and ethyl acetate (10 ml) to give title acid (1.51 g, 44%), m.p. 73°-76° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[S:10][C:9]=2[C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Cl[C:29]1[O:30][C:31]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][C:33](=[O:35])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[C:18]2[S:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[S:10][C:9]=2[C:8]([C:29]2[O:30][C:31]([N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)=[CH:32][C:33](=[O:35])[CH:34]=2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(B2OC(C)(C)C(C)(C)O2)c2c1Sc1ccccc1S2
Reactant: O=c1cc(Cl)oc(N2CCOCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COCOc1ccc(-c2cc(=O)cc(N3CCOCC3)o2)c2c1Sc1ccccc1S2
Temperature: 90 °C
Yield: 101.6 %

Procedure:
2-(4-Methoxymethoxy-thianthren-1-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (6.23 g, 17.14 mmol), 2-chloro-6-morpholin-4-yl-pyran-4-one (3) (6.99 g, 17.40 mmol) and powdered potassium carbonate (7.20 g, 52.20 mmol) were suspended in anhydrous dioxane (60 ml) under a nitrogen atmosphere. The mixture was degassed for 15 minutes before the addition of tetrakis(triphenylphosphino)palladium (1.2 g, 5% eq) and then degassed for a further 15 minutes after addition. The reaction was then heated at 90° C. for 24 hours. Water (60 ml) was added and the mixture extracted with EtOAc (3×30 ml). The organic extracts were then dried using MgSO4, filtered and concentrated in vacuo to yield a dark yellow oil. The crude residue was then purified by flash chromatography (SiO2) (9:1—EtOAc/MeOH) to give the title compound (7.93 g, 79%) as a green powder. m/z (LC-MS, ESP): RT=4.39 min, (M++1)=456
Reaction SMILES: [OH-].[K+].O.COC(=O)[NH:7][C:8]1[N:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH:16]([CH3:18])[SeH:17])[N:9]=1.Cl>CO>[CH3:15][O:14][C:12]1[CH:11]=[C:10]([CH:16]([CH3:18])[SeH:17])[N:9]=[C:8]([NH2:7])[N:13]=1
Reactant: COC(=O)Nc1nc(OC)cc(C(C)[SeH])n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(C)[SeH])nc(N)n1
Temperature: 0 °C

Procedure:
To a stirring solution of potassium hydroxide (15.6 mmol) in H2O (77.5 mmol) and 50 ml of methanol was added methyl[4-methoxy-6-(methylselenylmethyl)pyrimidin-2-yl]carbamate (5.2 mmol). The solution was heated to the reflux point for 3 hours, then cooled to 0° C. The solution was neutralized to pH7 with concentrated HCl and then the solvent was removed under reduced pressure. The resulting residue was washed with THF to afford 1.3 g, m.p. 88°-91° C.; NMR (200 MHz, CDCl3): δ 2.01 (s, 3H); 3.48 (s, 2H); 3.85 (s, 3H); 5.1 (br. s, 2H); 5.99 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]3)=[O:13])[C:6]=2[CH:21]=1.[C:22](Cl)(=[O:26])[O:23][CH2:24][CH3:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][C:12]([N:14]3[CH2:15][CH2:16][CH:17]([O:20][C:22]([O:23][CH2:24][CH3:25])=[O:26])[CH2:18][CH2:19]3)=[O:13])[C:6]=2[CH:21]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(Cn1c(=O)sc2ccc(Cl)cc21)N1CCC(O)CC1
Solvent: c1ccncc1
Product: CCOC(=O)OC1CCN(C(=O)Cn2c(=O)sc3ccc(Cl)cc32)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
5-Chloro-3-(4-hydroxypiperidinocarbonylmethyl)benzothiazolin-2-one (3.2 g) was dissolved in dry pyridine (15 ml) and the solution was cooled. After ethyl chlorocarbonate (1.5 g) was dropwise added to the solution, the resultant was stirred for 8 hours at 80° C. Pyridine was evaporated off under vacuum from the reaction mixture and the residue was recrystallized from a mixture of chloroform and ethanol to yield the title compound as colorless crystals (3.2 g). mp 196°-197° C.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:13][CH2:12]1.[CH3:25][O:26][C:27](OC)(OC)OC.C(O)(=O)CC>>[CH3:25][O:26][C:27]1[N:17]([CH:14]2[CH2:15][CH2:16][CH:11]([NH:10][C:2]3[NH:3][C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:1]=3)[CH2:12][CH2:13]2)[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:23]2[N:24]=1
Reactant: COC(OC)(OC)OC
Reactant: Nc1cccnc1NC1CCC(Nc2nc3ccccc3[nH]2)CC1
Solvent: CCC(=O)O
Product: COc1nc2cccnc2n1C1CCC(Nc2nc3ccccc3[nH]2)CC1
Temperature: 90 °C
Yield: 14.4 %

Procedure:
N2-[4-((1H-Benzo[d]imidazol-2-yl)amino)cyclohexyl)pyridine-2,3-diamine (320 mg, 0.99 mmol) was combined with tetramethylorthocarbonate (2 mL) and propionic acid (8 mg), the mixture was heated at 90° C. for 2 hours. After that, the reaction solution was concentrated under reduced pressure and the residue was purified by silica chromatography to give N-(4-(2-methoxy-3H-imidazo[4,5-b]pyridin-3-yl)cyclohexyl)-1H-benzo[d]imidazol-2-amine (50 mg, 0.14 mmol, 14.4% yield). M+1: 380.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)[CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[C:20](Cl)(Cl)=[S:21]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]=[C:20]=[S:21])=[N:10]2)[N:7]=1
Reactant: Nc1ccn(Cc2cccc(F)n2)n1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1cccc(Cn2ccc(N=C=S)n2)n1
Reaction time: 15 h
Yield: 76.8 %

Procedure:
Intermediate 48 (48 mg, 0.250 mmol) was dissolved in 2 mL of DCM. 2 mL of sodium bicarbonate solution (aqueous, saturated) were added to the mixture and finally thiocarbonyl dichloride (ALDRICH, 0.019 mL, 0.250 mmol) was added dropwise. The reaction was stirred for 15 h. The crude was dissolved in 5 mL of DCM and washed with 5 mL of distilled water. Organic layer was dried over MgSO4 (anh), filtered and concentrated to dryness to give the title compound as a brown oil (45 mg, 0.192 mmol, 77%). 1H NMR (300 MHz, CDCl3) δ ppm: 7.78 (q, 1H), 7.49 (d, 1H), 6.98 (dd, 1H), 6.89 (dd, 1H), 6.22 (d, 1H); 5.26 (s, 2H). [ES+MS] m/z 235 (MH+).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2)([O-:3])=[O:2].[OH-].[K+].[Br:15][CH2:16][CH2:17][CH2:18]Br>CN(C=O)C.O>[Br:15][CH2:16][CH2:17][CH2:18][N:8]1[C:9]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: O=[N+]([O-])c1cccc2[nH]ccc12
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cccc2c1ccn2CCCBr
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.2 %

Procedure:
To a solution of 4-nitroindole (5 g, 31 mmol) in anhydrous N,N′-dimethylformamide (200 mL) was added grounded potassium hydroxide (1.74 g, 31 mmol) in portions. Then a solution of 1,3-dibromopropane (18 g, 89 mmol) in N,N′-dimethylformamide was added dropwise. The mixture was stirred at room temperature for 12 hours, diluted with water and extracted with ethyl acetate. The organic phases were combined, washed by brine, dried over anhydrous sodium sulfate, filtrated and evaporated. The residue was purified by silica gel chromatography to afford the product 1-(3-bromopropyl)-4-nitro-1H-indole as brown-red oil (8.18 g, yield 94%).
Reaction SMILES: C(S([C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][N:13]2[CH2:16][CH2:17][F:18])=[CH:8][C:7]=1[F:25])(=O)=O)C.[C:26]([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)(=[O:28])[CH3:27].C(N(CC)CC)C>C(O)C>[C:26]([NH:29][CH:30]1[CH2:34][CH2:33][N:32]([C:6]2[N:15]=[C:14]3[C:9]([C:10](=[O:24])[C:11]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][N:13]3[CH2:16][CH2:17][F:18])=[CH:8][C:7]=2[F:25])[CH2:31]1)(=[O:28])[CH3:27]
Reactant: CC(=O)NC1CCNC1
Reactant: CCOC(=O)c1cn(CCF)c2nc(S(=O)(=O)CC)c(F)cc2c1=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(CCF)c2nc(N3CCC(NC(C)=O)C3)c(F)cc2c1=O
Yield: 77.8 %

Procedure:
A mixture of ethyl 7-ethylsulfonyl-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (19.8 g) obtained according to the Reference Example 2, 3-acetylaminopyrrolidine (10.2 g), triethylamine (7.4 ml), and ethanol (400 ml) was heated under reflux for 2 hours. After cooling, the resulting crystals were collected by filtration, and recrystallized from chloroform-ethanol to give 16.8 g of ethyl 7-(3-acetylamino-1-pyrrolidinyl)-6-fluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate melting at 269°-270° C. A solution of the above ester (15.0 g) in 20% hydrochloric acid (100 ml) was heated under reflux for 4 hours. After cooling, ethanol (100 ml) was added to the mixture and the resulting crystals were collected by filtration. The crystals were dissolved in hot water (100 ml) and treated with charcoal. The filtrate was adjusted to pH 8.5-9.0 by addition of aqueous 27% ammonia, and the resulting crystals were collected by filtration, washed with water, and dried to give 9.3 g of the compound 3, m.p. 251°-255° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[N:9][S:10][C:6]=2[CH:5]=[C:4]([CH3:14])[CH:3]=1.OS(O)(=O)=O.[C:20]([O-])(O)=O.[Na+]>CO>[CH3:20][O:12][C:11]([C:8]1[C:7]2[C:2]([CH3:1])=[CH:3][C:4]([CH3:14])=[CH:5][C:6]=2[S:10][N:9]=1)=[O:13]
Reactant: O=C([O-])O
Reactant: Cc1cc(C)c2c(C(=O)O)nsc2c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1nsc2cc(C)cc(C)c12
Temperature: 60 °C
Yield: 94 %

Procedure:
To a solution of 4,6-dimethyl-benzo[d]isothiazole-3-carboxylic acid (10 mg, 0.048 mmol) in MeOH (5 mL) was added conc. H2SO4 (0.1 mL) at room temperature. The solution was heated up to 60° C. for 24 hours. The solution was cooled and was neutralized with sat. NaHCO3. The solution was extracted with EtOAc. The combined organic layer was dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel flash column chromatography with 20% EtOAc in Hexane as the eluent to afford the title compound (10 mg, 94%) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[CH:3]=1.[Mg].[O:11]=[C:12]1[CH2:16][CH2:15][O:14][CH2:13]1>O1CCCC1>[F:9][C:4]1[CH:3]=[C:2]([C:12]2([OH:11])[CH2:16][CH2:15][O:14][CH2:13]2)[CH:7]=[C:6]([F:8])[CH:5]=1
Reactant: O=C1CCOC1
Reactant: Fc1cc(F)cc(Br)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: OC1(c2cc(F)cc(F)c2)CCOC1
Temperature: 85 °C
Reaction time: 72 h
Yield: 9.8 %

Procedure:
to a solution of 1-bromo-3,5-difluoro-benzene (4.00 g, 20.7 mmol) in tetrahydrofuran (70 mL) under nitrogen was added magnesium (6.0 equiv., 124 mmol) and the solution was heated at 85° C. for three hours. The solution was cooled to rt and 3-oxotetrahydrofuran (1 equiv., 20.726 mmol) in THF (20 mL) was added via syringe. The mixture was stirred at rt for three days. The reaction was quenched with sat NaHCO3, extracted with EtOAc and washed with brine. Purification by CombiFlash (0 to 100% EtOAc in heptane) provided the title compound (405 mg, 9.7%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: CSc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CSc1ccc(-c2cc(C(F)(F)F)ccn2)cc1
Temperature: 100 °C
Yield: 99.3 %

Procedure:
To a mixture of 2-chloro-4-(trifluoromethyl)pyridine (19.9 g, 0.11 mol), 4-(methylthio)phenylboronic acid (21.9 g, 0.13 mol), 1M aqueous sodium carbonate (180 mL) and 1,2-dimethoxyethane (270 mL) under an atmosphere of nitrogen was added palladium tetrakistriphenylphosphine (3.78 g, 3.3 mmol) and the reaction heated at 100° C. for 14 hours. After cooling and concentration in vacuo, the residue was partitioned between ethyl acetate (350 mL) and water (400 mL) and separated. The aqueous layer was further extracted with ethyl acetate (2×150 mL) and the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Filtration through a pad of silica gel (200 g) eluting with a gradient of ethyl acetate in cyclohexane gave the title compound (29.4 g) LC retention time 3.62 mins, MS m/z 269 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].[N:32]#CBr.O>CS(C)=O>[C:20]1([S:17]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([N:5]3[CH2:4][CH2:3][N:2]([C:1]#[N:32])[CH2:7][CH2:6]3)=[N:9]2)(=[O:18])=[O:19])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N#CBr
Reactant: CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#CN1CCN(c2nn(S(=O)(=O)c3ccccc3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
To a stirred mixture of 3-(4-methyl-1-piperazinyl)-1-phenylsulfonyl-1H-indazole (237 g, 0.67 mole), K2CO3 (102 g, 0.74 mole) and dimethylsulfoxide (DMSO, 2000 ml), under nitrogen, was added cyanogen bromide (72 g, 0.68 mmol) dissolved in DMSO (525 ml). The reaction was stirred at ambient temperature for 5.5 hours and was then poured into H2O (7 l). The solid, which precipitated from solution, was collected by filtration and was washed well with H2O affording 168 g (68%) of product. A 5.2 g sample was recrystallized twice from ethanol-H2O yielding 4.0 g of 4-[1-(phenylsulfonyl)-1H-indazol-3-yl]-1-piperazinecarbonitrile, m.p. =178°-180° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[C:9]([NH2:11])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13].[C:14]1(=O)[O:19][C:17](=[O:18])[C:16]2[CH2:20][CH2:21][CH2:22][CH2:23][C:15]1=2.O>C(O)(=O)C>[CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[C:9]([N:11]2[C:17](=[O:18])[C:16]3[CH2:20][CH2:21][CH2:22][CH2:23][C:15]=3[C:14]2=[O:19])[C:8]([Cl:12])=[CH:7][C:6]=1[Cl:13]
Reactant: CON=Cc1cc(N)c(Cl)cc1Cl
Reactant: O=C1OC(=O)C2=C1CCCC2
Solvent: CC(=O)O
Solvent: O
Product: CON=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(Cl)cc1Cl
Reaction time: 15 h

Procedure:
18 g (82 mmol) of 5-amino-2,4-dichlorobenzaldehyde (O-methyl)oxime were added to a solution of 12.5 g (82 mmol) of 3,4,5,6-tetrahydrophthalic anhydride in 300 ml of acetic acid, whereupon the mixture was stirred for 15 hours at reflux temperature. The reaction mixture was subsequently poured into 1 l water. The product was then extracted with 300 ml of methyl tert-butyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and finally concentrated. The residue was purified by means of silica gel chromatography (eluent: hexane/ethyl acetate=4:1). Yield: 20.9 g; m.p.: 122-124° C.
Reaction SMILES: C([O-])(=O)C.[Na+].[SH:6][C:7]1[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=1.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1>O.C(#N)C>[F:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][S:6][C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[C:9]([OH:14])[N:8]=2)=[CH:18][CH:19]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: Oc1cc(O)nc(S)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Oc1cc(O)nc(SCc2ccc(F)cc2)n1
Reaction time: 20 h
Yield: 89.3 %

Procedure:
Sodium acetate (113 g) was added to a suspension of 2-mercaptopyrimidine-4,6-diol (80 g) in water (900 mL) at room temperature. A solution of 1-(bromomethyl)-4-fluorobenzene (105 g) in acetonitrile (90 mL) was added dropwise over 2 hours. The reaction was allowed to stir for 20 hours before the suspension was filtered and washed with water (3×) and isohexane (3×). The solid was dried in vacuo for 2 hours and azeotroped with toluene (3×) to afford the sub-title product (125 g) as a white solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].Cl.N1C=CC=CC=1.[NH2:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[CH2:28][CH2:29][OH:30]>C(OCCO)C>[OH:30][CH2:29][CH2:28][C:27]1[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=1[NH:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccccc1CCO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccccc3CCO)c2cc1OC
Yield: 62.5 %

Procedure:
Using an analogous procedure to that described in Example 286, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 12 mL of 2-ethoxyethanol and in the presence of 115.6 mg (1 mmol) of pyridine hydrochloride was reacted with 178.3 mg (1.3 mmol) of 2-aminophenethyl alcohol to give 218.4 mg (64.4%) of the product as a pink solid, m.p 159-162° C., mass (electrospray, m/e): M+H 349.9.