Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C@:11]1([C:31]2([OH:35])[CH2:34][CH2:33][CH2:32]2)[CH2:15][C@H:14]([N:16]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[C@@H:17]2[C@H:22]([O:23][CH3:24])[CH2:21][O:20][CH2:19][CH2:18]2)[CH:13]=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:45](Cl)(=[O:47])[CH3:46]>CN(C1C=CN=CC=1)C.ClCCl>[C:45]([O:35][C:31]1([C@@:11]2([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:15][C@H:14]([N:16]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[C@@H:17]3[C@H:22]([O:23][CH3:24])[CH2:21][O:20][CH2:19][CH2:18]3)[CH:13]=[CH:12]2)[CH2:32][CH2:33][CH2:34]1)(=[O:47])[CH3:46]
Reactant: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(O)CCC2)C1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@@H]1COCC[C@@H]1N(C(=O)C(F)(F)F)[C@@H]1C=C[C@@](C(=O)OCc2ccccc2)(C2(OC(C)=O)CCC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
To a stirred solution of 3.58 g (7.2 mmol) of 1,5-anhydro-3-{[(1S,4R)-4-[(benzyloxy)carbonyl]-4-(1-hydroxycyclobutyl)cyclopent-2-en-1-yl](trifluoroacetyl)amino}-2,3-dideoxy-4-O-methyl-D-erythro-pentitol, 1.6 mL (9.2 mmol) of diisopropylethylamine, and 100 mg (0.82 mmol) of DMAP in 10 mL of dichloromethane was added dropwise 5.1 mL (72 mmol) of acetyl chloride. The solution was stirred at ambient temperature for 18 h, then cooled in ice and quenched with aqueous NaHCO3. The aqueous phase was extracted with additional dichloromethane, and the combined organic phases dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 8-10% ethyl acetate in dichloromethane provided 2.63 g (68%) of the title compound as a viscous yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35-1.48 (m, 1H) 1.54-1.61 (m, 1H) 1.82-1.94 (m, 1H) 1.88 (s, 3) 2.17-2.26 (m, 1H) 2.34 (dd, J=14.7, 9.9 Hz, 1H) 2.43-2.64 (m, 5H) 3.32 (d, J=12.6 Hz, 1H) 3.37-3.43 (m, 1H) 3.43 (s, 3H) 3.46-3.55 (m, 1H) 3.84-3.94 (m, 1H) 4.09-4.15 (m, 1H) 4.19 (d, J=13.0 Hz, 1H) 4.98-5.05 (m, 1H) 5.08 (d, J=12.3 Hz, 1H) 5.23 (d, J=12.3 Hz, 1H) 5.75 (dd, J=5.8, 2.0 Hz, 1H) 6.16 (dd, J=5.8, 2.4 Hz, 1H) 7.28-7.43 (m, 5H). TLC Rf 0.39 (10% ethyl acetate-dichloromethane). LC-MS ES+ 540.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=1.FC(F)(F)S(O[C:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=1[CH3:32])(=O)=O>>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([C:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C:27]=2[CH3:32])=[CH:8][CH:9]=1
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)CCCC1
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COC(=O)c1ccc(C2=C(C)CCCC2)cc1

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester of Step A (2.0 g, 7.63 mmol) and a mixture of 2-methyl-cyclohex-1-en-1-yl trifluoromethanesulfonate and 6-methyl cyclohex-1-en-1-yl trifluoromethanesulfonate (2.24 g, 9.16 mmol, approximately 5:1 ratio) were reacted in the manner of Example 1, Step F. Purification by preparative HPLC (Primesphere 5 silica, 5% methyl tert-butyl ether in hexane) afforded the title compound as an amorphous white solid.
Reaction SMILES: C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[NH:22][CH:23]=1.O[CH2:26][C:27]1([CH3:31])[CH2:30][S:29][CH2:28]1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[N:20][C:21](=[O:24])[N:22]([CH2:26][C:27]2([CH3:31])[CH2:30][S:29][CH2:28]2)[CH:23]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: CC1(CO)CSC1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: CC1(Cn2cc(Cl)cnc2=O)CSC1
Temperature: 100 °C
Yield: 7.9 %

Procedure:
N,N-Dimethylformamide dineopentyl acetal (2.72 ml) was added to a stirred suspension of 5-chloropyrimidin-2-one (789 mg) and 3-hydroxymethyl-3-methylthietane (1.000 g) in dry N,N-dimethylformamide (15 ml) under nitrogen and the mixture was then heated at 100° C. After 42.5 h the reaction mixture was evaporated and the resulting black residue was dissolved in ethyl acetate (300 ml), washed with water (3×70 ml), dried (MgSO4) and evaporated to a dark brown gum. Trituration of the gum with diethyl ether gave a pale brown solid which was crystallised from ethyl acetate to give cream crystals of the title pyrimidinone (110 mg), m.p. 200°-202° C., νmax (nujol) 1663, 1510 cm-1 (C=O), 1612, 1582 cm-1 (C=C, C=N).
Reaction SMILES: [Cl:1][C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.O.[NH2:15][NH2:16]>C(O)C>[Cl:1][C:2]1[C:11]([NH:15][NH2:16])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:13])[CH:8]=2)[N:3]=1
Reactant: Clc1ccc2nc(Cl)c(Cl)nc2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNc1nc2cc(Cl)ccc2nc1Cl

Procedure:
A mixture consisting of 23 g. (0.10 mole) of 2,3,6-trichloroquinoxaline and 11 g. (0.22 mole) of hydrazine hydrate in 500 ml. of ethanol was stirred at room temperature (~20° C.) overnight (~16 hours). The precipitate which formed was separated by filtration and washed with ethanol to ultimately afford 22.2 g. (97%) of pure 2,6-dichloro-3-hydrazinoquinoxaline, m.p. <250° C.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]3[N:22]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][C:36]([F:39])([F:38])[F:37])[N:23]=[CH:24][C:25]=3[CH:26]3[CH2:28][CH2:27]3)=[CH:15][C:14]=2[CH3:40])[CH3:12])=[CH:6][C:5]=1[O:41][CH3:42].[OH-].[Na+].C1COCC1.Cl>O.CO>[CH:26]1([C:25]2[CH:24]=[N:23][N:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][C:36]([F:37])([F:38])[F:39])[C:21]=2[CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([N:11]([CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([O:41][CH3:42])[CH:6]=3)[CH3:12])=[C:14]([CH3:40])[CH:15]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1ccc(CN(C)c2ccc(OCc3c(C4CC4)cnn3-c3ccccc3OC(F)(F)F)cc2C)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(CN(C)c2ccc(OCc3c(C4CC4)cnn3-c3ccccc3OC(F)(F)F)cc2C)ccc1C(=O)O
Yield: 96.1 %

Procedure:
A mixture of 4-[({4-[4-cyclopropyl-2-(2-trifluoromethoxy-phenyl)-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-methyl-amino)-methyl]-2-methoxy-benzoic acid methyl ester (0.30 g, 0.51 mmol), sodium hydroxide (5 N, 0.5 mL), THF (3 mL) and methanol (3 mL) is heated to reflux for 1 h. The reaction is cooled and acidified with 5 N HCl, then diluted with water and extracted with ethyl acetate. The combined organic layers are washed with brine and dried over MgSO4 to give the tile compound (285 mg, 97%) as an off-white foam. LC-ES/MS m/e 582.0 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[NH2:33][CH2:34][CH:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[C:10]([C:5]1[N:6]=[C:7]([CH2:8][CH3:9])[C:2]([NH:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)=[N:3][C:4]=1[NH:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[CH:16][CH:15]=1)(=[O:11])[NH2:12]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)cc2)nc1NCC1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 5-chloro-6-ethyl-3-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazine-2-carboxamide (200 mg), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (300 μL), diisopropylethylamine (240 μL), and N-methylpyrrolidone (0.8 mL) was reacted in a microwave reaction device at 160° C. for 2 hours. The mixture was subjected to liquid separation with ethyl acetate and water, and the organic phase was dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was washed with diisopropyl ether to obtain tert-butyl 4-({[5-carbamoyl-3-ethyl-6-({4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]amino}methyl)piperidine-1-carboxylate (195 mg) as a pale yellow solid.
Reaction SMILES: [O:1]([C:8]1[N:13]=[C:12]([CH:14]([C:16]([F:19])([F:18])[F:17])[OH:15])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26](Cl)=[O:27])[C:24]1([CH3:30])[CH3:29].C(N(CC)CC)C>O1CCCC1>[O:1]([C:8]1[N:13]=[C:12]([CH:14]([O:15][C:26]([C@H:25]2[C@@H:23]([CH:22]=[C:21]([Cl:20])[Cl:31])[C:24]2([CH3:30])[CH3:29])=[O:27])[C:16]([F:19])([F:17])[F:18])[CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Reactant: OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OC(c1cccc(Oc2ccccc2)n1)C(F)(F)F
Reaction time: 72 h
Yield: 74.6 %

Procedure:
To a solution of 2.04 g (7.6 mmol) of the 6-phenoxy-α-(trifluoromethyl)-2-pyridinemethanol of Step C and 1.72 g (7.6 mmol) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in 30 ml of dry tetrahydrofuran was added 2.0 ml (14.2 mmol) of triethylamine. The reaction was stirred for 72 hours. The precipitated triethylamine hydrochloride was then filtered off and the filtrate was concentrated under vacuum. The residue was chromatographed through silica gel and then distilled bulb to bulb (bp 155° C., 0.2 mm) to afford 2.61 g (74%) of the title compound as a clear, colorless oil, which was obtained as a mixture of diastereomers as indicated by the 1H NMR spectrum: 1H NMR (CDCl3) δ 1.14, 1.24, 1.26, 1.29 (4×s, 6H), 2.0-2.2 (m, 2H), 6.0-6.2 (m, 2H), 6.90 (d, 1H), 7.1-7.5 (m, 6H), 7.75 (t, 1H); IR (neat) 1742 cm-1.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:14]=[N:15][O:16][C:17]=2[CH3:18])=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]([F:19])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:12])/[C:13](/[C:14]#[N:15])=[C:17](\[OH:16])/[CH3:18])=[CH:6][CH:5]=1
Reactant: Cc1oncc1C(=O)Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C/C(O)=C(\C#N)C(=O)Nc1ccc(OC(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 96.8 %

Procedure:
0.1 mol (28.6 g) of N-(4-trifluoromethoxyphenyl)-5-methylisoxazole-4-carboxamide is dissolved in 100 ml of ethanol and a solution of 0.11 mol (4.4 g) of sodium hydroxide solution in 100 ml of water is added at 20° C. The mixture is stirred for 30 minutes and acidified with concentrated hydrochloric acid after diluting with water. The precipitated crystal magma is filtered off with suction, washed with water and dried in the air. 27.7 g (9.1% of theory) of N-(4-trifluoromethoxyphenyl)-2-cyano-3-hydroxycrotonamide of melting point 171°-176° C. (from ethanol) are thus obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][CH2:14][O:15][C:16](/[CH:18]=[CH:19]/[CH2:20]P(OCC)(OCC)=O)=[O:17].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37]([CH:44]=O)=[CH:36]2)[CH:30]=1>O1CCCC1.CCCCCC>[CH2:14]([O:15][C:16]([CH:18]=[CH:19][CH:20]=[CH:44][C:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:35]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[CH:36]=1)=[O:17])[CH3:13]
Reactant: O=Cc1cn(-c2cccnc2)c2ccccc12
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)C=CC=Cc1cn(-c2cccnc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
A solution of 1.27 ml of diisopropylamine in 25 ml of tetrahydrofuran is cooled to -65° under nitrogen and 5.7 ml of 1.6M n-butyllithium in hexane is added. After 30 minutes at -65°, 2.0 ml of triethyl 4-phosphonocrotonate is added dropwise. The reaction mixture is stirred for 30 minutes before a solution of 2.0 g of N-(3-pyridyl)indole-3-carboxaldehyde in 20 ml of tetrahydrofuran is slowly added while maintaining the temperature less than -60°. When the addition is complete, cooling is suspended and the reaction mixture slowly warms to room temperature at which temperature it is stirred for 4 hours. The solvent is evaporated and the residue is partitioned between 30 ml of methylene chloride and 20 ml of half saturated ammonium chloride solution. The organic phase is washed with 20 ml of water, dried over sodium sulfate and evaporated to give an oil which crystallizes from hot ethyl acetate to yield 3-[4-(ethoxycarbonyl)butadienyl]-N-(3-pyridyl)-indole, m.p. 112°-113°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=3)(O)[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1.S(=O)(=O)(O)O.[OH-].[K+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7](/[CH:11]=[C:12](/[C:15]3[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=3)\[CH3:13])[C:6]3[CH2:22][CH2:23][N:24]([CH3:26])[CH2:25][C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1ccc(C(C)(O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Product: C/C(=C\n1c2c(c3cc(Cl)ccc31)CN(C)CC2)c1ccc(C)nc1
Temperature: 0 °C

Procedure:
1-(8-Chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-2-(6-methylpyridin-3-yl)propan-2-ol (1 g, 2.70 mmol, 1 equiv.) was refluxed with 25% sulfuric acid (7 mL) for 2 h. The reaction mixture was cooled to 5° C. in ice-water bath. KOH (15% aqueous solution) was added dropwise to the reaction mixture until pH 9-10 was achieved. The reaction mixture was extracted with EtOAc (3×10 mL). The combined organic layer was washed with water (10 mL) followed by brine, dried over sodium sulfate and evaporated under vacuum. The crude product was purified by silica gel chromatography (100-200 mesh) using a gradient of MeOH-EtOAc (0-10%) to obtain a mixture of isomers, which were separated by HPLC. 1H NMR (CD3OD, oxalate salt) δ (ppm): 8.70 (s, 1H), 8.05 (d, 1H), 7.55 (s, 1H), 7.40 (d, 1H), 7.35 (m, 2H), 7.20 (m, 1H), 5.0 (m, 2H), 4.50 (m, 2H), 4.25 (m, 1H), 3.70 (m, 2H), 3.10 (s, 3H), 2.80 (m, 2H), 2.60 (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O1CCOCC1>[N:14]1([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:18]=[CH:17][N:16]=[CH:15]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1cn(C2CCNCC2)cn1

Procedure:
The title compound(0.21 g, 0.836 mmoles) from Step C was stirred in 4N HCl in dioxane (5 mL) for 2 h and then evaporated to dryness to give the title compound which was used to couple with the tricylic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:10](I)[C:3]=12.[F:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][C:24]=1B1OC(C)(C)C(C)(C)O1)[N:21]([CH3:34])[CH2:20][CH2:19]2.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:10]([C:24]3[CH:23]=[C:22]4[C:18]([CH2:19][CH2:20][N:21]4[CH3:34])=[CH:17][C:16]=3[F:15])[C:3]=12
Reactant: CN1CCc2cc(F)c(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: CC(C)n1cc(I)c2c(Br)ccnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)n1cc(-c2cc3c(cc2F)CCN3C)c2c(Br)ccnc21
Temperature: 60 °C
Yield: 57 %

Procedure:
To a stirred suspension of 4-bromo-3-iodo-1-isopropyl-1H-pyrrolo[2,3-b]pyridine (D10) (1.500 g, 4.11 mmol), 5-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (1.367 g, 4.93 mmol), bis(triphenylphosphine)palladium(II) chloride (0.288 g, 0.411 mmol), 2M sodium carbonate aq. solution. (20.55 mL, 41.1 mmol) in ACN (10 mL), DMF (10 mL) and DCM (5 mL) at RT was degassed under nitrogen for 10 mins. The reaction mixture was heated to 60° C. under nitrogen atmosphere for an hour. The reaction mixture was cooled to RT and partitioned between ethyl acetate/water (ca. 50 mL each). The aqeuous layer was separated and extracted with ethyl acetate (ca. 30 mL twice). The combined organic layer was dried over MgSO4 and solvent removed in vacuo. The residue was purified using silica chromatography (eluted with 0-20% ethyl acetate/cyclohexane) to afford the title compound (910 mg). LCMS (A): m/z (M+H)+ 388/390, C19H19BrFN3 requires 387/389 (acidic).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14](Cl)=[O:15].C1(C)C=CC=CC=1.[CH2:24]([OH:36])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].Cl>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:9])[CH3:10])[C:5]([OH:12])=[CH:4][C:3]=1[CH2:13][C:14]([O:36][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:15]
Reactant: Cc1cc(C(C)(C)C)c(O)cc1CC(=O)Cl
Reactant: CCCCCCCCCCCCO
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCOC(=O)Cc1cc(O)c(C(C)(C)C)cc1C
Reaction time: 8 h
Yield: 84.9 %

Procedure:
Into a 500-ml four-necked flask, were charged 24.1 g of 2-methyl-4-t-butyl-5-hydroxyphenylacetyl chloride, 300 ml of toluene and 50 ml of pyridine. After replacing air in the reactor by nitrogen, 18.7 g of dodecyl alcohol was added to the mixture at 30° to 40° C., and then the reaction was continued at 30° to 40° C. for about 8 hours. After completion of the reaction, pyridine was neutralized with diluted hydrochloric acid, and the reaction mixture was washed with water, dried over anhydrons sodium sulfate and then freed from the solvent under reduced pressure to obtain 33.2 g (85% yield) of viscous dodecyl 2-methyl-4-t-butyl-5-hydroxyphenylacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][O:12][CH3:13])[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:13][O:12][CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:24]([C:20]2[S:19][CH:23]=[CH:22][CH:21]=2)(=[O:26])=[O:25])[CH:7]=[C:8]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cc2cccc(N)c2n1COC
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2n1COC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.6 %

Procedure:
To a mixture of ethyl 7-amino-1-(methoxymethyl)-1H-indole-2-carboxylate (0.70 g) and pyridine (8 mL) was added thiophene-2-sulfonyl chloride (0.57 g) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (1.03 g, yield 93%) was obtained as a yellow oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [CH:1](NC(C)C)(C)[CH3:2].[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C:21](=[O:22])[CH2:20][C@H:19]([OH:23])[C@@H:18]2[CH3:24])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12].ICC.C(O)(=O)C>C1COCC1.O>[Cl:8][C:9]1[CH:16]=[C:15]([N:17]2[C@@H:18]([CH3:24])[C@@H:19]([OH:23])[C@H:20]([CH2:1][CH3:2])[C:21]2=[O:22])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]
Reactant: CC(C)NC(C)C
Reactant: C[C@H]1[C@@H](O)CC(=O)N1c1ccc(C#N)c(Cl)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H]1C(=O)N(c2ccc(C#N)c(Cl)c2)[C@@H](C)[C@H]1O
Temperature: -78 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
A solution of diisopropylamine (0.150 mL) in THF (8 mL) was cooled to −78° C., and n-butyllithium-hexane solution (0.650 mL, 1.6 mol/L) was added dropwise. After the completion of the dropwise addition, the mixture was stirred at −78° C. for 1 hr. Subsequently, a solution of 2-chloro-4-[(2S,3S)-3-hydroxy-2-methyl-5-oxopyrrolidin-1-yl]benzonitrile (100 mg) in THF (2.0 mL) was added dropwise, and the mixture was further stirred at −78° C. for 1 hr. Iodoethane (0.150 mL) was added dropwise at −78° C., and the mixture was further stirred at −78° C. to −30° C. for 1 hr. Acetic acid (1.0 mL) was added to the reaction mixture, and the mixture was warmed to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=20/1→1/4) to give the title compound as a colorless solid (yield: 6.7 mg, 6.0%).
Reaction SMILES: [ClH:1].[Cl:2][C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH:17]([OH:24])[CH2:18][NH:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:7][CH:8]=1.O.[NH2:26][NH2:27]>ClCCl>[ClH:2].[ClH:1].[C:20]([NH:19][CH2:18][CH:17]([OH:24])[CH2:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:6]1[N:5]=[N:4][C:3]([NH:26][NH2:27])=[CH:8][CH:7]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: NN
Reactant: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(Cl)nn1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)NCC(O)COc1ccccc1-c1ccc(NN)nn1

Procedure:
A stirred mixture of 3-chloro-6-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]pyridazine hydrochloride (0.3 g.) and hydrazine hydrate (3 ml.) was heated under reflux for 50 minutes. After cooling, dichloromethane was added and this mixture was extracted with water, the dichloromethane was removed by evaporation and the residue was treated with a mixture of n-propanol (1.2 ml.) and concentrated hydrochloric acid (0.13 ml.) to give 3-[2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-6-hydrazinopyridazine dihydrochloride, m.p. 163°-168°.