Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.N1C=CC=CC=1.ClC(Cl)(O[C:51](=[O:57])OC(Cl)(Cl)Cl)Cl.[CH2:59]([N:61]1[CH2:66][CH2:65][N:64]([C:67]2[CH:72]=[C:71]([F:73])[C:70]([NH2:74])=[C:69]([F:75])[CH:68]=2)[CH2:63][CH2:62]1)[CH3:60]>ClCCl>[CH2:59]([N:61]1[CH2:66][CH2:65][N:64]([C:67]2[CH:68]=[C:69]([F:75])[C:70]([NH:74][C:51]([N:27]3[C:17]4[N:18]=[C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[N:20]=[C:15]([C:12]5[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]6[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=6)[CH2:30][C:31]6[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=6)=[N:14][CH:13]=5)[C:16]=4[CH2:29][CH2:28]3)=[O:57])=[C:71]([F:73])[CH:72]=2)[CH2:63][CH2:62]1)[CH3:60]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(c2cc(F)c(N)c(F)c2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCN(c2cc(F)c(NC(=O)N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (2.48 g, 4.59 mmol) in dichloromethane (50 ml), pyridine (743 μl, 9.19 mmol) was added, followed by cooling to 0° C. To this, triphosgene (2.73 g, 9.19 mmol) was added, which was raised to room temperature, followed by stirring for 1 hour. The solvent was distilled off under reduced pressure, and dissolved again in dichloromethane (50 ml), to which a solution of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine (1.33 g, 5.51 mmol) obtained in Step C in dichloromethane (50 ml) was added dropwise over 30 minutes, followed by stirring for 1 hour. Dichloromethane (100 ml) was added, followed by further stirring at room temperature for 19 hours. 100 ml of Dichloromethane was added, followed by adsorption to silica gel, and subsequently the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 10/1), to obtain 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid [4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenyl]-amide as a crude product. This was dissolved in TFA (45 ml), and N-acetylcysteine (1.49 g, 9.15 mmol) was added, followed by refluxing for 6 hours. After the solvent was distilled off under reduced pressure, 5M-NaOH aqueous solution was added to adjust the pH to 8, and the resulting solid was washed with aqueous sodium bicarbonate (50 ml), water (50 ml) and methanol (50 ml), followed by purification by silica gel column chromatography (dichloromethane/methanol=100/1 to 10/1), to obtain the desired compound as a colorless solid (1.34 g, 52%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([O:17][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:28][C:29]([NH:31][C@@H:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@H:35]([O:42][C:43]3[CH:44]=[CH:45][C:46]4[N:47]([C:49]([N:52]5[CH2:58][CH2:57][CH2:56][O:55][CH2:54][CH2:53]5)=[N:50][N:51]=4)[CH:48]=3)[CH2:34][CH2:33]2)=[O:30])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([OH:17])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1cc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCOCC5)n4c3)c3ccccc32)ccc1Cl)(C(C)C)C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1cc(NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCOCC5)n4c3)c3ccccc32)n(-c2ccc(Cl)c(O)c2)n1
Yield: 29.8 %

Procedure:
A solution of Intermediate 64a (243 mg, 0.29 mmol) and TBAF (LM in THF, 1.3 mL, 1.33 mmol) in THF (3 mL) was stirred at RT for 1 h, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the product. This was further purified by HPLC (XBridge C18 column, 25-98% MeCN in H2O, 0.1% NH4OH) to give the title compound (58 mg, 29%). LCMS (Method 5): Rt 4.10 min, m/z 671 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.27 (9H, s), 1.84-2.13 (6H, m), 3.46-3.50 (4H, m), 3.81-3.92 (4H, m), 4.81-4.85 (1H, m), 5.52 (1H, t, J=4.4 Hz), 6.33 (1H, s), 6.94 (1H, dd, J=8.5, 2.4 Hz), 7.08 (1H, d, J=8.4 Hz), 7.12-7.19 (2H, m), 7.31-7.43 (4H, m), 7.43 (1H, d, J=8.5 Hz), 7.60-7.62 (2H, m), 8.12 (1H, s).
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:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:33][CH2:32]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: COc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Product: COc1cccc(N2CCN(C(=O)Nc3nc4ccc(C)cc4nc3OC)CC2)c1
Yield: 89 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 89%). 1H NMR (300 MHz, CDCl3): δ 2.49 (s, 3H), 3.19-3.32 (m, 4H), 3.61-3.90 (m, 4H), 3.79 (s, 3H), 4.17 (s, 3H), 6.44-6.58 (m, 4H), 7.00-7.65 (m, 3H), 7.72 (d, J=8.2 Hz, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].C(N(C(C)C)CC)(C)C.ClCCl.Cl[C:25]1[O:26][C:27]2[C:28](=[C:30]([C:42]#[N:43])[C:31]([CH3:41])=[C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:33]=2[F:34])[N:29]=1>C(OCC)(=O)C>[C:42]([C:30]1[C:28]2[N:29]=[C:25]([NH:2][CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[O:26][C:27]=2[C:33]([F:34])=[C:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:31]=1[CH3:41])#[N:43]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccccc2)c(F)c2oc(NCCC(=O)OC(C)(C)C)nc2c1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
With cooling with ice, tert-butyl 3-aminopropionate hydrochloride (230 mg, 1.26 mmol) and diisopropylethylamine (430 μl, 2.53 mmol) were added to a dichloromethane (10 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (302 mg, 1.05 mmol), followed by stirring at room temperature for 1 hour. The reaction liquid was cooled to room temperature, then ethyl acetate was added, and followed by washing with saturated brine. After drying over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the residue obtained by concentration was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=4:1→1:1, v/v) to obtain the entitled compound (402 mg, 97%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30]>C(OCC)C.[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10]([NH:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[OH:30])=[O:11]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](CN)O2)c(=O)[nH]c1=O
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
A solution of 1.12 g of (2,6-dichlorophenyl)acetyl chloride in 15 ml of diethyl ether was added to a solution of 1.275 g of 5'-amino-2',5'dideoxy-5-ethyluridine in 15 ml of 0.33M sodium hydroxide solution. The mixture was shaken vigorously for 10 minutes and then filtered. The solid was washed with 150 ml of water, 20 ml of ethanol and 40 ml of diethyl ether, and then recrystallized from 2.5 l of ethanol to give 1.53 g of 5'-[2-(2,6-dichlorophenyl)acetamido]-2',5'-dideoxy-5-ethyluridine in the form of a white solid of melting point 296°-297° C.
Reaction SMILES: CS(O[C@@H:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]1[O:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C)C=O.O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C@@H:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C@@H:6]2[N:20]=[N+:21]=[N-:22])=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)O[C@@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@H]1CCCC[C@H]1Oc1ccc(Br)cc1
Temperature: 120 °C

Procedure:
To a solution of (1R,2R)-2-(4-bromophenoxy)cyclohexyl methanesulfonate (3.55 g, 10.2 mmol) in dimethylformamide (21.8 mL) and water (2.43 mL) was added sodium azide (95%, 2.09 mg, 30.5 mmol) and the reaction was heated at 120° C. for 23 hours. The reaction was cooled to room temperature, diluted with water (400 mL) and extracted with ethyl acetate (4×400 mL). The combined organic layers were washed with aqueous lithium chloride solution (1N, 400 mL), washed with water (400 mL), and dried over magnesium sulfate. Filtration and removal of solvents in vacuo afforded (1R,2S)-2-azidocyclohexyl 4-bromophenyl ether as an orange oil, which was used in the next step without additional purification. Yield: 2.85 g, 9.62 mmol, 94%. 1H NMR (400 MHz, CDCl3) δ 1.36-1.48 (m, 2H), 1.62-1.76 (m, 4H), 1.96-2.07 (m, 2H), 3.63 (m, 1H), 4.43 (m, 1H), 6.85 (d, J=9.0 Hz, 2H), 7.39 (d, J=8.9 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][PH:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])=[O:5])[CH3:2].[H-].[Na+].Br[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.O>O1CCCC1>[CH2:1]([O:3][P:4]([CH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:5])[CH3:2]
Reactant: CCOC(OCC)[PH](=O)OCC
Reactant: BrCC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(OCC)P(=O)(CC1CCCCC1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon, a solution of 221 g of diethoxymethylphosphinic acid ethyl ester in 1000 ml of tetrahydrofuran is added dropwise in the course of 3 hours to a suspension of 26.4 g of 99% sodium hydride in 1500 ml of tetrahydrofuran, the temperature being maintained at 200°-25°. The reaction is exothermic and is associated with the evolution of gas. The mixture is stirred for 2 hours at room temperature and then 177.1 g of bromomethylcyclohexane are added in the course of 20 minutes; the mixture is stirred at reflux for 24 hours, then cooled to 0°, and 200 ml of water are carefully added. The solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and water. The organic phase is separated off, dried over sodium sulfate and concentrated by evaporation under reduced pressure. The oil that remains behind is distilled under reduced pressure and yields diethoxymethyl(cyclohexylmethyl)phosphinic acid ethyl ester having a boiling point of 85° (6×10-4 bar).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#N)=[CH:5][C:4]=1[O:11][CH:12]1[CH:16]([O:17][CH3:18])[CH2:15][O:14][CH2:13]1.[OH-:19].[K+].[OH2:21].Cl>OCC(CO)O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]([OH:21])=[O:19])=[CH:5][C:4]=1[O:11][CH:12]1[CH:16]([O:17][CH3:18])[CH2:15][O:14][CH2:13]1
Reactant: [OH-]
Reactant: O
Reactant: COc1ccc(C#N)cc1OC1COCC1OC
Agent: Cl
Agent: [K+]
Solvent: OCC(O)CO
Product: COc1ccc(C(=O)O)cc1OC1COCC1OC
Reaction time: 1 h

Procedure:
2.0 g (8.0 mmol) of 4-methoxy-3-(4-methoxytetrahydrofuran-3-yloxy)benzonitrile (A6) and 4.2 g (80.0 mmol) of potassium hydroxide are heated at 140° C. for 3 h in 20 ml of glycerol. The mixture is treated with 50 ml of water and acidified by dropwise addition of 40 ml of 2 N hydrochloric acid with ice-cooling. It is subsequently stirred for 1 h, filtered and the precipitate is washed with ice water. 1.79 g of the title compound of m.p. 166-168° C. are obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[S:19]1[CH:23]=[C:22](B(O)O)[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]1=2>>[S:19]1[CH:23]=[C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]1=2
Reactant: OB(O)c1csc2ccccc12
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(-c3csc4ccccc34)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and benzo[b]thiophene-3-boronic acid to give (1-benzo[b]thiophen-3-yl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 357(MH+).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[C:15]([F:18])[CH:14]=[CH:13][CH:12]=3)[C:5]([OH:8])=[N:6][CH:7]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[O:27][C:28]3[CH:38]=[C:37]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])[C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][C:29]=3[C:30]=2[C:31]([NH:33][CH3:34])=[O:32])=[CH:22][CH:21]=1>CC(O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:18][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:16]=1[CH:17]=[C:9]([C:4]1[N:3]=[C:2]([C:36]3[C:37]([N:39]([CH3:44])[S:40]([CH3:43])(=[O:42])=[O:41])=[CH:38][C:28]4[O:27][C:26]([C:23]5[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=5)=[C:30]([C:31]([NH:33][CH3:34])=[O:32])[C:29]=4[CH:35]=3)[CH:7]=[N:6][C:5]=1[OH:8])[NH:10]2
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: Oc1ncc(Br)nc1-c1cc2c(F)cccc2[nH]1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc(O)c(-c4cc5c(F)cccc5[nH]4)n3)cc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
To a degassed solution of 5-bromo-3-(4-fluoro-1H-indol-2-yl)pyrazin-2-ol (prepared using similar method described in Example 1, 1.23 g, 3.98 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (2 g, 3.98 mmol) and K3PO4.3H2O (2.12 g, 7.96 mmol) in IPA (20 mL) and H2O (2 mL) was added Pd2(dba)3 (50 mg) and X-Phos (50 mg) under nitrogen atmosphere. The reaction mixture was stirred at 100° C. for 16 h, concentrated in vacuo to remove IPA. The residue was diluted with H2O and extracted with DCM. Then the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated and purified by column chromatography (PE:EA=1:2) to give 5-(6-(4-fluoro-1H-indol-2-yl)-5-hydroxypyrazin-2-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (1 g, yield: 41%). 1H-NMR (CDCl3, 400 MHz) δ 8.52 (d, J=4.0 Hz, 1H), 8.06 (s, 1H), 8.02 (s, 1H), 7.71 (s, 1H), 7.66 (s, 1H), 7.42 (t, J=8.8 Hz, 2H), 7.33˜7.36 (m, 2H), 7.11˜7.18 (m, 2H), 6.80 (dd, J1=10.4 Hz, J2=8.0 Hz, 2H), 3.27 (s, 3H), 3.10 (s, 3H), 2.85 (d, J=4.8 Hz, 3H). MS (M+H)+: 604.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[H-].[Na+].[Cl:8][C:9]1[C:10]([F:43])=[C:11]([CH:40]=[CH:41][CH:42]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:22]=[C:23]([CH:28]=[C:29]([N:31]=[C:32]3[N:36]([CH2:37][O:38][CH3:39])[CH:35]=[CH:34][S:33]3)[N:30]=2)[C:24](OC)=O)[CH2:16][CH2:15]1)=[O:13]>O1CCCC1.C(OCC)(=O)C>[Cl:8][C:9]1[C:10]([F:43])=[C:11]([CH:40]=[CH:41][CH:42]=1)[C:12]([N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[N:30]=[C:29]([N:31]=[C:32]3[N:36]([CH2:37][O:38][CH3:39])[CH:35]=[CH:34][S:33]3)[CH:28]=[C:23]([C:24]3[O:1][N:2]=[C:3]([CH3:4])[N:5]=3)[CH:22]=2)[CH2:16][CH2:15]1)=[O:13]
Reactant: CC(=N)NO
Reactant: COCn1ccsc1=Nc1cc(C(=O)OC)cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COCn1ccsc1=Nc1cc(-c2nc(C)no2)cc(CN2CCN(C(=O)c3cccc(Cl)c3F)CC2)n1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a mixture of 9.4 mg of N-hydroxyacetamidine, molecular sieves 4A and 1 ml of tetrahydrofuran was added sodium hydride followed by stirring at 65° C. for 1 hour. To the reaction solution was added a solution of 22.6 mg of methyl 2-((4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl)-6-((3-(methoxymethyl)-thiazol-2(3H)-ylidene)amino)isonicotinate in 1 ml of tetrahydrofuran, followed by heating under reflux for 6 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, and washed with saturated sodium bicarbonate and brine. The resulting organic layer was dried over magnesium sulfate and filtered, and the filtrate was concentrated. The resulting residue was purified by a thin-layer chromatography for fractionation (eluent: chloroform/methanol=10/1) to give the title compound.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([Li])CCC.IC.C(OCC)(=O)C>O>[C:1]([NH:5][S:6]([C:9]1([CH3:13])[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)CCCCl
Reactant: [Li]CCCC
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)C1(C)CC1
Temperature: -69 °C
Yield: 99 %

Procedure:
To a four necked, 5 L round bottom flask was added N-(tert-butyl)-3-chloropropane-1-sulfonamide (Previously dried by azeotroping with 3×100 mL toluene) (100 g, 468 mmol) and THF (1500 mL). This was cooled to an internal temperature of −69° C. then butyl lithium (2.5M in hexanes, 412 mL, 1.02 mol) was added dropwise over a period of 55 min while keeping the internal temperature below −65° C. The ice bath was removed and the reaction mixture was warmed to rt over 1.5 h and then cooled back down to an internal temperature of −69° C. Butyl lithium (196 mL, 515 mmol) was added to the reaction mixture over a period of 25 min while keeping the internal temperature below −65° C. The reaction mixture was then warmed to rt over the course of 1.5 h. The reaction mixture was recooled to an internal temperature of −69° C. and iodomethane (58.5 mL, 936 mmol) was added dropwise over a period of 40 min while keeping the internal temperature below −65° C. The reaction mixture was then warmed to an internal temperature of −50° C. over the course of 4 h. The cold bath was removed and a solution of saturated NH4Cl (1000 mL) was added. The quenched reaction mixture was transferred to a separatory funnel along with ethyl acetate (100 mL) and water (500 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate. (3×75 mL). The combined organic layers were washed with brine (700 mL), dried with MgSO4, and concentrated in vacuo to an off white solid which was dried under high vac for 30 min to yield N-(tert-butyl)-1-methylcyclopropane-1-sulfonamide as a white solid (88.5 g, 99% yield). 1H NMR (500 MHz, CDCl3) δ 4.07 (bs, 1 H), 1.51 (s, 3 H), 1.38-1.41 (m, 2 H), 1.36 (s, 9 H), 0.77-0.80 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([NH:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:3]=1.[Cl:16][C:17]([Cl:23])([Cl:22])[C:18](=N)OC>C(O)(=O)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:18]([C:17]([Cl:23])([Cl:22])[Cl:16])[N:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:4]=2[CH:3]=1
Reactant: COCCCCNc1cc(F)ccc1N
Reactant: COC(=N)C(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: COCCCCn1c(C(Cl)(Cl)Cl)nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Fluoro-2-(4-methoxybutylamino)aniline (4.28 g) was dissolved in acetic acid (100 ml), methyl 2,2,2-trichloroethanimidate (2.49 ml) was added dropwise, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was azeotroped with toluene. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (6.53 g).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:11]([O:13][C:14](=[O:35])[CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:23]=[CH:22][N:21]=[C:20]2Cl)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:35])[CH2:15][O:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:26]=1[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:23]=[CH:22][N:21]=[C:20]2[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)[CH3:12]
Reactant: CCOC(=O)COc1cc2ncnc(Cl)c2cc1OCC(=O)OCC
Reactant: c1ccc2c(c1)CCCN2
Product: CCOC(=O)COc1cc2ncnc(N3CCCc4ccccc43)c2cc1OCC(=O)OCC
Yield: 19 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 19% yield from 1,2,3,4-tetrahydroquinoline and (4-chloro-7-ethoxycarbonylmethoxy-quinazolin-6-yloxy)-acetic acid ethyl ester. (film; LC-MS: 465 (MH+)).
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[CH3:12][O:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:12][O:13][C:14](=[O:19])[CH2:15][CH2:16][CH2:17][O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7]
Reactant: COC(=O)CCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCCOc1ccc(C=O)cc1OC
Yield: 62.3 %

Procedure:
A solution of vanillin (47)(40.00 g, 262.89 mmol) and methyl-4-bromobutyrate (50.00 g, 276.18 mmol) in DMF (200 mL) was allowed to stir over potassium carbonate (51.53 g, 372.40 mmol) for 16 hours. Water was added to the reaction mixture at which time the product crystallised. The resulting mixture was filtered and dried in vacuo for 16 hours to afford the keto-ester (48) as a white solid (41.3 g, 66%). MP=57-59° C. 1H NMR (250 MHz, CDCl3) δ 9.80 (s, 1H), 7.46-7.40 (m, 2H), 6.97 (d, J=8.1 Hz, 1H), 4.16 (t, J=6.3 Hz, 2H), 3.92 (s, 3H), 3.70 (s, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.20 (pent, J=6.7 Hz, 2H). 13C NMR (67.8 MHz, CDCl3) 188.2 (Cl), 173.7 (C12), 153.8 (Cquat.), 152.0 (Cquat.), 144.1 (Cquat.), 125.8 (Cmethine), 110.3 (C3), 108.5 (C6), 69.0 (C9), 57.0 (C8), 52.2 (C13), 30.6 (C11), 24.5 (C10). It was decided to adopt the numbering system shown in the figure below for the molecule for ease of peak assignment in 13C NMR.