Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH3:10][C@H:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:12][NH2:13].[OH-].[Na+]>CC#N.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:10])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C[C@@H](CN)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: C[C@@H](CNc1nc(Cl)nc(Cl)n1)c1ccccc1

Procedure:
A mixture of cyanuric chloride (75 mg, 0.407 mmol, 1 equivalent) in CH3CN/H2O (1/1, 5 ml) was cooled to 0° C. (R)-(+)-beta-methylphenethylamine (55 mg, 0.407 mmol, 1 equivalent) was added, followed by 1N NaOH (0.366 ml). LCMS analysis showed the complete consumption of the 2,4,6-trichloro-1,3,5-triazine. The crude product was used in the next step. MS (ES+): m/e 283.06 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(N(CC)CC)C>C(Cl)Cl>[CH3:19][S:20]([O:1][CH:2]1[CH2:5][N:4]([C:6]2[O:7][CH:8]=[C:9]([C:11]([N:13]3[CH2:16][CH:15]([O:17][CH3:18])[CH2:14]3)=[O:12])[N:10]=2)[CH2:3]1)(=[O:22])=[O:21]
Reactant: COC1CN(C(=O)c2coc(N3CC(O)C3)n2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1CN(C(=O)c2coc(N3CC(OS(C)(=O)=O)C3)n2)C1
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
To a solution of 3-hydroxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (480 mg, 1.89 mmol) (obtained as described in Reference Example 73(2)) in methylene chloride (24 ml) were added methanesulfonyl chloride (439 μl, 5.67 mmol) and triethylamine (795 ml, 5.67 mmol) in an ice bath and the mixture was stirred for 10 minutes and then at room temperature for 30 minutes. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium chloride, filtered and concentrated under reduced pressure. To the residue were added ethyl acetate and diisopropyl ether to give a solid and the solid was collected by filtration, washed with diisopropyl ether to afford 3-methanesulfonyloxy-1-[4-(3-methoxyazetidine-1-carbonyl)-1,3-oxazol-2-yl]azetidine (586 mg, yield 94%) as a pale yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][O:36][C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M150) (232 mg, 0.43 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (113 mg, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[C:16]4=[C:11]3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[C:15]4[C:19](=[O:20])[N:18]([CH2:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[C:17](=[O:21])[C:16]4=[C:11]3[CH:10]=[N:9]2)=[CH:22][CH:23]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)NC4=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2ncc3c4c(cnc32)C(=O)N(CCc2ccccc2)C4=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.9 %

Procedure:
To an ice cooled solution of 3-(4-methoxybenzyl)pyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (2.5 g, 8.1 mmol) in anhydrous N,N-dimethylformamide (25 ml), sodium hydride (60% emulsion in paraffin oil, 500 mg, 12 mmol) was added. The reaction mixture was warmed to room temperature and stirred for 10 minutes. The reaction mixture was again cooled to 0° C. and (2-bromoethyl)benzene (1.5 ml, 8.9 mmol) was added. The solution was then heated to 90° C. for 2 hours. The reaction was monitored by TLC and LCMS, and on completion of reaction, it was cooled to room temperature and ice cooled water (75 ml) was added. The reaction mixture was then extracted with ethyl acetate (3×150 ml). The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel using a gradient of 0-20% ethyl acetate in hexanes to afford 3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (2 g, 60%) as a solid. 1HNMR (400 MHz, DMSO-d6) δ: 9.05 (s, 1H), 8.65 (s, 1H), 7.15-7.3 (m, 7H), 6.85 (d, 2H), 5.77 (s, 2H), 3.85 (t, 2H), 3.70 (s, 3H), 2.95 (t, 2H); LCMS: [M+H] 413. Trifluoroacetic acid (20 ml) was added to 3-(4-methoxybenzyl)-7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (1 g, 2.1 mmol) at 0° C., and then stirred at 100° C. for 5 hours. The reaction was monitored by TLC, and on completion of the reaction, trifluoroacetic acid was evaporated under reduced pressure and the residue was basified using aqueous ammonia to form a solid precipitate. The solid was filtered over a sintered funnel. The solid was washed with hexane and dried under reduced pressure to afford 7-phenethylpyrazolo[3,4-b]pyrrolo[3,4-d]pyridine-6,8(3H,7H)-dione (500 mg, 80%). The compound was used next without further purification. 1HNMR (400 MHz, DMSO-d6) δ: 14.50 (s, 1H), 9.00 (s, 1H), 8.50 (s, 1H), 7.05-7.15 (m, 5H), 3.95 (t, 2H), 2.95 (t, 2H); LCMS: [M+H] 293.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[C:12]2B1OC(C)(C)C(C)(C)O1.Cl[C:38]1[N:43]=[C:42]([O:44][C@@H:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]2)[CH:41]=[N:40][CH:39]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:22]=[CH:23][C:24]([CH3:25])=[CH:26][CH:27]=1)(=[O:19])=[O:20])[CH:13]=[C:12]2[C:38]1[N:43]=[C:42]([O:44][C@@H:45]2[CH2:50][CH2:49][CH2:48][N:47]([C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[CH2:46]2)[CH:41]=[N:40][CH:39]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2cncc(Cl)n2)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(O[C@@H]4CCCN(C(=O)OC(C)(C)C)C4)n3)c3cc(-c4c(F)cccc4F)ccc32)cc1
Temperature: 110 °C
Yield: 88.3 %

Procedure:
A glass microwave reaction vessel was charged with 5-(2,6-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-indole (2.75 g, 5.40 mmol) and (R)-tert-butyl 3-(6-chloropyrazin-2-yloxy)piperidine-1-carboxylate (1.694 g, 5.40 mmol) in p-dioxane/H2O (4:1, 16 mL) followed by A-Phos (0.191 g, 0.270 mmol) and potassium phosphate (2.92 g, 10.80 mmol). The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Uppsala, Sweden) at 110° C. for 80 min. The reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried, filtered and concentrated. The residue was purified with silica gel chromatography (eluting with 10-20% EtOAc in Hexanes) to give (R)-tert-butyl 3-(6-(5-(2,6-difluorophenyl)-1-tosyl-1H-indol-3-yl)pyrazin-2-yloxy)piperidine-1-carboxylate (3.15 g, 4.77 mmol, 88% yield) as a solid. MS (ESI, pos. ion) m/z: 661 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1.[CH2:15]([N:23]=[C:24]=[O:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][C:24]([NH:23][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH:10]=[N:9]2)=[C:5]([CH3:14])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C=NCCc1ccccc1
Product: Cc1noc(C)c1Cn1cc(NC(=O)NCCc2ccccc2)cn1
Yield: 29 %

Procedure:
Prepared as in example 9-6b from 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine and phenethyl isocyanate. Yield: 29%. 1H NMR (DMSO-d6, 400 MHz): δ2.10 (s, 3H), 2.36 (s, 3H), 2.69 (t, J=7.2 Hz, 2H), 3.25 (q, J=7.4 Hz, 2H), 5.02 (s, 2H), 6.00 (t, J=5.8 Hz, 1H), 7.16-7.30 (m, 6H), 7.68 (s, 1H), 8.13 (s, 1H). LC/MS; [M+H] calculated for C18H21N5O2; expected 340.17; found 340.20.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][NH:18][CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:21][C:2]([F:20])([F:1])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][N:18]([C:23]4[C:28]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CNCC3)cn1
Reactant: CS(=O)(=O)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1cccnc1N1CCc2ncnc(Nc3ccc(C(F)(F)F)nc3)c2C1

Procedure:
The title compound was prepared according to the procedure described for Compound 4 and reacting N-(6-(trifluoromethyl)pyridin-3-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-amine (140 mg, 0.47 mmol) with 2-chloro-3-(methylsulfonyl)pyridine (Ponticello, JOC, 44(17), 1979) (0.115 g, 0.06 mmol) in the presence of N,N-diisopropylethylamine (0.17 mL, 0.98 mmol) to give the desired Compound 5 as an off-white powder (55 mg, 26%).
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:27])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:23]=[N:24][S:25][CH:26]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.[C:28](O)(=[O:34])[CH2:29][CH2:30][C:31]([OH:33])=[O:32].[I-].[K+]>CC(C)=O.Cl.O1CCOCC1>[ClH:1].[C:31]([CH2:30][CH2:29][C:28]([S:20][CH:17]1[CH2:18][CH2:19][N:14]([CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[C:5]([CH:2]2[CH2:4][CH2:3]2)=[O:27])[CH2:15]/[C:16]/1=[CH:21]\[C:22]1[N:23]=[N:24][S:25][CH:26]=1)=[O:34])([OH:33])=[O:32]
Reactant: O=C(O)CCC(=O)O
Reactant: O=C(C1CC1)C(c1ccccc1F)N1CCC(S)/C(=C/c2csnn2)C1
Agent: Cl
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)SC1CCN(C(C(=O)C2CC2)c2ccccc2F)C/C1=C\c1csnn1
Temperature: 25 °C
Yield: 34.5 %

Procedure:
To a solution of (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4-sulfanyl-3-[(1,2,3-thiadiazol-4-yl)methylidene]piperidine hydrochloride (100 mg) in acetone (10 ml) were added anhydrous succinic acid (26 mg) and potassium iodide (45 mg) with stirring at room temperature, and the resulting mixture was stirred at room temperature for 2 hours. After stirring, anhydrous succinic acid (130 mg) and potassium iodide (180 mg) were further added, and the resulting mixture was furthermore stirred at room temperature for 1.5 hours. After the reaction mixture was evaporated in vacuo, the residue was purified by chromatography on a silica gel column using methanol and dichloromethane (1:50) as the eluent. The amorphous solid obtained was dissolved in a 4N solution of hydrogen chloride in dioxane (2 ml), and the resulting mixture was evaporated in vacuo to afford the title compound (40 mg, yield: 29%) as a colourless amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH2:18][C:19]([F:22])([F:21])[F:20].C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl.O>[NH2:1][C:2]1[C:3]([O:17][CH2:18][C:19]([F:20])([F:21])[F:22])=[CH:4][C:5]([C:8]2([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][C:7]=1[Br:30]
Reactant: CCOC(=O)C1(c2ccc(N)c(OCC(F)(F)F)c2)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1(c2cc(Br)c(N)c(OCC(F)(F)F)c2)CCC1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
To a stirred solution of ethyl 1-(4-amino-3-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (2.4 g, 8.3 mmol) in dry CHCl3 (50 mL), NBS (1.4 g, 7.8 mmol) was added at 0° C. The reaction mixture was allowed to stir for 3 hat room temperature to complete the reaction. The reaction mixture was diluted with water, extracted with DCM (2×50 mL), the combined organic solvents were dried over Na2SO4, filtered and concentrated under educed pressure. The crude reaction mixture was purified by column chromatography to give ethyl 1-(4-amino-3-bromo-5-(2,2,2-trifluoroethoxy)phenyl)cyclobutanecarboxylate (1.5 g) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.[SH:18][CH2:19][C:20]([NH2:22])=[O:21].[OH-].[K+]>CN(C)C=O.O>[NH2:13][C:12]1[C:11]2[C:2](=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=3)[S:18][C:19]=1[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)CS
Reactant: COc1cc2cc(C#N)c(Cl)nc2cc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2cc3c(N)c(C(N)=O)sc3nc2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 20 g of 2-chloro-6,7-dimethoxy-3-quinolinecarbonitrile in 500 ml of dimethylformamide was added 20 g of 2-mercaptoacetamide. To the resultant mixture was added dropwise a solution of 15 g of potassium hydroxide in 100 ml of water. The mixture was stirred at room temperature for 30 minutes and enough additional water was added to give a homogeneous solution. The mixture was stirred at room temperature for 16 hours and then poured into 4 liters of water. The yellow precipitate which formed was separated by filtration and dried to give 3-amino-6,7-dimethoxy thieno[2,3-b]quinoline-2-carboxamide melting at about 278.5°-279.5° C. with decomposition.
Reaction SMILES: C(N(CC)CC)C.B(F)(F)F.[C:12]([C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:18]=2[CH:19]=1)(=O)[CH3:13].[Cl-].[Na+]>ClCCl>[CH2:12]([C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:18]=2[CH:19]=1)[CH3:13]
Reactant: CC(=O)c1cc2cc([N+](=O)[O-])ccc2s1
Agent: FB(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc2cc([N+](=O)[O-])ccc2s1
Temperature: 0 °C
Yield: 123.2 %

Procedure:
A solution of 22.6 g (0.195 mole) of triethylamine in 50 ml of dichloromethane is cooled to 0° C. by means of an ice-sodium chloride bath. Boron trifluoride is then added to saturate the solution (about 25 g). A solution of 14.4 g (0.065 mole) of 2-acetyl 5-nitro benzothiophene in 50 ml of dichloromethane is added while the temperature is maintained at 0° C. Stirring is continued at 0° C. for 0.5 h while a very gentle stream of boron trifluoride is introduced. The complex formed is decomposed with a saturated solution of sodium chloride, the organic fraction is washed three times with a solution of sodium chloride and dried over anhydrous sodium sulfate. It is filtered and the solvent is evaporated at a rotary evaporator. In this manner, 16.6 g of 2-ethyl 5-nitro benzothiophene are obtained in the form of a yellow solid which is purified by chromatography on a column of silica (eluant: heptane/ethyl acetate 9/1).
Reaction SMILES: [Na].[C:2]([O:6][CH3:7])(=[O:5])[CH2:3][SH:4].[Cl:8][C:9](Cl)=[CH:10][C:11]#[N:12]>CO>[NH2:12][C:11]1[CH:10]=[C:9]([Cl:8])[S:4][C:3]=1[C:2]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CS
Reactant: N#CC=C(Cl)Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sc(Cl)cc1N

Procedure:
In a flame dried flask under a nitrogen atmosphere, and with mechanical stirring, a solution of about 1.2 g (0.05 mole) of sodium metal dissolved in 30 ml of dry methanol was treated dropwise with 2.35 g (1.98 ml, 0.022 mole) of methyl thioglycolate while maintaining the temperature below 25° C. A solution of 2.70 g (0.022 mole) of 3,3-dichloroacrylonitrile [R. L. Soulen, D. B. Clifford, F. F. Crim and J. A. Johnston, J. Org. Chem. 36 (22), 3386-3391 (1971)] and 10 ml of methanol was then added dropwise at a rate such as to keep the reaction temperature <28° C. The reaction mixture became cloudy and orange. Stirring was continued for an hour. The mixture was concentrated under reduced pressure, was diluted with water, and was extracted five times with 60 ml portions of chloroform. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to furnish an oil which was chromatographed under moderate pressure ("flash" chromatography) on a column of silica gel (Woelm 32-63 micrometers, i.d. 5 cm×height 18 cm); the eluant was isopropyl ether; 15 ml fractions were taken. Fractions 15-20 were combined and evaporated to give methyl 3-amino-5-chloro-2-thiophenecarboxylate as a colorless solid: m.p. 99°-101° C.; yield 0.60 g (14%); ir (KBr) 3448 cm-1, 3343, 1674, 1615, 1546, 1455, 1425 among others; 1H-nmr (CDCl3) delta 3.8 ppm (s, 3H), 5.3 (broad s, 2H), 6.4 (s, 1H); mass spectrum 191 (molecular ion), 159 (-32, CH3OH, parent peak) and others.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][CH:5]([CH2:20][CH2:21][N:22]1C(=O)C2=CC=CC=C2C1=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH2:14][CH2:15][C:16](O)=[O:17])=[CH:9][CH:8]=1>C(O)C>[NH2:22][CH2:21][CH2:20][CH:5]([CH3:4])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:14][CH2:15][C:16](=[O:17])[NH:2][N:3]=2)=[CH:9][CH:8]=1
Reactant: CC(CCN1C(=O)c2ccccc2C1=O)Cc1ccc(C(=O)CCC(=O)O)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(CCN)Cc1ccc(C2=NNC(=O)CC2)cc1
Yield: 82 %

Procedure:
9.61 g of hydrazine monohydrate was added to an ethanol solution (500 ml) containing 15.06 g of 4-(2-methyl-4-phthalimidobutyl)-1-(3-hydroxycarbonylpropionyl)benzene, and the mixture was refluxed under heating for 2.5 hours. After cooling, precipitated crystal was collected by filtration and recrystallized from ethyl acetate to obtain 8.14 g of 6-[4-(4-amino-2-methylbutyl)phenyl]-4,5-dihydropyridazin-3(2H)-one.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([OH:9])[CH3:8].C(N(CC)C(C)C)(C)C.[CH3:19][O:20][CH2:21][CH2:22][O:23][CH2:24]Cl>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH:7]([O:9][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH3:8]
Reactant: CC(O)c1ccsc1Br
Reactant: COCCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCOCOC(C)c1ccsc1Br
Temperature: 25 °C
Yield: 65.7 %

Procedure:
A solution of 2-bromo-3-(l-hydroxyethyl)thiophene (97.5 g, 0.47 mol) in dry methylene chloride (400 ml) was cooled in ice and N,N-diisopropylethylamine (68.2 g, 0.517 mol) was added followed by methoxyethoxymethYl chloride (64.4 g, 0.517 mol). The solution was stirred at room temperature over night. The dark solution was washed with water, 3N HCl, saturated NaHCO3 and finally with water. The solution was dried over anhydrous Na2SO4 filtered and concentrated in vacuo at room temperature. A dark amber oil was obtained (123.1 g). The impure product was distilled and the product was collected at 108-116° C. at 0.7 mm Hg. to give 91.1 g (66%) of colorless liquid. NMR supported the structure.
Reaction SMILES: [K].[C:2]([NH:7][C:8](=[S:14])[O:9][CH2:10][CH2:11][CH2:12][CH3:13])([O:4]CC)=O.Cl[CH2:16][C:17]#[N:18].C[O-].[K+]>CO>[CH2:10]([O:9][C:8]1[S:14][C:16]([C:17]#[N:18])=[C:2]([OH:4])[N:7]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOC(=S)NC(=O)OCC
Reactant: N#CCCl
Agent: C[O-]
Agent: [K+]
Agent: [K]
Solvent: CO
Product: CCCCOc1nc(O)c(C#N)s1
Reaction time: 5 h

Procedure:
A mixture of 35 g of the potassium salt of n-butyl N-carbethoxy-thiocarbamate, 500 ml of methanol and 7.7 ml of chloroacetonitrile was stirred for 5 hours and then 10.1 g of potassium methylate were added thereto. The reaction mixture was refluxed for 16 hours and was then evaporated to dryness. The residue was dissolved in water and the aqueous phase was washed with ether and then acidified. The acid aqueous phase was extracted with ether and the ether phase was evaporated to dryness to obtain 16 g of 2-n-butoxy-4-hydroxy-5-cyano-thiazole in the form of beige crystals melting at 80° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([NH2:12])=[O:11])#[CH:2].Cl[C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:27][CH:26]=2)[N:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[Cu]I>[NH2:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:18]1[C:19]([C:20]([F:21])([F:22])[F:23])=[CH:14][N:15]=[C:16]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[CH:29][CH:30]=2)[N:17]=1
Reactant: C#Cc1ccccc1CC(N)=O
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1c1ccc(Nc2ncc(C(F)(F)F)c(C#Cc3ccccc3CC(N)=O)n2)cc1
Temperature: 120 °C
Yield: 74 %

Procedure:
To a nitrogen de-gassed solution of 2-(2-ethynylphenyl)acetamide (I39) (0.054 g, 0.788 mmol) and tert-butyl 2-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I37) in dry DMF (4 mL) were added triethylamine (0.159 mL, 1.138 mmol), triphenylphosphine (0.011 g, 0.043 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.020 g, 0.028 mmol) and CuI (0.008 g, 0.04 mmol). The reaction mixture was heated under microwave irradiation at 120° C. for 20 minutes. The reaction was concentrated to dryness in vacuo and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-100% EtOAc in petroleum benzine 40-60° C., then 0-5% methanol in EtOAc) to give the title compound (I40) (0.122 g, 74% yield) as a yellow glassy solid; 1H NMR (400 MHz, d6-DMSO) δ 10.48 (s, 1H), 8.82 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.65-7.55 (m, 1H), 7.55-7.47 (m, 1H), 7.47-7.33 (m, 3H), 7.16 (d, J=8.5 Hz, 2H), 7.01 (s, 1H), 5.29-5.22 (m, 1H), 3.92 (d, J=13.1 Hz, 1H), 3.70 (s, 2H), 2.71 (t, J=13.3 Hz, 1H), 2.34-2.24 (m, 1H), 1.82-1.68 (m, 1H), 1.54 (d, J=11.3 Hz, 2H), 1.45-1.22 (m, 11H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[S:16][C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])=O)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1(C)C=CC=CC=1>C1COCC1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([CH2:10][C:12]2[S:16][C:15]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[N:14][C:13]=2[CH3:27])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cccc3ccccc23)sc1C(=O)N1CCN(C(C)C)CC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc3ccccc23)sc1CN1CCN(C(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-isopropyl-piperazin-1-yl)-(4-methyl-2-naphthalen-1-yl-thiazol-5-yl)-methanone (25 mg, 0.066 mmol) in anhydrous THF (2.5 ml) is added a solution of alane-dimethylethylamine complex in toluene (0.5 M, 0.4 ml, 0.2 mmol, 3.0 eq.) dropwise at 0° C. The resulting mixture is stirred at rt overnight. The reaction is quenched with one drop of water, followed by one drop of 10 N sodium hydroxide solution and two more drops of water. The resulting mixture is diluted with EtOAc (10 ml), dried over magnesium sulfate, and concentrated. The residue is purified through PTLC (EtOAc/Et3N, 25:1) to give the desired product. 1H NMR (300 MHz, CDCl3) δ 8.78 (1H, dd), 7.89 (2H, m), 7.78 (1H, dd), 7.60˜7.45 (3H, m), 3.74 (2H, s), 2.76˜2.54 (9H, m, overlapped), 2.51 (3H, s), 1.06 (6H, d); LC-MS (M+1) 366.2.