Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].[F:9][C:10]1[CH:11]=[C:12]([CH2:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][OH:22])[CH:13]=[C:14]([F:18])[C:15]=1[S:16][CH3:17].[Cl-].[NH4+].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C>[F:18][C:14]1[CH:13]=[C:12]([C:19]2[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:21][O:22][C:1]=2[CH3:2])[CH:11]=[C:10]([F:9])[C:15]=1[S:16][CH3:17]
Reactant: CC(C)[N-]C(C)C
Reactant: CSc1c(F)cc(CC(=NO)c2ccccc2)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1c(F)cc(-c2c(-c3ccccc3)noc2C)cc1F
Temperature: -25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
To a solution of lithium diisopropylamide (82 mmol) in anhydrous THF (200 mL), cooled to −45° C., was added a solution of 2-[3,5-difluoro-4-(methylthio)-phenyl]-1-phenylethanone oxime (5.7 g, 19 mmol) in anhydrous THF (15 mL), controlling the reaction temperature between −40 and −50° C. The mixture was allowed to warm to −25±5° C., held there for 1 hour, and cooled to −55° C. Excess ethyl acetate (20 g, 220 mmol) was gradually added to the mixture, and the mixture allowed to warm to 10° C. Dilute ammonium chloride solution was added, and the mixture extracted with dichloromethane (1×500 mL, 2×100 mL). The combined extracts were washed with dilute ammonium chloride, dried using magnesium sulfate, and concentrated. The residue was dissolved in dichloromethane (100 mL). The P-toluenesulfonic acid (1.0 g, 6.4 mmol) was added, and the mixture heated and held at reflux for 1 hour. The cool mixture was washed with dilute sodium bicarbonate, and the aqueous wash extracted with dichloromethane. The combined organic phases were dried using magnesium sulfate, and concentrated. The product was isolated by silica gel chromatography using 5% ethyl acetate in hexanes to give 4-[3,5-difluoro-4-(methylthio)phenyl]-5-methyl-3-phenylisoxazole as a yellow solid (2.9 g, 47%). 1H NMR (CDCl3/400 MHz) 7.33-7.42 (m, 5H), 6.68-6.73 (m, 2H), 2.48 (s, 3H) 2.47 (s, 3H). HRMS m/z 318.0769 (M+H+, calcd 318.0764). Anal. Calcd for C17H13F2NOS: C, 64.34; H, 4.13; N, 4.41; Found: C, 64.22; H, 4.16, N 4.28.
Reaction SMILES: [C:1]([NH:9][NH2:10])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CS[C:25]1[C:26]2[CH:39]=[CH:38][CH:37]=[CH:36][C:27]=2[NH:28][C:29]2[N:35]=[CH:34][CH:33]=[CH:32][C:30]=2[N:31]=1>CO.ClCCl>[C:2]1([C:1]2[N:31]3[C:30]4[CH:32]=[CH:33][CH:34]=[N:35][C:29]=4[NH:28][C:27]4[CH:36]=[CH:37][CH:38]=[CH:39][C:26]=4[C:25]3=[N:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC1=Nc2cccnc2Nc2ccccc21
Reactant: NNC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: c1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 90 °C

Procedure:
To a solution benzoic hydrazide (0.98 g, 7.2 mmol) and p-toluenesulfonic acid monohydrate (0.68 g, 3.6 mmol) in methanol (50 ml) was added a solution of 6-(methylthio)-11H-benzo[e]pyrido[3,2-b][1,4]diazepine (0.87 g, 3.6 mmol) in dichloromethane (25 ml). The reaction mixture was heated at 90° C. for 3 hours. The solvent was removed under reduced pressure and the crude product purified using flash chromatography (SiO2, 2% MeOH in DCM). The desired product, 3-phenyl-9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepine, was obtained as a tan solid (0.352 mg, 31%). M.p.=273-275° C.; 400 MHz 1H NMR (CDCl3) δ: 8.20 (d, J=7.8 Hz, 1H), 8.17 (d, J=3.9 Hz, 1H), 7.5-7.3 (m, 6H), 7.18 (t, J=7.6 Hz, 1H), 7.04 (d, J=7.8 Hz, 1H), 7.00 (d, J=8.2 Hz, 1H), 6.79 (dd, J=7.8, 4.7 Hz, 1H), 6.49 (s, 1H); LCMS [M+H]: 312; Calculated for C19H13N5. 0.44 water, C, 71.48; H 4.38; N 21.94, found, C 71.48, H 4.43, N 21.67.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH:14]([N:17]=[C:18]=[O:19])([CH3:16])[CH3:15]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:18]([NH:17][CH:14]([CH3:16])[CH3:15])=[O:19])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 53.8 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (150 mg, 0.67 mmol) and isopropyl isocyanate (80 μL, 0.81 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), followed by recrystallization from acetone and hexane, gave the desired product (111 mg, 54%). LC-MS (m/z) 308.0 (M+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH2:45][C:46]1[N:50]([C:51]2[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=2)[N:49]=[CH:48][C:47]=1[C:58]([NH:60][CH2:61][C:62]([CH2:68][NH2:69])([OH:67])[C:63]([F:66])([F:65])[F:64])=[O:59]>CN(C=O)C.C(#N)C.O>[NH2:45][C:46]1[N:50]([C:51]2[CH:52]=[CH:53][C:54]([F:57])=[CH:55][CH:56]=2)[N:49]=[CH:48][C:47]=1[C:58]([NH:60][CH2:61][C:62]([CH2:68][NH:69][C:4]([C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])=[O:6])([OH:67])[C:63]([F:66])([F:65])[F:64])=[O:59]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: NCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Nc1c(C(=O)NCC(O)(CNC(=O)c2c(F)cccc2F)C(F)(F)F)cnn1-c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 65.6 %

Procedure:
2,6-Difluorobenzoic acid (0.069 mmol) was weighed into a micronic tube. To this O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) (0.069 mmol, 26 mg) was added as a solution in DMF (200 μl). Diisopropylethylamine was then added (0.20 mmol, 36 μl) and the solution shaken for 5 minutes. 5-Amino-N-[2-(aminomethyl)-3,3,3-trifluoro-2-hydroxypropyl]-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (0.069 mmol, 25 mg) was then added as a solution in DMF (200 μl). The solution was then shaken for a further 10 minutes and left to stand overnight at room temperature. LC-MS was taken after this time, the sample (20 μl) was diluted in acetonitrile (100 μl). LC-MS showed product present. The crude mixture was filtered and purified by mass directed HPLC. The products seemed to crash out when introduced to 90% H2O (0.1% TFA)/10% MeCN (0.1% TFA) (of CAT-norm method) resulting in high back pressure. Method Cat-GR was used instead as 70% H2O (0.1% TFA)/30°/0 MeCN (0.1% TFA) ensured no solid crashed out on introduction to column. The collected solution from the purification was transferred to a scintillation vial where MeCN/H2O/TFA was removed in Genevac. The dried compound was then transferred to pre-tared vial. Weight obtained for desired product 22.7 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21]CC2C=CC=CC=2)=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13].[H][H]>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36][CH3:37])=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(OCc3ccccc3)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCCCC3)c2)c(OC)c(OC)c1OC
Yield: 93.3 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoyl]piperidine (1.02 g, 2.09 mmol) was dissolved in ethanol (50 ml) and the resulting solution was added to an ethanol suspension (5 ml) of 5% Pd—C (0.200 g) and stirred at room temperature for 16 hours in a hydrogen stream. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was recrystallized from ether to obtain the titled compound (0.760 g, 1.95 mmol, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:30]([F:33])([F:32])[F:31])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]4[CH:22]=[N:23][CH:24]=[N:25][CH:26]=4)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CI.[C:36](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2([C:30]([F:31])([F:33])[F:32])[O:13][N:12]=[C:11]([C:14]3[CH:28]=[CH:27][C:17]([C:18]([N:20]([CH3:36])[C:21]4[CH:26]=[N:25][CH:24]=[N:23][CH:22]=4)=[O:19])=[C:16]([CH3:29])[CH:15]=3)[CH2:10]2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)Nc1cncnc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)c1cncnc1
Yield: 35 %

Procedure:
In a solution of 0.25 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl-N-(5-pyrimidinyl)benzoic acid amide in 4 mL of N,N-dimethylformamide, 0.36 g of methyl iodide and 0.35 g of potassium carbonate were added at room temperature with stirring, and stirred at 80° C. for 1 hour. After the completion of the reaction, 10 mL of water was added in the reaction mixture, and extracted with ethyl acetate (20 mL×1), the organic phase was dehydrated with and dried over saturated sodium chloride aqueous solution and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:2) to obtain 0.09 g of the aimed product as white crystal.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](=[O:37])(=[O:36])[N:23]([CH2:32][CH2:33][O:34][CH3:35])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[CH:5]1)([CH3:3])[CH3:2].C([Li])CCC.CN([CH:46]=[O:47])C.O>C1COCC1>[CH:46]([C:5]1[N:4]([CH:1]([CH3:3])[CH3:2])[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([S:22](=[O:36])(=[O:37])[N:23]([CH2:32][CH2:33][O:34][CH3:35])[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])=[CH:20][CH:21]=3)[N:10]=2)=[CH:7][N:6]=1)=[O:47]
Reactant: CN(C)C=O
Reactant: COCCN(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cncn3C(C)C)n2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COCCN(COCC[Si](C)(C)C)S(=O)(=O)c1ccc(Nc2nccc(-c3cnc(C=O)n3C(C)C)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
4-(1-Isopropylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(2-trimethylsilylethoxymethyl)sulphamoyl]anilino}pyrimidine (Method 106; 1.22 g, 2.33 mmol), was dissolved in anhydrous THF (70 ml), under nitrogen. The solution was cooled to −78° C. and n-butyl lithium (3.48 ml of a 1.6 N solution in hexanes, 5.57 mmol), was added slowly, maintaining the temperature at less than −65° C. The reaction mixture was then stirred at −78° C. for 30 minutes, then DMF (345 μl, 4.46 mmol), was added and mixture allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was then poured into water (100 ml), and extracted with EtOAc (2×50 ml). The organic extracts were combined, washed with water (50 ml), brine (50 ml), and dried. The volatiles were removed and the residue was purified by chromatography on silica gel eluting with 3% MeOH in DCM, to give the title product, (307 mg, 24%), as a pale yellow foam. NMR: 0.02 (s, 9H), 0.83 (dd, 2H), 1.63 (d, 6H), 3.28 (s, 3H), 3.37 (t, 2H), 3.42 (dd, 2H), 3.52 (t, 2H), 4.78 (s, 2H), 5.71 (m, 1H), 7.40 (d, 1H), 7.82 (d, 2H), 7.92 (s, 1H), 8.01 (d, 2H), 8.78 (d, 1H), 9.91 (s, 1H); m/z: 573 [MH]−.
Reaction SMILES: [Mg].Br[C:3]1[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Br-].[CH3:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Br:25])[CH:20]=1)=O>O1CCCC1.BrCCBr>[Br:25][C:21]1[CH:20]=[C:19]([C:17]([C:3]2[CH:4]=[CH:5][C:6]([O:13][CH3:14])=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=2)=[CH2:16])[CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(Br)cc1C(F)(F)F
Reactant: CC(=O)c1cccc(Br)c1
Agent: [Br-]
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: C=C(c1cccc(Br)c1)c1ccc(OC)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a suspension of magnesium turnings (565 mg, 23.5 mmol, 1.2 eq) in 5 mL of dry tetrahydrofuran, 0.1 mL of 1,2-dibromoethane were added followed by 5 mL of a tetrahydrofuran solution of 5-bromo-2-methoxy-benzotrifluoride (5.0 g, 19.6 mmol, 1.0 eq in 30 mL tetrahydrofuran). The resulting mixture was gently heated to initiate the reaction. The remaining solution of bromide was added dropwise at such a rate that the reaction could reflux without external heating. After the addition the reaction mixture was heated at reflux for further 2 hours. The mixture was cooled to 0° C. and a solution of 3-bromoacetophenone (3.9 g, 19.6 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added dropwise. After 2 hours LC-MS showed complete conversion to the desired product. 50 mL of water were added followed by 25 mL of 1 M aqueous HCl. The organic fraction was washed with brine, dried over sodium sulfate and concentrated to give a yellow oil. The oil was dissolved in toluene (50 mL) and a few crystals of p-toluenesulfonic acid were added. The solution was heated to reflux for 2 hours in a flask equipped with a Dean-Stark apparatus. After this time, the mixture was cooled to room temperature, concentrated and the crude purified by flash chromatography eluting with cyclohexane/ethyl acetate (100:0 to 95:5). 5.1 g of clean product was obtained as colorless liquid (yield: 73%).
Reaction SMILES: F[B-](F)(F)F.[CH3:6][O:7][C:8]1[C:13]2[O:14][CH2:15][CH2:16][CH2:17][O:18][C:12]=2[CH:11]=[C:10]([CH:19]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]=[C:33]([CH3:35])[O:32][N:31]=3)=[CH:26][CH:25]=2)[C:20]([NH2:22])=[S:21])[CH:9]=1.[C:36](=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH3:36][S:21][C:20](=[NH:22])[CH:19]([C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:13]2[O:14][CH2:15][CH2:16][CH2:17][O:18][C:12]=2[CH:11]=1)[NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[N:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[CH:28][CH:29]=1
Reactant: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(N)=S)cc2c1OCCCO2
Reactant: O=C([O-])O
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc2c1OCCCO2
Temperature: 25 °C

Procedure:
After adding 1.63 g of Me3O+BF4− to a solution of 4.7 g of 2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetamide in 50 ml of acetonitrile, the mixture was stirred at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off, and the filtrate was concentrated under reduced pressure to give 2-(9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetimidic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH:8]=[CH:9][C:10](Cl)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)([O-:17])=[O:16].N1C=CC=CC=1>CC(C)=O>[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:10](=[O:11])[CH:9]=[CH:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][CH:13]=2)=[CH:20][CH:19]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)C=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(C=Cc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Yield: 95.5 %

Procedure:
193.2 g (1 mole) of 4-nitrocinnamic acid and 650 g of ethyl acetate were placed in a reaction vessel. While 200 g of thionyl chloride with some drops of DMF was dropped into the reaction mixtures, the reaction mixtures were refluxed with stirring until the generation of hydrogen chloride gas stopped. The reacted solution was concentrated until a solid could be precipitated and was poured into hexane and then the precipitated solid was separated by filtration and dried. 210 g of 4-nitrocinnamoyl chloride was yielded. 64.5 g (0.3 mole) of 4-nitrocinnamoyl chloride and 300 g of acetone were placed in a reaction vessel. The reaction mixtures were heated at 50° C. with stirring under a nitrogen current. 41.73 g (0.3 mole) of 4-nitrophenol, 60 g of pyridine, and 300 g of acetone were added dropwise to the above reaction vessel using a dropping funnel. After the completion of the addition, the reaction mixtures were refluxed with stirring under a nitrogen current for 2 hours. After the reaction, a precipitate was separated by filtration, and the filtrated solid was washed by water and dried. 90 g of light yellow colored needle-like crystals ((4-nitrophenyl)-4-cinnamate)was yielded.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[C:5](I)[CH:4]=1)#[N:2].[CH2:19]([S:21][CH2:22][C:23]([CH3:27])([OH:26])[C:24]#[CH:25])[CH3:20]>>[CH2:19]([S:21][CH2:22][C:23]([C:24]1[N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[C:6]2[C:5]([CH:25]=1)=[CH:4][C:3]([C:1]#[N:2])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:7]=2)([OH:26])[CH3:27])[CH3:20]
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c(C#N)cc1I
Reactant: C#CC(C)(O)CSCC
Product: CCSCC(C)(O)c1cc2cc(C#N)c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira procedure as describe in General Procedures Example C, reacting N-(4-cyano-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (1.0 g, 2.56 mmol) and 1-ethylsulfanyl-2-methyl-but-3-yn-2-ol (0.37 g, 2.56 mmol) to yield the title compound as a yellow sticky oil.
Reaction SMILES: [C:1]1([C@@H:7]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([O:10]C(C)(C)C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>>[C:1]1([C@@H:7]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([OH:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)[C@@H](c1ccccc1)N1CCCCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@@H](c1ccccc1)N1CCCCC1

Procedure:
The product from Example 92A was treated with TFA (1.5 mL) at rt for 3 h. The volatiles were removed under vacuum, the residue concentrated from toluene (×2) and dried in a vacuum oven to give title compound which was used without further purification. MS (DCI; M+H) m/z=220.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5](Br)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.CB1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+].NC1C=CC(C)=C2C=1C(=O)NC2>C(COC)OC.O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: Nc1ccc(Br)c2c1C(=O)NC2
Agent: CB1OB(C)OB(C)O1
Agent: Cc1ccc(N)c2c1CNC2=O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: Nc1cccc2c1C(=O)NC2
Yield: 96.5 %

Procedure:
In a similar manner to Step 1 of Example 152, 7-amino-4-bromoisoindolinone (100 mg, 0.440 mmol) was dissolved in dimethoxyethane (5 mL), and the solution was treated with trimethylboroxine (0.184 mL, 1.76 mmol), [bis(diphenylphosphino)ferrocene]dichloropalladium (28.7 mg, 0.0352 mmol), potassium carbonate (304 mg, 2.20 mmol) and water (0.158 mL), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=4/1) to obtain a mixture of 7-amino-4-methylisoindolinone and 7-aminoisoindolinone (62.9 mg, ratio 10/1, yield 89%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[NH2:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([NH:12][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:7][CH2:6]2)[O:4][CH:3]=[CH:2]1
Reactant: CCOC(=O)C(=CN)C(=O)OCC
Reactant: O=C1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNC1CCC2(CC1)OC=CO2)C(=O)OCC

Procedure:
1,4-Dioxaspiro[4.5]decan-8-one (40 g) and diethyl aminomethylenemalonate (47.94 g) are dissolved in 500 ml of toluene. p-Toluenesulfonic acid monohydrate (2.44 g) and 100 ml of toluene are then added and the mixture is refluxed for 3 days collecting water in a Dean-Stark trap. The resulting mixture is decanted and solvent is removed to leave on oil. This oil is flash chromatographed on 750 g silica gel using 9:1 CH2Cl2, EtOAc as eluant to yield diethyl N-(1,4-dioxaspiro[4.5]decen-8-yl)aminomethylenemalonate as an oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[CH3:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:10][C:11]1[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: CSc1nccc(I)n1
Reactant: Cc1ncccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCO
Product: CSc1nccc(-c2cccnc2C)n1
Temperature: 96 °C
Reaction time: 1.5 h
Yield: 109.8 %

Procedure:
To a solution of 4-iodo-2-methylsulfanyl-pyrimidine (600 mg, 2.38 mmol), 2-methylpyridine-3-boronic acid (533 mg, 3.09 mmol), Na2CO3 (756 mg, 7.14 mmol), triphenylphosphine (62 mg, 0.24 mmol) in nPrOH (10 ml), Pd(OAc)2 (16 mg, 0.07 mmol) was added and the mixture was stirred at 96° C. for 1.5 hours. The solvent was evaporated under vacuum, and the crude was dissolved in DCM and washed with water. The organic phase was dried (Na2SO4) and evaporated. A second batch of this compound was prepared according to the same protocol starting from 0.45 mmol of 4-iodo-2-methylsulfanyl-pyrimidine. The residues, deriving from the two batches, were purified by flash chromatography with DCM-MeOH—NH4OH (20-0.1-0.2) to give 568 mg of the title compound (92% yield).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O.CCCCC>C1(OC2C=CC=CC=2)C=CC=CC=1>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc2ncc(C(=O)O)c(O)c2c1
Solvent: CCCCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc2nccc(O)c2c1
Temperature: 20 °C
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
A suspension of 53.5 g of 4-hydroxy-6-methoxyquinoline-3-carboxylic acid in 1000 cm3 of diphenyl ether was heated with stirring, at a temperature of between 250° C. and 260° C., for 2 hours 45 minutes. The reaction mixture was cooled to about 20° C. After stirring for 16 hours at this temperature, the mixture was poured with stirring into 1 liter of pentane and then filtered. The cake obtained was washed with 3 times 100 cm3 of pentane and then with 3 times 100 cm3 of diisopropyl ether. After drying in air, 37 g of 4-hydroxy-6-methoxyquinoline were obtained in the form of a beige-colored solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[S:13]([OH:23])(=[O:22])([C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)=[O:14]>C(O)C>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:21][C:18]1[CH:19]=[CH:20][C:15]([S:13]([OH:23])(=[O:14])=[O:22])=[CH:16][CH:17]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: Clc1ccc2ncnc(Cl)c2c1
Solvent: CCO
Product: O=S(=O)(O)c1ccc(Nc2ncnc3ccc(Cl)cc23)cc1
Yield: 91.3 %

Procedure:
4,6-Dichloroquinazoline (5.9 g, 0.03 mole) was added portionwise to sulphanilic acid (5.2 g, 0.03 mole) in 50% aqueous ethanol (200 ml) at 90° C. with stirring. The mixture was refluxed for 2 hours, cooled and filtered. The solid was washed with 50% aqueous ethanol and dried in an oven to give the title compound (9.2 g) as the hemihydrate m.p. greater than 300° C.