Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].I[CH3:34].[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH3:34])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:14][CH2:15][C@H:16]([CH3:19])[CH2:17][CH2:18]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-cyclohex-1-enyl-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (1.007 g, 2.19 mmol) in dry DMF was added iodomethane (4.10 mL, 65.7 mmol), the mixture was cooled to 0° C., and NaH (60% suspension in oil, 175 mg, 4.38 mmol) was added in portions over 5 min. The mixture was stirred at 0° C. for 1 h 40 min, and it was quenched by addition of water and acidified with 2N HCl. The mixture was diluted with CH2Cl2 and washed with brine. The organic fraction was separated, dried over Na2SO4, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 0→50% ethyl acetate in hexane to give 5-cyclohex-1-enyl-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (857 mg, 83%). 1H NMR (DMSO-d6, 400 MHz): δ [ppm] 13.1-13.0 (bs, 1H), 6.96 (s, 1H), 6.41 (s, 1H), 4.31-4.24 (m, 1H), 3.12 (s, 3H), 2.90-2.84 (m, 1H), 2.42-2.20 (m, 2H), 2.15 (m, 2H), 1.98-1.78 (m, 4H), 1.68-1.64 (m, 2H), 1.58-1.35 (m, 8H), 1.21-1.02 (m, 5H), 0.87-0.77 (m, 1H), 0.72 (d, J=6.5 Hz, 3H), 0.63-0.46 (m, 2H)
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1.C(O)(=O)CCCCCCC.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>ClCCl>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([CH:2]=[O:1])=[CH:7][CH:8]=1)#[N:11]
Reactant: NCc1ccc(C2OCCO2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCCCCCCC(=O)O
Solvent: ClCCl
Product: N#Cc1ccc(C=O)cc1
Yield: 40 %

Procedure:
The 4-(1,3-dioxacyclopent-2-yl)benzylamine is condensed with octanoic acid in dichloromethane in the presence of a peptide coupling system consisting of DCC and HOBt according to a method already described (Ouari O.; Polidori A.; Pucci B.; Tordo P.: Chalier F. J. Org. Chem. 1999, 64, 3554-3556) and then the dioxolane protecting group is removed by treatment in a 1:1, v/v, acetic acid/water mixture. Compound 3 is subsequently purified by silica gel chromatography (eluent: cyclohexane/EtOAc, 6:4, v/v) to give a white powder with a yield of 40% from the 4-cyanobenzaldehyde.
Reaction SMILES: C1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)[CH2:7]3.C1CC=CC=1.[C:16]([O:20][C:21](=[O:24])C=C)([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([C:6]12[CH2:7][CH:8]([CH2:4][CH2:5]1)[CH:9]=[CH:10]2)=[O:24])([CH3:19])([CH3:18])[CH3:17]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: C1=CCC=C1
Product: CC(C)(C)OC(=O)C12C=CC(CC1)C2
Temperature: 180 °C
Yield: 100.7 %

Procedure:
200 grams of dicyclopentadiene was put into a 500-ml flask equipped with a distillatory, and then was heated for reflux at 180° C. Then, about 100 grams of cyclopentadiene cracked at about 40° C. was dropped into 200 grams of t-butylacrylate with being cooled with ice bath. The resultant solution was stirred over a night. The resultant mixture was distilled under reduced pressure (66°-67° C./1 mmHg). As a result, there was obtained 296 grams of norbornenecarboxylic acid t-butylester. The yield was 98%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH2:38]Cl)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([F:22])[CH:16]=2)[CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(F)c(F)c2)CC1
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2cccc(CN(c3ccc(F)c(F)c3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[(3,4-difluorophenyl)amino]piperidine (625 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1>COCCOCCOCCOCCOC>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][C:4]2[CH:5]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(F)cc1
Agent: COCCOCCOCCOCCOC
Product: O=C(Oc1cccc(F)c1)c1ccc(F)cc1
Temperature: 240 °C
Yield: 1.1 %

Procedure:
A 25-ml Kjeldahl flask fitted with an air-cooling line was charged with 1.4 g of p-flurobenzoic acid, 0.976 g of cupric hydroxide, and 3 ml of tetraglyme as solvent, after which it was heated at 240° C. over an oil bath. This temperature was maintained for 60 minutes. After cooling, the reaction mixture was eluted with diethyl ether followed by filtration using Celite. the resulting filtrate was then submitted to column chromatography (solid phase: silica gel, developing solvent: hexane→methylene chloride) to give 0.013 g of m-fluorophenyl p-fluorobenzoate.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:35]=[CH:36][CH:37]=1)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][C:30]1=[O:34].Cl>O1CCCC1.C(OCC)(=O)C>[OH:34][C:30]1([C:9]2[O:10][C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=2)[CH2:31][CH2:32][CH2:33][CH:29]1[CH2:28][C:27]1[CH:35]=[CH:36][CH:37]=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: c1ccc(-c2ncoc2-c2ccccc2)cc1
Reactant: COc1cccc(CC2CCCC2=O)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(CC2CCCC2(O)c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4,5-diphenyloxazole in tetrahydrofuran (100 ml) at -78° C. under nitrogen was added n-butyllithium (in hexane, 1,7N, 12 ml). After 30 minutes, at the same temperature a solution of 2-(3-methoxybenzyl)cyclopentanone (3.8 g) in tetrahydrofuran (10 ml) was added dropwise thereto. After being stirred for 1 hour at 0° C., the reaction mixture was poured into a mixture of ethyl acetate (200 ml) and 1N-hydrochloric acid (50 ml). The organic layer was washed with saturated sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed (n-hexane--ethyl acetate:5:1-2:1) on silica gel to afford 1-hydroxy-1-(4,5-diphenyloxazol-2-yl)-2-(3-methoxybenzyl)cyclopentane (8.0 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[CH2:21]([C:23]1[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=1)[CH3:22]>>[CH2:21]([C:23]1[CH:24]=[C:25]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)[CH:26]=[CH:27][CH:28]=1)[CH3:22]
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CCc1cccc(N)c1
Product: CCc1cccc(Nc2nc(Nc3cc(C)[nH]n3)cc3cc(OC)ccc23)c1

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 3-ethyl-phenylamine give N1-(3-ethyl-phenyl)-6-methoxy-N3-(5-methyl-1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 374(MH+).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([O:19][CH2:20][C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])[C:7]3[N:8]([C:10]([C:14]([O:16]CC)=[O:15])=[C:11]([CH3:13])[N:12]=3)[CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Li+].Cl>O1CCCC1.CO>[CH:1]1([C:4]2[CH:5]=[C:6]([O:19][CH2:20][C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])[C:7]3[N:8]([C:10]([C:14]([OH:16])=[O:15])=[C:11]([CH3:13])[N:12]=3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C3CC3)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(C3CC3)cn2c1C(=O)O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
470 mg of ethyl 6-cyclopropyl-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 41A) were initially charged in 36 ml of tetrahydrofuran/methanol 5:1, and 6.1 ml of 1N aqueous lithium hydroxide solution were added. The mixture was stirred at 40° C. for 4 h and then acidified with 6 N hydrochloric acid and concentrated. The residue was taken up in water and repeatedly extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried with magnesium sulphate and filtered, and the filtrate was concentrated. This gave 470 mg of the desired product (90% pure; 97% of theory) which was reacted without further purification.
Reaction SMILES: C(OC([N:8]([C:16]1[C:21]([C:22]2[O:26][N:25]=[C:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)=[CH:30][CH:29]=3)[CH:23]=2)=[CH:20][CH:19]=[CH:18][N:17]=1)C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O.O.C(=O)(O)[O-].[Na+]>ClCCl>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[O:35][CH2:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:24]2[CH:23]=[C:22]([C:21]3[C:16]([NH2:8])=[N:17][CH:18]=[CH:19][CH:20]=3)[O:26][N:25]=2)=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncccc1-c1cc(Cc2ccc(COc3ccccn3)cc2)no1
Reaction time: 14 h

Procedure:
To a solution of di-tert-butyl(3-(3-(4-((pyridin-2-yloxy)methyl)benzyl)isoxazol-5-yl)pyridin-2-yl)imidodicarbonate described in Preparation Example 3-1-2 (11.8 g, purity approximately 70%) and dichloromethane (120 mL) was added trifluoroacetic acid (40 mL) at 0° C. Stirring was carried out at room temperature for 14 hours. To the reaction solution was added saturated sodium bicarbonate water at 20° C or lower, extracted with ethyl acetate, and then purified by NH-silica gel column chromatography (heptane:ethyl acetate=1:1). The solvent was concentrated under a reduced pressure, tert-butyl methyl ether was added to the resulting residue, and solids were filtered to obtain the title compound (7.29 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:13]1([C:19]#[C:20][C:21]2[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[F:12][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:25][C:24]2[CH:27]=[CH:28][C:21]([C:20]#[C:19][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:22][CH:23]=2)=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)ccc1F
Reactant: O=Cc1ccc(C#Cc2ccccc2)cc1
Product: COC(=O)c1cc(NCc2ccc(C#Cc3ccccc3)cc2)ccc1F

Procedure:
The title compound was prepared following the procedure described in Example 23 step a) using methyl 5-amino-2-fluorobenzoate (500 mg, 2.96 mmol) and 4-(phenylethynyl)benzaldehyde (Fluorochem, 640 mg, 3.10 mmol). The title compound was obtained as a white powder (717 mg, 68%). HPLC, Rt: 4.78 min (purity: 97.4%). LC/MS, M−(ESI): 358.1. 1H NMR (CDCl3) δ: 7.52-7.48 (m, 4H), 7.32 (m, 5H), 7.15 (dd, J=5.3, 3.1 Hz, 1H), 6.94 (dd, J=10.5, 9.2 Hz, 1H), 6.72 (m, 1H), 4.33 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=3)[CH:20]=[CH:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([CH2:27][C:28]([OH:30])=[O:29])[CH:25]=2)[CH:20]=[CH:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClCCCc1ccccc1
Agent: O=C(O)Cc1ccc2ccn(Cc3ccccc3)c2c1
Product: O=C(O)Cc1ccc2ccn(CCCc3ccccc3)c2c1

Procedure:
The titled compound (44 mg) as a white solid was prepared from the compound [4-6] obtained in the process (6) of Example 4 (100 mg) and 3-phenylpropyl chloride according to the method of the process (7) of Example 4.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[CH:16]=[C:15]([C:34]([F:37])([F:36])[F:35])[CH:14]=1>>[CH3:33][O:32][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[CH:16]=[C:15]([C:34]([F:36])([F:37])[F:35])[CH:14]=[C:13]([NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=3)[N:18]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COc1cc(Nc2cc(C(F)(F)F)cc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cc(C(F)(F)F)cc(Nc3cccc(C(F)(F)F)c3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 3-trifluoromethylaniline and (6-chloro-4-trifluoromethyl-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a yellowish solid (Yield=60%). MS ISP (m/e): 508.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.74 (s, 1H), 7.65 (d, 1H), 7.60 (d, 1H), 7.43 (t, 1H), 7.30 (d, 1H), 7.18 (d, 1H), 7.11 (d, 1H), 7.00 (dxd, 1H), 6.89 (s, 1H), 6.87 (s, 1H), 6.82 (s, 1H), 6.51 (s, 1H), 6.44 (s, 1H9, 3.70 (s, 3H), 3.31 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([C:9]2[S:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)[CH:2]=[CH2:3].[Cl:15][SiH:16]([Cl:18])[Cl:17]>[Pt].C1(C)C=CC=CC=1>[Cl:15][Si:16]([Cl:18])([Cl:17])[CH2:3][CH2:2][CH2:1][C:4]1[S:8][C:7]([C:9]2[S:10][C:11]([CH3:14])=[CH:12][CH:13]=2)=[CH:6][CH:5]=1
Reactant: Cl[SiH](Cl)Cl
Reactant: C=CCc1ccc(-c2ccc(C)s2)s1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(CCC[Si](Cl)(Cl)Cl)s2)s1

Procedure:
The hydrosilylation reaction of Example 1 was repeated using 5.0 g of 5-allyl-5′-methyl-2,2′-bithiophene in place of 2-allylthiophene, 2.5 g of anhydrous toluene, 6.0 g of trichlorosilane, and 50 mg of Platinum Catalyst. 5-(3-Trichlorosilylpropyl)-5′-methyl-2,2′-bithiophene was obtained as a colorless liquid: 1H NMR (CDCl3) δ 6.92 (d, 1H, J=3.6 Hz); 6.91 (d, 1H, J=2.7 Hz); 6.70 (d, 2H, J=3.6 Hz); 6.65 (m, 1H); 2.91 (t, 2H, J=7.2 Hz); 2.48 (d, 3H, J=1.2 Hz); 1.97 (m, 2H); 1.47 (m, 2H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[CH:10]=[C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)[S:8][C:6]=3[N:7]=2)=[CH:38][CH:39]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4ccc(N)nc4)nc3s2)CC1

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[2,3-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (265 mg) was reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to give 113 mg of 183. MS (Q1) 484.3 (M)+.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2NNS(C1C=CC(C)=CC=1)(=O)=O>CCO>[N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[NH2:3])[CH:9]=[N:10][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)NNc2ncnc3c(N)cccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc2cncnc12
Yield: 10.6 %

Procedure:
1N NaOH (9 ml) was added to a solution of N′-(8-aminoquinazolin-4-yl)-4-methylbenzene-1-sulfonohydrazide 479 (300 mg, 9.1 mmol) in EtOH (20 ml) and the mixture was heated under reflux for 3 h. After cooling, the mixture was concentrated in vacuo. The residue was diluted with water (10 ml) and the aqueous phase was extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), and concentrated in vacuo to give title compound (140 mg, 76%) which was used in the next step without further purification. The structure was confirmed by 1H NMR.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[N:28][OH:29])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:37](=O)([O-])[O-].[K+].[K+].IC.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[N:28][O:29][CH3:37])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccccc4c3=NO)cc2)CCC1
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CON=c1c(-c2ccc(C3(NC(=O)OC(C)(C)C)CCC3)cc2)c(-c2ccccc2)oc2ccccc12
Reaction time: 2 h
Yield: 90.3 %

Procedure:
To a stirred solution of {1-[4-(4-hydroxyimino-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (27 mg, 0.056 mmol) in DMF (2 mL) was added potassium carbonate (15.5 mg, 0.112 mmol) and iodomethane (0.011 mL, 0.168 mmol) at RT. After 2 hours, cesium carbonate (36.5 mg, 0.112 mmol) and iodomethane (0.021 mL, 0.336 mmol) were added and the mixture stirred for a further 1.5 hours. The reaction mixture was partitioned between EtOAc and water. The aqueous phase was isolated and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 25% EtOAc in cyclohexane) to afford the title compound (25.1 mg, 90%) as a colourless gum. LCMS (Method A): RT=5.20 min, [M+H]+=497.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][CH:6]([NH2:8])[CH3:7].CC1[C:20]([O:21]CC(N)C)=[C:19](C)C=CC=1.C(N)(=O)C.C(Cl)(=O)C.C(OC(=O)C)(=O)C>C(OCC)(=O)C>[CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([CH3:13])[C:3]=1[O:4][CH2:5][CH:6]([NH:8][C:20](=[O:21])[CH3:19])[CH3:7]
Reactant: Cc1cccc(C)c1OCC(C)N
Agent: CC(N)=O
Solvent: CC(=O)Cl
Solvent: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)NC(C)COc1c(C)cccc1C

Procedure:
In Step 1, 2-(2,6-dimethylphenoxy)-1-methyl-ethylamine (mexiletine) is converted to mexiletine acetamide. Mexiletine is treated with an acetylating agent, such as an acetyl chloride or acetic anhydride, in the presence of concentrated aqueous alkali and an organic solvent, e.g., ethyl acetate. The reaction temperature is maintained at about 0°-25° C., preferably below 10° C., for about 10 minutes to 3 hours, preferably about 35 minutes. Following completion of the reaction, the resulting N-[2-(2,6-dimethylphenoxy)-1-methylethyl]-acetamide is isolated by conventional techniques, and used as such in Step 2.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]3)=[C:10]([CH3:29])[CH:9]=1.Cl[CH2:31][C:32]1[C:33]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[N:34][O:35][C:36]=1[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[C:33]1[C:32]([CH2:31][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]4)=[C:10]([CH3:29])[CH:9]=2)=[C:36]([CH:37]([CH3:39])[CH3:38])[O:35][N:34]=1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(O)cc3C)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3C)ccc2n1
Yield: 67.7 %

Procedure:
Cesium carbonate (55.4 mg, 170.0 μmol) was added to ethyl 6-(4-hydroxy-2-methylphenyl)-2-quinolinecarboxylate (47.5 mg, 154.5 μmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (51.8 mg, 170.0 μmol) in N,N-dimethylformamide (3.1 mL) at room temperature. The resulting suspension was stirred for eighteen hours, then water added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to give 60.2 mg (68%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-methylphenyl]-2-quinolinecarboxylate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 8.56 (d, J=9 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 7.97 (d, J=2 Hz, 1H), 7.80 (dd, J=9, 2 Hz, 1H), 7.66-7.60 (m, 2H), 7.56 (dd, J=9, 7 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 6.78 (d, J=2 Hz, 1H), 6.73 (dd, J=9, 2 Hz, 1H), 4.86 (s, 2H), 4.43 (q, J=7 Hz, 2H), 3.47 (septet, J=7 Hz, 1H), 2.21 (s, 3H), 1.38 (t, J=7 Hz, 3H), 1.35 (d, J=7 Hz, 6H). ESI-LCMS m/z 575 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[CH:5][C:4]=1[CH2:15][OH:16].[Li]CCCC.[CH3:22][S:23]SC.Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([S:23][CH3:22])[C:4]=1[CH2:15][OH:16]
Reactant: COc1cc(CO)c(OC)c2ccccc12
Reactant: CSSC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1c(CO)c(SC)c(OC)c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
Following the procedure of Flader et al.,22 alcohol 26 (0.521 g, 2.39 mmol) was dissolved in THF (9.0 ml) in a flame-dried 25 mL round bottom flask under Argon, and then cooled to 0° C. At 0° C. nBuLi (2.5 M in hexanes, 2.4 ml, 6.0 mmol) was added slowly, then the ice bath was removed and the reaction was stirred at room temperature for 1 hour. Dimethyldisulfide (0.50 mL, 5.6 mmol) was added slowly at room temperature and the reaction was stirred for another 30 minutes at room temperature before being poured into water, acidified with 2 M HCl, and extracted with ethyl acetate. The organic fractions were combined and washed with brine, dried over MgSO4, and filtered. The resulting solid was purified via flash column chromatography (1:4 EtOAc:hexanes) to afford 56 (0.446 g, 1.69 mmol, 71%) as a green solid.