Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].Cl[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>O1CCCC1>[CH2:28]([O:27][CH2:26][N:3]1[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[C:2]1[CH3:1])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1[nH]c(-c2ccccc2)cc1C(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)OCc2ccccc2)cc(-c2ccccc2)n1COCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 500 mg portion of benzyl 2-methyl-5-phenyl-1H-pyrrole-3-carboxylate was dissolved in 10 ml of tetrahydrofuran, and 79 mg of sodium hydride (55% dispersion in oil) was added under ice-cooling, followed by stirring at room temperature for 30 minutes. A 0.357 ml portion of benzyl chloromethyl ether was added dropwise to this solution under ice-cooling, followed by stirring at room temperature for 1.5 hours. After adding water under ice-cooling, extraction was carried out with ethyl acetate. Then, after washing with saturated brine and then drying with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:8) to obtain 503 mg of benzyl 1-[(benzyloxy)methyl]-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate as a colorless liquid.
Reaction SMILES: [C:1]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C([Li])CCC.CON(C)[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1.O>O1CCCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([C:13]2[CH:12]=[N:11][CH:10]=[CH:9][C:8]=2[NH:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[O:30])=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)c1ccc(F)cc1
Reactant: CC(C)(C)C(=O)Nc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccncc1C(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 85.4 %

Procedure:
To a solution of 4-pivaloylaminopyridine (7.0 g, 39 mmol) in tetrahydrofuran (100 ml) was added n-butyllithium (39.3 ml, 98 mmol, 2.5 M solution in tetrahydrofuran) at −78° C. under a N2 atmosphere. The reaction mixture was stirred at 0° C. for 5 h, re-cooled to −78° C. and quenched with a solution of N-methoxy-N-methyl-4-fluorobenzamide (7.9 g, 43 mmol) in 100 ml tetrahydrofuran. The reaction mixture was warmed to room temperature and poured into water. The product was extracted into ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography (10% ethyl acetate/hexanes gradient) to afford N-[3-(4-fluorobenzoyl)-pyridin-4-yl]-2,2-dimethylpropanamide (10 g).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[S:10]1[CH:14]=[CH:13][N:12]2[CH:15]=[N:16][CH:17]=[C:11]12.O>ClCCCl>[Cl:1][CH2:2][C:3]([C:17]1[N:16]=[CH:15][N:12]2[CH:13]=[CH:14][S:10][C:11]=12)=[O:4]
Reactant: c1cn2cncc2s1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: O=C(CCl)c1ncn2ccsc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Chloroacetyl chloride (5.97 ml) was added to a solution of 12.5 g of aluminum chloride in 40 ml of 1,2-dichloroethane. The mixture was stirred at room temperature for 20 min. A solution of 1.93 g of imidazo[5,1-b]thiazole in 20 ml of 1,2-dichloroethane was added thereto. The mixture was heated under reflux for 2 hr. Water was added thereto, followed by extraction with dichloromethane. The organic layers were combined together. The combined organic layers were washed with a dilute aqueous sodium hydroxide solution and saturated brine in that order. The solvent was removed by distillation. Isopropyl ether was added to the residue. The resultant powder was collected by filtration to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([OH:8])=[O:7].O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>C1COCC1.O>[CH2:13]([O:12][C:10]([NH:9][C@@H:5]([CH2:4][CH2:3][CH2:2][NH:1][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)[C:6]([OH:8])=[O:7])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-5-amino-2-(benzyloxycarbonylamino)pentanoic acid (50 g, 188 mmol) was dissolved in THF (800 mL) and water (100 mL). Tert-butyl 4-oxopiperidine-1-carboxylate (37 g, 188 mmol) was added and the reaction was stirred for 1 hour. The reaction was cooled to 0° C. and sodium cyanoborohydride (12 g, 188 mmol) was added and the reaction stirred at ambient temperature overnight. The reaction was concentrated to provide (S)-2-(benzyloxycarbonylamino)-5-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)pentanoic acid, which was used directly in the next step.
Reaction SMILES: [Al](Cl)([CH2:4][CH3:5])[CH2:2]C.C(OP(O[CH2:16][CH3:17])(OCC)=O)C.CO.CN(C)P(=O)(N(C)C)N(C)C.[CH3:31][CH2:32][CH2:33][CH2:34][CH3:35]>>[CH2:31]=[CH:32][CH2:33][CH2:34][CH2:4][CH3:5].[CH2:31]=[CH:32][CH2:33][CH2:34][CH2:35][CH2:2][CH:16]=[CH2:17]
Reactant: CCOP(=O)(OCC)OCC
Reactant: CC[Al](Cl)CC
Reactant: CCCCC
Solvent: CO
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCCCC
Product: C=CCCCCC=C
Reaction time: 24 h

Procedure:
A solution of 54 grams (0.64 mole) 1-hexene and 3.8 grams (0.034 mole) 1,7-octadiene (molar charge ratio 95:5) in 80 ml pentane was polymerized with Et2AlCl/triethylphosphate/δ-TiCl3 catalyst (1.0 millimole δ-TiCl3). The molar ratio of Et2AlCl to δ-TiCl3 was 1.5:1 and of triethylphosphate to Et2AlCl was 0.7:1. After agitation for 24 hours at 25° C., the resulting copolymer was isolated by methanol coagulation and dried. The conversion to copolymer was 74 percent, with an inherent viscosity of 5.1 and zero percent gel. A copolymer prepared similarly but without triethylphosphate was obtained in 84 percent conversion. It had an inherent viscosity of 4.8 and 20 percent gel. These data show that triethylphosphate, like hexamethylphosphoric triamide, suppresses gel formation during polymerization.
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([CH:15]=[O:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[NH:4][N:3]=1.O.[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl>CN(C=O)C.C(N(C(C)C)CC)(C)C>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:9]3[CH:10]=[C:11]([CH:15]=[O:16])[CH:12]=[CH:13][C:14]=3[C:5]=2[N:4]([CH2:31][O:30][CH2:29][CH2:28][Si:27]([CH3:34])([CH3:33])[CH3:26])[N:3]=1
Reactant: O=Cc1ccc2c(c1)c(-c1c(F)cccc1F)nc1c(Br)n[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(Br)c2nc(-c3c(F)cccc3F)c3cc(C=O)ccc3c21
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A 150 ml round-bottomed flask equipped with a magnetic stirrer and with a septum having a top-mounted argon intake is charged with 780 mg of 3-bromo-5-(2,6-difluorophenyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde in 20 ml of DMF, 2.5 ml of diisopropylethylamine and 0.75 ml of 2-(trimethylsilyl)ethoxymethyl chloride. The mixture is stirred at RT for 24 h and then poured into water, extracted with AcOEt, washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under RP. This gives 1.18 g of a crude product, which is purified by chromatography on silica gel (20-45 μm), eluting with a mixture of DCM and methanol (99.5/0.5 by vol.), to give on one hand 545 mg of 3-bromo-5-(2,6-difluorophenyl)-1-(2-trimethylsilanylethoxymethyl)-1H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde in the form of a cream solid: MS (E/I): m/z=388 (M+); 1H NMR: −0.13 (s, 9H); 0.86 (t, J=7.8 Hz, 2H); 3.66 (t, J=7.8 Hz, 2H); 618 (s, 2H); 7.43 (t, J=7.9 Hz, 2H); 7.79 (m, 1H); 8.39 (broad s, 1H) 8.48 (dd, J=8.3, 1.5 Hz, 1H) 8.80 (d, J=8.3 Hz, 1H) 10.17 (s, 1H), and on the other hand 354 mg of 3-bromo-5-(2,6-difluorophenyl)-2-(2-trimethylsilanylethoxymethyl)-2H-pyrazolo[4,3-c]isoquinoline-7-carbaldehyde (cream solid). MS (E/I): m/z=388 (M+); 1H NMR: −0.08 (s, 9H); 0.90 (t, J=8.0 Hz, 2H); 3.73 (t, J=8.0 Hz, 2H); 5.91 (s, 2H); 7.41 (t, J=7.8 Hz, 2H); 7.77 (m, 1H); 8.22 (broad s, 1H) 8.42 (dd, J=8.3, 1.5 Hz, 1H) 8.72 (d, J=8.3 Hz, 1H) 10.13 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29]>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:35]2[CH2:34][CH2:33][N:32]([C:24]3[CH:23]=[C:22]([O:21][CH3:20])[C:27]([O:28][CH3:29])=[C:26]([O:30][CH3:31])[CH:25]=3)[CH2:37][CH2:36]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Product: COc1cc(N2CCN(C(=O)Nc3nc4ccc(C)cc4nc3OC)CC2)cc(OC)c1OC
Yield: 91 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3,4,5-trimethoxyphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 91%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 3.16-3.23 (m, 4H), 3.71-3.95 (m, 4H), 3.80 (s, 3H), 3.86 (s, 6H), 4.13 (s, 3H), 6.19 (s, 2H), 7.08-7.62 (m, 3H), 7.72 (d, J=8.6 Hz, 1H).
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([S:17]([N:20]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:26]=2[CH3:32])[CH2:21][CH:22]([CH3:24])[CH3:23])(=[O:19])=[O:18])[CH:6]=C[C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#N.[OH-:33].[Na+].[CH2:35]([OH:37])[CH3:36]>>[CH3:32][C:26]1[CH:27]=[C:28]([CH3:31])[CH:29]=[CH:30][C:25]=1[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[S:17]([C:5]1[CH:4]=[CH:3][C:8]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:36]([CH:6]=1)[C:35]([OH:33])=[O:37])(=[O:19])=[O:18]
Reactant: CCO
Reactant: [OH-]
Reactant: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)c(C#N)c2)c(C)c1
Agent: [Na+]
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCC3CCOCC3)c(C(=O)O)c2)c(C)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
To a stirred solution of 3-cyano-N-(2,4-dimethylphenyl)-N-isobutyl-4-((tetrahydro-2H-pyran-4-yl)methoxy)benzenesulfonamide (50 mg, 0.110 mmol) in ethanol (1 mL) at 25° C. was added sodium hydroxide (0.548 mL, 2.190 mmol). After which the reaction mixture was stirred at 80° C. for 15 hours, then cooled, ethanol removed and crude partitioned between ethyl acetate (20 mL) and HCl (2N, 15 mL). The organic layer was separated, dried over MgSO4 and the solvent removed in vacuo to give a yellow oil. The crude was purified by mass directed autoprep (ammonium carbonate modifier). The relevant fractions were evaporated in vacuo to give the required product, 16.1 mg. LCMS [LCMS2] Rt 0.91 mins, m/z (ES+) 476 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[O:7])=[CH:4][C:3]=1[C:20]1[CH:21]=[N:22][C:23]([C:26]#[N:27])=[CH:24][CH:25]=1.C([O-])([O-])=[O:29].[K+].[K+].CCOC(C)=O.O>C1COCC1.[Li+].[OH-]>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6](=[O:7])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[CH3:9])=[CH:4][C:3]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]([NH2:27])=[O:29])=[N:22][CH:21]=1
Reactant: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2ccc(C#N)nc2)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2ccc(C(N)=O)nc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 4-chloro-3-(6-cyano-pyridin-3-yl)-N-(2-methoxy-phenyl)-N-methyl-benzamide 2-2 (29 mg, 0.077 mmol) in THF (0.5 mL), 1N LiOH (0.5 mL) and K2CO3 (10 mg, 0.073 mmol) were added. After stirring for 48 hrs at room temperature, EtOAc and water were added. The aqueous layer was removed and the organic layer was concentrated, dissolved in MeOH and subjected to preparative LCMS to yield 5-{2-chloro-5-[(2-methoxy-phenyl)-methyl-carbamoyl]-phenyl}-pyridine-2-carboxylic acid amide 24-1. MS (M+H)+: 396.0, tR=5.93 min (method 2).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>CS(C)=O.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
4-benzyloxy-2(1H)-pyridone (50.0 g, 248.47 mmol) was dissolved in dimethyl sulfoxide (300 mL). Potassium carbonate (68.68 g, 496.94 mmol) was added, followed by 4-fluorobenzonitrile (31.60 g, 260.89 mmol). The reaction was stirred at 100° C. for 20 hours. After cooling to room temperature the reaction was diluted with H2O (600 mL) and the solids were collected by filtration washing with diethyl ether. The solids were then washed with hot methanol to provide a tan solid (55.6 g, 74%). 1H NMR (300 MHz, CDCl3) δ 7.79 (d, J=8.3 Hz, 2H), 7.54 (d, J=8.5 Hz, 2H), 7.44-7.41 (m, 5H), 7.22 (d, J=13.3, 1H), 6.13 (dd, J=2.6, 7.7 Hz, 1H), 6.06 (d, J=2.6 Hz, 1H), 5.07 (s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH2:5].[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12](=O)[CH2:11][CH2:10]2.C(N(CC)CC)C.C(Cl)Cl>CN(C=O)C.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[C:12]1=[N:5][CH2:4][CH2:3][CH2:2][CH:11]1[CH2:10]2
Reactant: NCCCBr
Reactant: O=C1CCc2cc(F)ccc21
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Fc1ccc2c(c1)CC1CCCN=C21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Bromopropylamine (4.7 g. 21.7 mmole) and 5-Fluoro-1-indanone (2.5 g, 16.7 mmole) were dissolved in 50 ml DMF and the reaction was cooled to 0° C. Triethylamine (13.5 g, 133 mmole) was added. 20 ml DCM was also added to help with the stirring. Titanium chloride (1M in DCM, 15 ml) was then added and the ice bath was removed. The reaction was stirred at room temperature overnight. 200 ml ether was added and the reaction was filtered though a Celite cake. The filtrate was concentrated to dryness under vacuum. The residue was dissolved in 200 ml ether and washed with brine (2×200 ml). The organic layer was dried over sodium sulfate and concentrated to dryness. 2.6 g Black oil was obtained and it was used in next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[I-:16].[Na+].CNCCNC>O1CCOCC1.C(OCC)(=O)C.[Cu]I>[I:16][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Brc1cncc(C#Cc2ccccc2)c1
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Ic1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
Heat a mixture of 3-bromo-5-phenylethynylpyridine (5.71 g, 22.12 mmol), (prepared essentially as described in EXAMPLE 9), copper (I) iodide (211 mg, 1.1 mmol), sodium iodide (6.63 g, 44.24 mmol) and N,N′-dimethylethylenediamine (0.24 mL, 2.21 mmol) in 1,4-dioxane (20 mL) at 110° C. for 60 h. Cool to room temperature, dilute with ethyl acetate and wash with a saturated aqueous solution of sodium chloride, and dry (sodium sulfate). Purify the residue by silica gel chromatography, eluting with 15:1 hexanes:ethyl acetate, to give the title compound (5.45 g, 81%).
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.C(N)C1C=CC=CC=1.[N+:22]([CH3:25])([O-:24])=[O:23]>O>[Cl:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:25][N+:22]([O-:24])=[O:23])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Product: O=[N+]([O-])C=Cc1ccc(Cl)cc1
Temperature: 78 °C
Reaction time: 2 h

Procedure:
To 1066.8 g of acetic acid were added 200.14 g (1.356 mol) of 4-chlorobenzaldehyde, and 153.4 g (1.429 mol) of benzylamine, and the added components were dissolved in the acid. This solution was heated to 78° C., and 325.7 g (5.336 mol) of nitromethane was dropwise added thereto at 78 to 80° C. over 2 hours and 50 minutes. Thereafter, the solution was stirred at about 79° C. for 40 minutes. Next, 1016 g of water was dropwise added thereto at about 50° C. over 2 hours and 25 minutes. The mixture was cooled to about 10° C. and was stirred at 6 to 10° C. for 1 hour and 50 minutes. The obtained crystals were filtrated, and washed with 1016.2 g of water. The wet crystals were dissolved into 572.8 g of toluene at about 50° C. The resultant was separated into two phases, and the water phase thereof was removed. The remaining phase was washed with 330.8 g of water. By HPLC, 803.24 g of the toluene phase was analyzed. As a result, the phase contained 253.8 g of 4-chloro-β-nitrostyrene. The yield thereof was 97.1%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16](=O)[NH:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:27])=O.Cl.N>O>[Cl:27][C:16]1[C:17]2[C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:10]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3nc[nH]c(=O)c23)cc1
Agent: Cl
Agent: N
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Suspend 135 g (424 mmol) 5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4(3H)-one at RT in 675 ml (7241 mmol) phosphoryl chloride and heat the mixture to boiling (evolution of HCl). After 1 h, cool the dark solution to RT and add dropwise to a vigorously stirred mixture of 2.25 liter water and 4.05 liter conc. ammonia solution (25 wt. %) (heating to 55-75° C., pH>9). At the end of addition, cool to RT and extract the mixture three times with 1.0 liter dichloromethane each time. Combine the organic phases, dry, and concentrate by vacuum evaporation. Stir the residue with diethyl ether, filter with suction and dry at high vacuum. 134.4 g (94.1% of theor.) of the title compound is obtained.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[C:11]([NH2:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>O.C(O)=O>[C:1]1([S:7]([CH:20]([NH:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S([O-])c1ccccc1
Reactant: NC(=O)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Solvent: O
Product: O=C(NC(c1ccccc1)S(=O)(=O)c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
A solution of 40.2 g of sodium phenylsulphinate in 200 cm3 of water is introduced into a 500 cm3 reactor equipped with a magnetic stirrer and a reflux condenser. A mixture of 12.35 g of benzamide and 21.22 g of benzaldehyde is then added. 60 cm3 of methanol are then added so as to obtain an off-white emulsion and then 7.54 cm3 of formic acid (d=1.22) are added. After stirring for 41 hours 30 minutes at a temperature in the region of 20° C., the mixture is heated for 3 hours at 65° C. After filtration through sintered glass No. 4, the product obtained is washed with twice 15 cm3 of isopropyl ether and then with twice 15 cm3 of water. After drying, there are obtained, with a yield of 15.6%, 5.48 g of N-(α-phenylsulphonyl-benzyl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[CH:19][C:18]([F:30])=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=1.CCN(C(C)C)C(C)C.[S:40](Cl)(=[O:43])(=[O:42])[NH2:41].[Cl-].[NH4+]>C(Cl)Cl>[F:30][C:18]1[CH:19]=[C:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])[C:2]([NH:1][S:40](=[O:43])(=[O:42])[NH2:41])=[C:3]([CH:17]=1)[O:4][C:5]1[CH:6]=[C:7]([NH:11][S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2N)c1
Reactant: NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 34.7 %

Procedure:
244 mg N-(3-{2-amino-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}-phenyl)ethanesulfonamide (0.448 mmol, 1 eq.) were dissolved in 10 mL DCM, treated with 0.781 mL DIPEA (4.5 mmol, 10 eq.) and 388 mg sulfamoyl chloride (3.36 mmol, 7.5 eq.) and the resulting solution stirred at rt for four days. The reaction mixture was portioned between ammonium chloride solution and DCM, the aqueous layer reextracted with DCM, the combined organic layers dried, filtered and concentrated in vacuo. Flash column chromatography provided 97 mg of the target compound (35% yield). A second product fraction was further purified by thick layer chromatography (hexane/ethyl acetate 1:1 as eluent) yielding additional 67 mg of the target compound (22% yield).
Reaction SMILES: [CH2:1]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C1C(=O)N([Br:25])C(=O)C1.O>C(Cl)(Cl)Cl.CC(O)=O>[Br:25][C:14]1[S:15][CH:16]=[CH:17][C:13]=1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCCCCCCCCCc1ccsc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCCCCCCCCCCCc1ccsc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of 3-dodecylthiophene (5.00 g, 19.8 mmol) in CHCl3/HOAc (1:1) (Vt=20.0 mL) at 0° C. was added NBS (3.52 g, 19.8 mmol) in portions over a period of 45 minutes. The reaction mixture was stirred for 1 hour at 0° C., and overnight at room temperature. The reaction mixture was poured into water (50.0 mL) and extracted with chloroform (3×50.0 mL). The combined organic phases were washed with water (50.0 mL), NaOH solution, and dried over MgSO4. After filtration through Celite, the chloroform was removed in vacuo, and the product was obtained as a colorless oil (6.05 g, 93% yield). 1H NMR (CDCl3): δ 0.84-1.54 (m, 23H), 2.53 (t, 2H), 6.76 (d, 1H, J=4.5 Hz), 7.15 (d, 1H, J=4.5 Hz).