Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[N:26]([C:28](=[O:36])[CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[NH2:27].[CH2:37](P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:26]([C:28](=[O:36])[CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[NH:27][CH3:37])=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1
Reactant: CN(N)C(=O)CN1CCOCC1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CNN(C(=O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)C(=O)CN1CCOCC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.3 g, 1.0 eq.) was dissolved in THF:EtOAc (15 mL, 2:1) and cooled to −60° C. where N-methyl-2-morpholinoacetohydrazide (0.23 g, 1.5 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.27 mL, 2.5 eq.) was added dropwise followed by DIPEA (0.45 mL, 3 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-methyl-N-(2-morpholinoacetyl)acrylohydrazide (0.052 g, yield: 12%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[I:10]I>N1C=CC=CC=1>[I-:10].[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1]([CH2:2][N+:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:4]=1)=[O:3]
Reactant: II
Reactant: CC(=O)c1ccccn1
Solvent: c1ccncc1
Product: O=C(C[n+]1ccccc1)c1ccccn1
Product: [I-]

Procedure:
2-Acetylpyridine (1.21 g, 10.0 mmol) and iodine (2.54 g, 10.0 mmol) were heated to reflux in pyridine (12 ml) for 1 hour. The solution was cooled, and the dark precipitate was filtered and washed with pyridine.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].CO[C:10]1[CH:16]=CC(O)=C[CH:11]=1.CO>C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Zr+4].C(O)CCC>[C:1]([O:6][CH2:7][CH2:11][CH2:10][CH3:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: COc1ccc(O)cc1
Reactant: C=C(C)C(=O)OC
Agent: [Zr+4]
Agent: CC(=O)/C=C(/C)[O-]
Solvent: CCCCO
Solvent: CO
Product: C=C(C)C(=O)OCCCC
Reaction time: 1.5 h
Yield: 99.2 %

Procedure:
An 74.1 g (1.0 mole) amount of n-butanol, 250.2 g (2.5 moles) of methyl methacrylate, 0.488 g (0.001 mole) of zirconium acetylacetonate and 0.28 g of hydroquinone monomethyl ether were added to a one liter flask fitted with an agitator, thermometer and fractionating tower and were heated and agitated. An azeotropic mixture of methyl methacrylate and methanol from the upper part (top) of the fractionating tower was removed at a reflux ratio of 5 to 10:1 to continuously advance the reaction. The reaction was conducted for 1.5 hours while the temperature at the top was 65° to 70° C. and the flask temperature was 104° to 130° C. The reaction showed a 99.5% conversion of n-butanol and a 99.2% yield of n-butyl methacrylate.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Br:31][C:32]1[N:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[Br:31][C:32]1[N:33]=[CH:34][C:35]([NH:38][C:8](=[O:10])[C@@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:36][CH:37]=1
Reactant: Nc1cnc(Br)cn1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Nc1cnc(Br)cn1)[C@H](CC1CCCC1)N1Cc2c(cccc2C(F)(F)F)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 1, 100 mg, 0.29 mmol) in methylene chloride (4 mL) and N,N-dimethylformamide (4 drops) was treated with a solution of oxalyl chloride in methylene chloride (2.0 M, 150 μL, 0.30 mmol) and stirred for 15 min at room temperature. After this time, the reaction mixture was then concentrated in vacuo and the resulting residue was dissolved in methylene chloride (4 mL) and then added dropwise to a separate reaction flask containing a mixture of 5-bromo-pyrazin-2-ylamine (76 mg, 0.44 mmol) and 2,6-lutidine (100 μL, 0.87 mmol) in methylene chloride (3 mL) at room temperature. The resulting reaction mixture was the stirred room temperature for 1.5 h. The reaction mixture was quenched by the addition of methanol and then diluted with methylene chloride and the organic layer was washed with a 1N aqueous hydrochloric acid solution. The organic layer was then dried, filtered and the filtrate concentrated in vacuo. The crude material was purified via Biotage flash column chromatography (40 S silica gel column, 25% ethyl acetate/hexanes) to afford (S)—N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (74 mg, 51%) as a white foam: HR-ES(+) m/e calcd for C21H20N4O2F3Br [M+H]+ 497.0795, observed 497.0796; 1H NMR (400 MHz, DMSO-d6) δ ppm 11.50 (s, 1H), 9.09 (d, J=1.07 Hz, 1H), 8.65 (d, J=1.28 Hz, 1H), 8.02 (dd, J=7.88, 10.44 Hz, 2H), 7.77 (t, J=7.67 Hz, 1H), 5.22 (dd, J=4.90, 10.66 Hz, 1H), 5.04 (d, J=18.33 Hz, 1H), 4.76 (d, J=18.11 Hz, 1H), 1.04-2.19 (m, 11H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[Br:34][C:35]1[N:40]=[C:39]([C:41](=[O:44])[NH:42][CH3:43])[C:38]([NH:45][C:46]2[C:51]([C:52]([F:55])([F:54])[F:53])=[CH:50][N:49]=[C:48]([NH:56][C:57]3[CH:67]=[CH:66][C:60]([CH2:61][CH2:62][PH:63](=[O:65])[OH:64])=[CH:59][C:58]=3[O:68][CH3:69])[N:47]=2)=[CH:37][CH:36]=1.[CH3:70][C:71]1([CH3:87])[C:75]([CH3:77])([CH3:76])[O:74][B:73]([C:78]2[CH:79]=[N:80][N:81]([CH2:83][CH2:84][CH2:85]O)[CH:82]=2)[O:72]1.CN1C=CN=C1>ClCCCl>[Br:34][C:35]1[N:40]=[C:39]([C:41](=[O:44])[NH:42][CH3:43])[C:38]([NH:45][C:46]2[C:51]([C:52]([F:55])([F:53])[F:54])=[CH:50][N:49]=[C:48]([NH:56][C:57]3[CH:67]=[CH:66][C:60]([CH2:61][CH2:62][PH:63](=[O:64])[O:65][CH2:85][CH2:84][CH2:83][N:81]4[CH:82]=[C:78]([B:73]5[O:74][C:75]([CH3:77])([CH3:76])[C:71]([CH3:70])([CH3:87])[O:72]5)[CH:79]=[N:80]4)=[CH:59][C:58]=3[O:68][CH3:69])[N:47]=2)=[CH:37][CH:36]=1
Reactant: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CC[PH](=O)O)cc2OC)ncc1C(F)(F)F
Reactant: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Agent: Cn1ccnc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCCl
Product: CNC(=O)c1nc(Br)ccc1Nc1nc(Nc2ccc(CC[PH](=O)OCCCn3cc(B4OC(C)(C)C(C)(C)O4)cn3)cc2OC)ncc1C(F)(F)F
Yield: 16.5 %

Procedure:
(Benzotriazol-1-yloxy)tripyrrolidino-phosphonium hexafluorophosphate (2.24 g, 4.30 mmol) was added to stirring suspension of (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)methylphosphinic acid (Compound 61B, 845 mg, 1.43 mmol), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 362 mg, 1.43 mmol), and 1-methylimidazole (1.37 ml, 17.2 mmol) in 1,2-dichloroethane (31.2 ml) at 60° C. for 16 hrs. The reaction was quenched with water and extracted with EtOAc (3×), dried over sodium sulfate, filtered, and concentrated in vacuo and purified using a Teledyne ISCO Combiflash® Rf system [0→10% MeOH in 1:1 EtOAc/DCM] to afford 194 mg of the title compound as a racemic mixture (16%). MS (ESI): m/z=824.65 [M+H]+. UPLC: tR=1.17 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Cl[CH2:14][CH2:15][N:16]1[C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:19]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:18]=[CH:17]1.O>CN(C=O)C.C(Cl)(Cl)Cl>[C:1]1(=[O:11])[N:5]([CH2:14][CH2:15][N:16]2[C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:19]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:18]=[CH:17]2)[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: ClCCn1cnc(-c2ccccc2)c1-c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCn1cnc(-c2ccccc2)c1-c1ccccc1
Yield: 73 %

Procedure:
Step 2): A mixture of potassium phthalimide (0.21 g, 1.1 mmol) and 1-(2-chloroethyl)-4,5-diphenylimidazole (0.32 g, 1.1 mmol) in dry DMF (10 ml) was heated at 60°-70° C. for 6 hours. The reaction mixture was cooled, diluted with chloroform, poured into water and extracted with chloroform. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (40% ethyl acetate in chloroform) to give 1-(2-phthalimidoethyl)-4,5-diphenylimidazole (73.0%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([I:11])[CH:5]=1.N([O-])=O.[Na+].Cl.[N-:18]=[N+:19]=[N-].[Na+]>O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N+:18]=[N-:19])=[C:6]([I:11])[CH:5]=1
Reactant: COC(=O)c1ccc(N)c(I)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc(N=[N+]=[N-])c(I)c1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a suspension of the 4-amino-3-iodo-benzoic acid methyl ester from Step 1 (1.0 eq) in water (0.36M) was added NaNO2 (1.2 eq). The resulting mixture was cooled to 0° C. and aqueous HCl (6M; 2.5 eq) was added dropwise over 45 min. The mixture was stirred at 0° C. for 4 h, then NaN3 (1.1) dissolved in water (1.0M) was added over 30 min. The final mixture was stirred at room temperature for 1 h and extracted with Et2O (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (Hex:EtOAc; 4:1) afforded the desired compound as a light brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([S:30]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)(=[O:32])=[O:31])=[CH:28][CH:29]=1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CCC(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Product: CCC(=O)[O-]
Product: COc1ccc(S(=O)(=O)Nc2ccc3[nH]c(=O)c4[nH]ccc4c3c2)cc1
Yield: 50.9 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 44 mg (0.21 mmol) of 4-methoxy-benzenesulfonyl chloride. After recrystallization from methanol, 45 mg (53%) of 8-(4-methoxy-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5](Cl)=[N:6][CH:7]=1.BrC1C=N[CH:15]=[C:16]([O:18]C)C=1.[O-]CC.[Na+].C(O)C>O>[Br:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[C:5]([O:18][CH2:16][CH3:15])=[N:6][CH:7]=1
Reactant: COc1cc(Br)cnc1Cl
Reactant: COc1cncc(Br)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ncc(Br)cc1OC

Procedure:
As shown in step 3(b)-i of Scheme 3(b), 5-bromo-2-chloro-3-methoxypyridine (1.0 g, 4.5 mmol, prepared in the same manner as Compound 2003 in Example 2 starting with 3-bromo-5-methoxypyridine) was treated with a sodium ethoxide/ethanol solution (5.05 mL, 21% w/v, 13.5 mmol) and the reaction mixture microwave irradiated at 100° C. for 20 minutes. Water was added and the ethanol evaporated under reduced pressure. The resulting aqueous solution was extracted with DCM and ether, followed by drying the combined extracts over MgSO4. After filtration, removal of the volatiles under reduced pressure provided 5-bromo-2-ethoxy-3-methoxypyridine (Compound 2011), 0.72 g, 69% yield): ESMS (M+H) 232.32/234.23. As shown in step 3(b)-ii of Scheme 3(b), Compound 2012 (ESMS (M+H) 218.32/220.23) was prepared in the same manner as Compound 2011, using sodium methoxide in methanol instead of sodium ethoxide in ethanol.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:20]=3)[N:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:14]=2)C=CC=CC=1.[N:31]1[CH:36]=[CH:35][C:34]([O:37][C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[CH:33][CH:32]=1>C1COCC1>[C:15]([C:13]1[CH:14]=[C:10]([NH:9][C:8]([NH:44][C:41]2[CH:40]=[CH:39][C:38]([O:37][C:34]3[CH:35]=[CH:36][N:31]=[CH:32][CH:33]=3)=[CH:43][CH:42]=2)=[O:30])[N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:20]=2)[N:12]=1)([CH3:17])([CH3:18])[CH3:16]
Reactant: Nc1ccc(Oc2ccncc2)cc1
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2cccc(OCCCO)c2)n1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(Oc3ccncc3)cc2)n(-c2cccc(OCCCO)c2)n1
Temperature: 60 °C

Procedure:
To a solution of 3-[3-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-propan-1-ol (400 mg, 1.38 mmol) and phenyl chloroformate (324 mg, 2.07 mmol) in THF (14 mL) was added cesium carbonate (673 mg, 2.07 mmol). The mixture was stirred at room temperature for 4 h, additional phenyl chloroformate (108 mg, 0.69 mmol) was added, and then the mixture was stirred for an additional two hours. The reaction mixture was washed with saturated NaHCO3 (3×30 mL), water, brine, dried (Na2SO4), and evaporated at reduced pressure to give the crude carbamate intermediate {5-tert-butyl-2-[3-(3-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-carbamic acid phenyl ester (500 mg). Step 2. To a solution of {5-tert-butyl-2-[3-(3-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-carbamic acid phenyl ester (200 mg, 0.49 mmol) in THF was added 4-(pyridin-4-yloxy)-phenylamine (109 mg, 0.59 mmol). The reaction mixture was heated at 60° C. for 16 h. The reaction mixture was cooled to room temperature, concentrated at reduced pressure, and the residue was dissolved in DMF and methanol. The product was isolated by preparative HPLC, and the HPLC fraction containing the desired product was concentrated at reduced pressure and then partitioned between EtOAc (20 mL) and saturated aq Na2CO3 (10 mL). The organic layer was dried over Na2SO4 and evaporated to give 1-{5-tert-butyl-2-[3-(3-hydroxy-propoxy)-phenyl]-2H-pyrazol-3-yl}-3-[4-(pyridin-4-yloxy)-phenyl]-urea (51.3 mg, 21%). 1H-NMR (DMSO-d6) δ 7.50 (d, 2H), 7.10 (m, 5H), 6.90 (d, 2H), 6.70 (m, 3H), 6.40 (s, 1H), 4.0 (t, 2H), 3.60 (t, 3H), 1.80 (m, 2H), 1.30 (s, 9H); MS LC-MS [M+H]+=502.1, RT=2.36 min.
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>ClCCl.C(N(CC)CC)C>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[S:1][CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13]
Reactant: OCc1ccccc1S
Reactant: C=CC(=O)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCSc1ccccc1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a stirring solution of 2-mercaptobenzyl alcohol (1.00 g, 7.10 mmol) in dichloromethane (20 mL) at 0° C. was added methyl acrylate (0.70 mL, 7.70 mmol) followed by triethylamine (50 μL, 0.35 mmol). The mixture was allowed to warm to room temperature and stir for 4 h, at which point the solvent was removed with a rotary evaporator. The residue was subjected to column chromatography on silica gel (0-10% ethyl acetate in dichloromethane), affording 1.40 g (86%) of methyl 3-(2-hydroxymethylphenylthio)propionate. 1H NMR (CDCl3) δ 2.63 (t, 2, J=7), 3.18 (t, 2, J=7), 3.68 (s, 3), 4.79 (s, 2), 7.27 (m, 2), 7.43 (m, 2).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:12][CH:13]=2)[N:8]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[N:7]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1nn(C2CCCCO2)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C2CCCCO2)c2cc(OCc3ccccc3)ccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ethyl6-hydroxy-1-(tetrahydro-2H-pyran-2-yl)-indazole-3-carboxylate (148 mg) which can be prepared according to the method described in Reference example 20, etc. was dissolved in dehydrated DMF (5.2 mL; manufactured by Kanto Chemical Co., Inc.), added with potassium carbonate (227 mg; manufactured by Sigma-Aldrich Co.) and benzyl bromide (73.6 μL; manufactured by Wako Pure Chemical Industries, Ltd.), followed by stirring for overnight at 60° C. After cooling to room temperature, the reaction solution was added to water, and then extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with ethyl acetate, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography “COLUMN-A”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (187 mg).
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:21]([O:23]C)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20].C1COCC1.Cl>CO.O>[Br:3][C:4]1[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Sodium hydroxide (32.6 mL, 65.19 mmol) was added to a stirred suspension of methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (8 g, 21.73 mmol) dissolved in MeOH (42 mL) and THF (21 mL) at 0° C. The resulting suspension was stirred at room temperature for 1 h. MeOH (60 mL), THF (10 mL) and water (10 mL) were then added to help stirring. Upon completion, the reaction was cooled to 0° C. and HCl 2N was added to the suspension until pH 2. The solid was collected by filtration, washed with water, AcOEt, diethyl ether and dried with P205 under vacuum at 50° C. to give 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (7.0 g, 91%). Mass Spectrum: m/z [M+H]+=354.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:7]=[C:6]2[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C[O:26][C:27](=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34]Br)[CH:29]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]1[CH:18]=[CH:17][S:16][CH:15]=1)[CH:7]=[C:6]2[CH:19]1[CH2:24][CH2:23][N:22]([CH2:34][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:27]([OH:36])=[O:26])[CH2:21][CH2:20]1
Reactant: COc1ccc2c(c1)c(C1CCNCC1)cn2CCc1ccsc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: COc1ccc2c(c1)c(C1CCN(Cc3cccc(C(=O)O)c3)CC1)cn2CCc1ccsc1

Procedure:
This compound was prepared following the procedure described in example 13 (part D) starting with 1.7 g (5 mmol) of 5-methoxy-3-piperidin-4-yl-1-(2-thiophen-3-yl-ethyl)-1H-indole and 1.3 g (5.5 mmol) of 3-bromomethyl-benzoic acid methyl ester. After standard work-up, 0.8 g (34% of yield) of the expected acid were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:29][C:30]1[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)[CH2:10][CH2:11][C:12]([NH:14][NH:15][C:16]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][C:22]([F:28])=[CH:21]2)=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:49])=CC=1>C1COCC1.C(Cl)Cl>[F:28][C:22]1[N:23]=[CH:24][C:25]2[C:20]([CH:21]=1)=[CH:19][C:18]([C:16]1[S:49][C:12]([CH2:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:29][C:30]3[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)=[N:14][N:15]=1)=[CH:27][CH:26]=2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)NNC(=O)c1ccc2cnc(F)cc2c1)Cc1ccc(C(F)(F)F)nc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc3cnc(F)cc3c2)s1)Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 84.7 %

Procedure:
A mixture of (R)—N′-(4-(tert-butyloxycarbonylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentanoyl)-3-fluoroisoquinoline-6-carbohydrazide (108 mg, 207 μmol) and Lawesson's reagent (101 mg, 249 μmol) in THF (2 mL) was heated in a Biotage® microwave reactor at 100° C. for 10 minutes. The mixture was diluted with DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 2-8% MeOH/DCM) providing tert-butyl (R)-4-(5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (96 mg, 88%) as a white solid. LCMS (API-ES) m/z: 548.1 (M+H+).
Reaction SMILES: [OH-].[K+].[C:3]1([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19](=[S:21])=[S:20].[CH3:22]O>>[C:3]1([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[S:21])[S:20][CH3:22])[CH2:13][CH2:14]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: NCCCN1CCN(c2ccccc2)CC1
Reactant: CO
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Product: CSC(=S)NCCCN1CCN(c2ccccc2)CC1
Reaction time: 3 h

Procedure:
To a solution of potassium hydroxide (2.85 g) in methanol (25 ml) was added 3-(4-phenyl-1-piperazinyl)propylamine (11.1 g) and thereto was added carbon disulfide (3.85 g) under ice cooling over a period of 10 minutes. The resulting mixture was stirred for 3 hours under ice cooling. The reaction mixture was evaporated under reduced pressure. The residual oil was dissolved in water (40 ml) and washed with diethyl ether. The washed aqueous layer was ice-cooled and thereto was added methyl iodide (7.2 g) with stirring. The resulting mixture was stirred for 2 hours under ice-cooling and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and then evaporated to give methyl N-[3-(4-phenyl-1-piperazinyl)propyl]dithiocarbamate (12.9 g), mp 75° to 79° C.