Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7](=[N:15][NH2:16])[NH:8][C@@H:9]([CH3:14])[C:10]([F:13])([F:12])[F:11])[S:5][CH:6]=1.[CH2:17](OC(OCC)OCC)C>>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[N:8]([C@@H:9]([CH3:14])[C:10]([F:13])([F:11])[F:12])[CH:17]=[N:16][N:15]=2)[S:5][CH:6]=1
Reactant: C[C@H](NC(=NN)c1nc(Br)cs1)C(F)(F)F
Reactant: CCOC(OCC)OCC
Product: C[C@H](n1cnnc1-c1nc(Br)cs1)C(F)(F)F

Procedure:
(S)-4-bromo-N-(1,1,1-trifluoropropan-2-yl)thiazole-2-carbohydrazonamide (55 g,) in triethoxymethane (500 ml) was stirred at 90 OC for 3 hours and then at 130° C. overnight and the reaction was concentrated. The residue was purified by column to obtain (S)-4-bromo-2-(4-(1,1,1-trifluoropropan-2-yl)-4H-1,2,4-triazol-3-yl)thiazole. 1HNMR (400 MHz, CDCl3): δ 8.46 (1H, s), 7.43 (1H, s), 6.48-6.52 (1H, m), 1.83 (3H, d, J=7.2 Hz).
Reaction SMILES: [F:1][C:2]1[C:3]([O:45]C)=[C:4]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[N:10](COCC[Si](C)(C)C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.N>>[F:1][C:2]1[C:3]([OH:45])=[C:4]([C:8]2[C:16]3[C:15]([NH:17][C@H:18]([C:20]4[N:25]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=5)[C:24](=[O:32])[C:23]5=[C:33]([CH3:36])[CH:34]=[CH:35][N:22]5[N:21]=4)[CH3:19])=[N:14][CH:13]=[N:12][C:11]=3[NH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(F)cccc1-c1cn(COCC[Si](C)(C)C)c2ncnc(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)c12
Agent: BrB(Br)Br
Agent: N
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cccc(F)c5O)c34)n(-c3ccccc3)c(=O)c12
Yield: 75.7 %

Procedure:
(S)-2-(1-((5-(3-Fluoro-2-methoxyphenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (79 mg, 0.12 mmol) was treated with boron tribromide (1 M in dichloromethane, 1.23 mL, 1.23 mmol) and a solution of ammonia (7N in methanol, 1.6 mL, 11.2 mmol) according to the method described in Example 41 to give 45 mg (73% yield) of the title compound as a white solid. Purity 99%.
Reaction SMILES: NC1C=CC(S(NC2C=CC=CC=2C)(=O)=O)=CC=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-])=O)=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[NH2:37][C:34]1[CH:35]=[CH:36][C:31]([S:28]([NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH3:19])(=[O:29])=[O:30])=[CH:32][CH:33]=1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccccc1NS(=O)(=O)c1ccc(N)cc1
Product: COc1ccccc1NS(=O)(=O)c1ccc(N)cc1

Procedure:
(RK1-1-27C II) I This compound was prepared according to the procedure described for compound 12a except using 11e to obtain required the product as a white solid (85 mg, 57%). Mp not determined; 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J=8.6 Hz, 2H), 7.42 (dd, J=7.8, 1.1 Hz, 1H), 7.19 (br s, 1H), 6.96-6.89 (m, 2H), 6.81 (td, J=7.8, 1.1 Hz, 1H), 6.67 (dd, J=8.2, 1.1 Hz, 1H), 6.49 (d, J=8.6 Hz, 2H), 3.60 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[CH2:48][C:49]([F:52])([F:51])[F:50])(=O)=O>O1CCCC1>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH2:48][C:49]([F:52])([F:51])[F:50])[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:32])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(CC(F)(F)F)CC1
Yield: 43.7 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (180 mg, 0.41 mmol), (prepared as described for the starting material in Example 11), was suspended in tetrahydrofuran (15 ml), and diisopropylethylamine (108 μl, 0.45 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulphonate (98 mg, 0.62 mmol) were added. The mixture was heated at reflux for 1.5 hours. Diisopropylethylamine (36 μl, 0.21 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulphonate (45 mg, 0.21 mmol) were added and the mixture was heated at reflux for a further 2 hours. The mixture was concentrated under reduced pressure and column chromatography of the residue, eluting with 1% methanol/methylene chloride gave a sticky solid. This was triturated with diethyl ether and filtered to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[1-(2,2,2-trifluoroethyl)piperidin-4-ylmethoxy]quinazoline (93 mg, 44%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.[NH:17]1[CH:21]=[C:20](B(O)O)[CH:19]=[N:18]1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[NH:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)[CH:19]=[N:18]1
Reactant: NC(=O)C1CCN(c2ccncc2Br)CC1
Reactant: OB(O)c1cn[nH]c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: NC(=O)C1CCN(c2ccncc2-c2cn[nH]c2)CC1
Yield: 46 %

Procedure:
General procedure D was followed using 1-(3-bromopyridin-4-yl)piperidine-4-carboxamide E36 (25 mg, 0.088 mmol), 1H-pyrazol-4-boronic acid pinnacol ester (21 mg, 0.11 mmol), tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %), 0.5 M sodium carbonate (0.25 mL, 0.12 mmol) and acetonitrile (1 mL) for 50 min. The crude product was purified by preparative hplc (H2O, MeCN, 95:5) to furnish the title compound as a white solid (11 mg, 46%), m/z (ESI) C14H18N5O requires 272.1506 found [M+H]+272.1509.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[O:12])[C:5]2[O:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH3:13][N:14]1[C:18]([Sn](CCCC)(CCCC)CCCC)=[CH:17][N:16]=[N:15]1>C1(C)C=CC=CC=1.C(=O)(O)[O-].[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:13][N:14]1[C:18]([C:2]2[CH:3]=[C:4]([CH:11]=[O:12])[C:5]3[O:9][CH:8]=[CH:7][C:6]=3[CH:10]=2)=[CH:17][N:16]=[N:15]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnn1C
Reactant: O=Cc1cc(Br)cc2ccoc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1nncc1-c1cc(C=O)c2occc2c1
Yield: 251.5 %

Procedure:
A mixture of 5-bromo-benzofuran-7-carbaldehyde (0.315 g), 1-methyl-5-tributylstannanyl-1H-[1,2,3]-triazole (0.525 g) and bis(triphenylphosphine)palladium (II) chloride (0.05 g) in toluene (7 ml) was stirred and refluxed under nitrogen for 5 h. The cooled mixture was diluted with 8% sodium bicarbonate (30 ml) and extracted with ethyl acetate (3×25 ml). The combined extracts were dried (MgSO4) and the solvent removed in vacuo to give a yellow solid (0.8 g). Purification by FCC, eluting with ethyl acetate-hexane, then ethyl acetate gave a cream solid, which was crystallised from ethyl acetate to give the title compound as pale green crystals (0.18 g), m.p. 180-2°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH:28]1[CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[N:13]([CH:28]3[CH2:31][CH2:30][CH2:29]3)[N:14]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClC1CCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2nn(C3CCC3)c(-c3ccc(Cl)cc3)c2CC1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.40 mmol) in DMF (2 mL) was added NaH (60% dispersion in oil, 60 mg) at 25° C. After 10 min, the mixture was heated to 80° C., and chloro-cyclobutane (1.5 mmol) was added. The mixture was heated at this temperature for 16 h. The mixture was concentrated and purified by chromatography (SiO2, EtOAc/hexanes) to provide 3-(4-chloro-phenyl)-2-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester. The title compound (0.030 mg) was obtained from this ester according to the deprotection method in Example 103, Step C. The reaction sequence also yielded 3-(4-chloro-phenyl)-1-cyclobutyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C17H20ClN3, 301.13; found, m/z 302.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.52-7.51 (m, 2H), 7.30-7.29 (m, 2H), 4.70-4.60 (m, 1H), 3.40-3.89 (m, 2H), 3.27-3.21 (m, 4H), 2.79-2.76 (m, 2H), 2.60-2.50 (m, 2H), 2.30-2.20 (m, 2H), 1.81-1.65 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:20])[CH3:19].O>CS(C)=O>[N+:15]([C:5]1[CH:4]=[CH:3][C:2]([N:24]2[CH2:25][CH2:26][N:21]([C:18](=[O:20])[CH3:19])[CH2:22][CH2:23]2)=[CH:14][C:6]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:17])=[O:16]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccccc1
Reactant: CC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The compound (300 mg) prepared in Step 1 and N-acetylpiperazine (300 mg) were dissolved in dimethyl sulfoxide (3 mL), and stirred at 90° C. for 3 hours. The mixture was added with water, and extracted with ethyl acetate. The thus obtained organic layer was washed with saturated brine, the water was removed with sodium sulfate, and the solvent was removed by distillation under reduced pressure. Then, the compound was added with ethyl ether to form a solid, and the solid was filtered to obtain a target compound as a yellow solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[C:15]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:9]=[N:8]1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20].CCOC(C1CC(C(OCC)=O)=C(C)NC=1C)=O>C1COCC1>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH:13]=[CH:14][C:15]2[N:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: c1cnc(-n2nnc3cnccc32)cn1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Solvent: C1CCOC1
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1C=Cc2c(nnn2-c2cnccn2)C1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 85 %

Procedure:
A solution of 1-pyrazin-2-yl-1H-[1,2,3]triazolo[4,5-c]pyridine (Intermediate 40) (50 mg, 0.25 mmol) in THF (2.0 mL) was treated with 2-chloro-3-(trifluoromethyl)benzoyl chloride (67 mg, 0.28 mmol) and stirred for 5 minutes. The reaction was treated with Hantzsch Ester (269 mg, 1.0 mmol) and heated to 80° C. in sealed tube for 90 min. Reaction was concentrated and purified on 16 g SiO2 with 0-50% EtOAc/hexanes to yield 87 mg (85% yield) MS (ESI): mass calcd. for C17H10ClF3N6O, 406.1. m/z found, 407.1 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=2)[C:12]2[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=2[CH:23]=1)C1C=CC=CC=1.CS(O)(=O)=O>ClCCl.C(OCC)(=O)C>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([C:11]2[C:12]3[S:16][C:15]([NH:17][C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[N:14][C:13]=3[CH:23]=[C:9]([OH:8])[CH:10]=2)=[N:25][CH:26]=1)#[N:31]
Reactant: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(-c3ccc(C#N)cn3)c2s1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC(=O)Nc1nc2cc(O)cc(-c3ccc(C#N)cn3)c2s1
Reaction time: 2 h
Yield: 90.7 %

Procedure:
A stirred solution of 1-[5-Benzyloxy-7-(5-cyano-pyridin-2-yl)-benzothiazol-2-yl]-3-ethyl-urea (110 mg, 0.26 mmol) in anhydrous dichloromethane (3 ml) was treated with methanesulfonic acid (1 ml) and kept at ambient temperature for 2 h. The organic layer was diluted with ethyl acetate then washed with water (3×30 ml), dried (MgSO4) and the solvent removed in vacuo to give the crude 1-[7-(5-Cyano-pyridin-2-yl)-5-hydroxy-benzothiazol-2-yl]-3-ethyl-urea (80 mg, 90%) as an off-white solid which was used without further purification.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][CH:10]=[C:9]([C:16]([OH:18])=[O:17])[CH:8]=2)[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.[CH2:24](O)[CH3:25]>>[CH2:1]([C:5]1[NH:6][C:7]2[C:12]([C:13](=[O:15])[N:14]=1)=[CH:11][CH:10]=[C:9]([C:16]([O:18][CH2:24][CH3:25])=[O:17])[CH:8]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCO
Reactant: CCCCc1nc(=O)c2ccc(C(=O)O)cc2[nH]1
Agent: O=S(=O)(O)O
Product: CCCCc1nc(=O)c2ccc(C(=O)OCC)cc2[nH]1

Procedure:
A mixture of 5.0 g of 2-butyl-7-carboxy-4(1H)-quinazolinone in 100 ml of absolute ethanol containing 2 ml of sulfuric acid is refluxed for 48 hours. The solvent is evaporated in vacuo and the residue partitioned between water and chloroform. The organic layer is washed with aqueous saturated sodium bicarbonate, dried with anhydrous sodium sulfate, filtered and evaporated to a residue which crystallizes from ethyl acetate-hexane to afford 4.5 g of the desired product, mp 145° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][C:14](=[O:21])[CH2:13]3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22]([O:25][C:26](=O)C)(=O)C.COC(OC)OC>CN(C)C=O>[CH3:22][O:25][CH:26]=[C:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:11]=2)[C:16](=[O:20])[NH:15][C:14]1=[O:21]
Reactant: O=C1Cc2cc(OCCN3CCOCC3)ccc2C(=O)N1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Solvent: COC(OC)OC
Product: COC=C1C(=O)NC(=O)c2ccc(OCCN3CCOCC3)cc21

Procedure:
A mixture of 6-(2-morpholin-4-yl-ethoxy)-4H-isoquinoline-1,3-dione (390 mg, 1.34 mmole), 10 mL of a 4:1 mixture of acetic anhydride and N,N-dimethylformamide and trimethylorthoformate (1.1 mL, 10.1 mmole) is stirred and heated to reflux. After 30 minutes the solvents are removed and the residue treated with 2:1 hexanes/ethyl acetate, the product is collected by filtration, a yellow solid, 230 mg, (52%), MS (ES+): m/z 333.2 (M+H), used as is in the next step.
Reaction SMILES: O[CH:2]([CH2:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16])[CH2:3][C:4](=[O:6])[CH3:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[S:9][CH2:8][CH2:7][CH:2]=[CH:3][C:4](=[O:6])[CH3:5]
Reactant: CC(=O)CC(O)CCSc1ccccc1C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(=O)C=CCCSc1ccccc1C
Yield: 99.8 %

Procedure:
1.00 Gram of 4-hydroxy-6-(2-methylphenylthio)-2-hexanone was dissolved in 100 ml of toluene, and 0.02 g of p-toluene sulfonic acid was added thereto. The resulting mixture was refluxed for 2.5 hours with stirring. After having been cooled, the mixture was washed with a saturated aqueous sodium hydrogencarbonate solution and then saturated aqueous sodium chloride solution. Then the mixture was dried over anhydrous magnesium sulfate. Removing the solvent from the mixture under reduced pressure gave 0.97 g of 6-(2-methylphenylthio)-3-hexen-2-one. (trans : cis =3.8 : 1) (purity: 94.7%). The yield was 99.8%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]([CH3:16])[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)C(C)C)C.[Cl:58][C:59]1[CH:60]=[C:61]([N:65]2[C:69]([CH2:70][NH2:71])=[CH:68][C:67]([C:72]([F:75])([F:74])[F:73])=[N:66]2)[CH:62]=[CH:63][CH:64]=1>C1COCC1>[Cl:58][C:59]1[CH:60]=[C:61]([N:65]2[C:69]([CH2:70][NH:71][C:13](=[O:15])[CH:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([F:1])[CH:3]=3)[CH3:16])=[CH:68][C:67]([C:72]([F:73])([F:74])[F:75])=[N:66]2)[CH:62]=[CH:63][CH:64]=1
Reactant: NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1
Reactant: CC(C(=O)O)c1ccc(S(C)(=O)=O)c(F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C(=O)NCc1cc(C(F)(F)F)nn1-c1cccc(Cl)c1)c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.6 %

Procedure:
To a solution of 2-(3-fluoro-4-(methylsulfonyl)phenyl)propanoic acid (60 mg, 0.244 mmol) in THF (1.9 mL) was added 1-hydroxybenzotriazole (32 mg, 0.244 mmol), O-(1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (78 mg, 0.244 mmol), N-ethyldiisopropylamine (0.083 mL, 0.488 mmol) and (1-(3-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine (67 mg, 0.244 mmol). The solution was stirred for 48 h at room temperature. The reaction mixture was concentrated in vacuo and purified by column chromatography (ethyl acetate/cyclohexane (2:1)) to give pure N-[[2-(3-chlorophenyl)-5-(trifluoromethyl)-2H-pyrazol-3-yl]-methyl]-2-(3-fluoro-4-methylsulfonyl-phenyl)-propionamide (example compound D2) (93 mg, 76%).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16]([Br:28])=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH2:26][OH:27])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C>C(Cl)Cl.CS(C)=O>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:16]([Br:28])=[C:17]2[C:22](=[CH:23][C:24]=1[CH3:25])[N:21]=[C:20]([CH:26]=[O:27])[CH:19]=[CH:18]2)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:3])[CH3:4]
Reactant: Cc1cc2nc(CO)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1cc2nc(C=O)ccc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-(5-bromo-2-(hydroxymethyl)-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate (180 mg, 0.4 mmol) in DCM/DMSO (0.5 ml/0.5 ml) at 0° C. was added triethylamine (192 μl), followed by SO3-pyridine (222 mg). The mixture was stirred for 1 hour, and was quenched with ice-water. The water phase was extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, water and brine, and was dried over sodium sulfate. Concentration gave (S)-2-(5-bromo-2-formyl-7-methylquinolin-6-yl)-2-tert-butoxyethyl pivalate. ESI+ (m/z): [M+H]+ calc'd for C22H29BrNO4: 450.1; Found: 450.2.
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][C:7]1[S:15][C:14]2[C:9](=[N:10][CH:11]=[CH:12][C:13]=2[O:16][C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][C:18]=2[F:24])[CH:8]=1)C.Cl.O1CCOCC1>[Pd].C(Cl)Cl.CCO>[F:24][C:18]1[CH:19]=[C:20]([NH2:21])[CH:22]=[CH:23][C:17]=1[O:16][C:13]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:8]=[C:7]([CH2:6][CH2:5][CH3:4])[S:15][C:14]=12
Reactant: CCN(CC)CC#Cc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCc1cc2nccc(Oc3ccc(N)cc3F)c2s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 9.2 %

Procedure:
Obtained as a by-product during hydrogenation of the alkyne of 4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluoroaniline (Example 6, Step B). A mixture of N-4-(2-(3-(diethylamino)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)-3-fluorobenzenamine (Example 6, Step B; 106 mg, 0.287 mmol), 4N HCl in dioxane (72 μL, 0.29 mmol), palladium on carbon (61 mg, 0.029 mmol; Degussa type, 10 wt % Pd. 50% water), and 1:1 CH2Cl2/EtOH (10 mL) was purged with N2 (3×), and then shaken under H2 (50 psi) for 18 hours at room temperature on a Parr shaker. The mixture was filtered, rinsing the Pd/C with MeOH. The resulting filtrate was concentrated, and the residue was partitioned between EtOAc (20 mL) and a saturated aqueous solution of NaHCO3 (20 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative TLC (25% MeOH in CH2Cl2). The product was obtained as a waxy solid (8 mg, 8%). 1H NMR (400 MHz, CDCl3) δ 8.41 (m, 1H), 7.23 (s, 1H, overlaps with chloroform), 7.03 (m, 1H), 6.52 (m, 3H), 3.81 (br s, 2H), 2.93 (m, 2H), 1.80 (m, 2H), 1.03 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[CH2:19]([NH2:22])[CH2:20][NH2:21]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:22][CH2:19][CH2:20][N:21]=2)=[CH:4][CH:3]=1
Reactant: NCCN
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Solvent: CCO
Product: Fc1ccc(C2=NCCN=C2c2ccc(F)cc2)cc1
Temperature: 105 °C
Yield: 93 %

Procedure:
First, with dehydrated ethanol as a solvent, 16.8 g of 4,4′-difluorobenzil (by Tokyo Chemical Industry Co., Ltd.) and 4.5 g of ethylenediamine (by Kanto Chemical Co., Inc.) were mixed, and the mixture was refluxed at 105° C. for six hours. After reaction, a reaction solution was condensed by using an evaporator, and an obtained residue was recrystallized by using ethanol; thus, 2,3-bis(4-fluorophenyl)-5,6-dihydropyrazine was obtained (reddish brown powder, yield: 93%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]1([CH2:33][CH2:34][NH2:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:35][CH2:34][CH2:33][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NCCc1ccccc1
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)NCCc2ccccc2)cc1OC
Yield: 80.2 %

Procedure:
A solution of 3,4-dimethoxyphenylacetic acid (17.1 g, 0.090 mol) and carbonyldimidazole (14.6 g, 0.090 mol) in THF (200 ml) was stirred for 2.5 h in a flask fitted with a drying tube. To this solution was added 2-phenylethylamine (10.9 g, 0.090 mol) in THF (50 ml). After 1 h the THF was evaporated and the residue was treated with water (200 ml) and filtered. The crude amide was washed with water and recrystallized from mixture of 200 ml of methanol and 100 ml of water with a charcoal treatment to afford 21.6 g (80.3%) of the title compound mp 123°-124°. A second crop (2.1 g, (7.8%) was obtained after concentrating the mother liquors.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[C:27]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:26][C@H:23]2[CH2:22][CH2:21][C@H:20]([CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][CH:12]([C:11]4[C:6]5[CH2:5][CH2:4][O:3][C:7]=5[CH:8]=[CH:9][CH:10]=4)[CH2:13][CH2:14]3)[CH2:25][CH2:24]2)=[O:37])=[CH:39][CH:40]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)(C)Oc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4CCO5)CC3)CC2)cc1

Procedure:
The title compound, white solid (74 mg, 59%), MS (ISP) m/z=505.3 [(M+H)+], mp 216° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 4-tert-butoxy-benzoic acid.