Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH2:9][C:10]1[N:15]=[C:14]([NH2:16])[N:13]=[C:12]([NH2:17])[C:11]=1[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])C1C=CC=CC=1.[BrH:26]>C(O)(=O)C>[NH2:16][C:14]1[N:13]=[C:12]([NH2:17])[C:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[C:10]([CH2:9][Br:26])[N:15]=1
Reactant: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(COCc2ccccc2)n1
Reactant: Br
Solvent: CC(=O)O
Product: Nc1nc(N)c(-c2ccc(Cl)cc2Cl)c(CBr)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
2,4-Diamino-6-benzyloxymethyl-5-(2,4-dichlorophenyl)pyrimidine (Example 26) (6.5 g) was dissolved in a 47% solution of hydrobromic acid in acetic acid (75 ml) and the mixture stirred and heated at 100° C. for 6 hours. After standing at room temperature overnight the dihydrobromide salt was filtered off, washed with ether and dried in vacuo, 6 g. To a stirred solution of the dihydrobromide salt (0.43 g) in dimethylsulphoxide (4 ml) was added dropwise a solution of sodium bicarbonate (0.84 g) in water (10 ml). After 30 minutes the precipitate was filtered off washed with water then ether and dried in vacuo, 0.26 g, mp.>270° C. (decomposes).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][N:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:36])=[CH:31][CH:30]=1>>[C:24]([C:10]1[C:9]([CH:7]([NH:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]([NH:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[O:36])=[CH:33][CH:34]=2)[CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][N:15]=2)[N:11]=1)([CH3:25])([CH3:26])[CH3:27]
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)c1nn(-c2ccc(C(F)(F)F)cn2)cc1C(O)C1CCCCC1
Product: CC(C)(C)c1nn(-c2ccc(C(F)(F)F)cn2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Yield: 15.5 %

Procedure:
Using cyclohexyl{3-tert-butyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazol-4-yl}methanol (0.53 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.32 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (0.12 g, 15%) was obtained as a white solid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl.O>O1CCCC1>[I:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]([CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc(S(=O)(=O)Nc2ccccc2I)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N(COCC[Si](C)(C)C)c2ccccc2I)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred suspension of sodium hydride (1.17 g, 29.25 mmol, 60% in oil) in anhydrous tetrahydrofuran (40 mL), which had been cooled to 0° C., was added N-(2-iodophenyl)-4-methoxybenzenesulfonamide (9.36 g, 19.6 mmol) in tetrahydrofuran (20 mL). After the addition was complete, the cooling bath was removed and the mixture stirred at room temperature for 90 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (4.25 g, 25.5 mmol) in tetrahydrofuran (20mL) was added dropwise and the reaction mixture stirred for an additional 16 hours. Water (10 mL) was added and the mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with a saturated, aqueous sodium chloride solution. After drying over anhydrous magnesium sulfate, the organic phase was filtered and the filtrate was evaporated in vacuo to yield the crude title compound as a colorless oil. Purification by silica gel chromatography by elution with hexane-ethyl acetate (10:1) provided the title compound as a colorless oil. Trituration with hexane provided the title compound as a white solid (8.55 g, 16.5 mmol, 84%), m.p. 69-70° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]2)=[N:23][CH:24]=1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:2]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:26]2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(N)cn2)C1
Reactant: O=C(c1cnc2ccc(Cl)nc2c1Cl)C1CC1
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Cl)nc34)cn2)C1
Yield: 76.5 %

Procedure:
Following general procedure I, 4,6-dichloro-1,5-naphthyridin-3-yl(cyclopropyl) methanone (400 mg, 1.5 mmol) was reacted with (R)-tert-butyl [1-(5-aminopyridin-2-yl) piperidine-3-yl]carbamate (550 mg, 1.9 mmol) to afford the product (600 mg, 76%) as an orange foam: ESI MS m/z 523 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2=[N+:6]([O-])[CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.O=P(Cl)(Cl)[Cl:13].[NH4+].[OH-]>>[Cl:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1cccc2cc[nH]c21
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccnc2[nH]ccc12
Temperature: 125 °C

Procedure:
4-chloro-7-azaindole 24 was synthesized by reacting 1H-Pyrrolo[2,3-b]pyridine 7-oxide 23 with a chlorinating agent (e.g. POCl3) neat as described by Schneller, S. W.; Luo, Jiann-Kuan. J. Org. Chem. 1980, 45:4045-4048. The resulting solution after heating for 3-5 h at elevated temperatures (100-150° C.) was neutralized with a base (e.g. NH4OH) until a solid precipitated. The solid was isolated by filtration.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=2)[NH:4][N:3]=1.FC(F)(F)C(O)=O.C(Cl)Cl>>[CH3:1][C:2]1[C:10]2[C:5](=[C:6]([CH:15]([O:17][CH2:18][C:19]3([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)[CH3:16])[CH:7]=[C:8]([C:11]([F:13])([F:14])[F:12])[CH:9]=2)[NH:4][N:3]=1
Reactant: Cc1n[nH]c2c(C(C)OCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2c(C(C)OCC3(c4ccccc4)CCNCC3)cc(C(F)(F)F)cc12

Procedure:
(±)-tert-Butyl 4-((1-(3-methyl-5-(trifluoromethyl)-1H-indazol-7-yl)ethoxy)methyl)-4-phenylpiperidine-1-carboxylate (62 mg, 0.12 mmol) was treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvent was evaporated to afford 42 mg (77%) as a clear oil. 1H-NMR (CDCl3, 500 MHz) δ 7.82 (s, 1H), 7.37-7.40 (m, 2H), 7.29-7.32 (m, 3H), 7.19 (m, 1H), 4.55 (q, J=6.7 Hz, 1H), 3.41 (q, J=8.9 Hz, 1H), 3.30 (d, J=8.9 Hz, 1H), 2.87-2.93 (m, 2H), 2.68-2.84 (m, 2H), 2.55 (s, 3H), 2.10-2.25 (m, 2H), 1.81-1.93 (m, 2H), 1.42 (m, 3H); 13C-NMR (126 MHz, CDCl3) δ ppm 143.8, 143.6, 139.2, 128.7, 127.3, 127.1, 126.7, 124.9 (q, J=272 Hz), 122.9, 122.4 (q, J=32.6 Hz), 119.8, 117.4, 78.3, 50.5, 42.6, 41.5, 33.5, 22.0, 11.9. Mass spec.: 418.19 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][NH:30][CH3:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][NH:30][CH3:31])=[CH:4][CH:3]=1
Reactant: CNCCCl
Reactant: COc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: CNCCn1cc(C(=O)N2CCN(c3ccccc3OC)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperazin-1-yl]-methanone (prepared herein) with (commercially available) (2-chloro-ethyl)-methyl-amine gave the title compound.
Reaction SMILES: [CH2:1]([CH:4]([C:8]1[N:13]2[N:14]=[C:15]([CH3:17])[CH:16]=[C:12]2[N:11]=[C:10]([CH3:18])[CH:9]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[I:19]N1C(=O)CCC1=O>C(#N)C.ClCCl>[CH2:1]([CH:4]([C:8]1[N:13]2[N:14]=[C:15]([CH3:17])[C:16]([I:19])=[C:12]2[N:11]=[C:10]([CH3:18])[CH:9]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCC(CCC)c1cc(C)nc2cc(C)nn12
Solvent: ClCCl
Solvent: CC#N
Product: CCCC(CCC)c1cc(C)nc2c(I)c(C)nn12
Temperature: 25 °C
Yield: 236.4 %

Procedure:
Dissolve 7-(1-propyl-butyl)-2,5-dimethyl-pyrazolo[1,5-a]pyrimidine (3.08 g, 12.5 mmol) in anhydrous acetonitrile (25 mL) and add 6 portions (0.70 g each) of N-iodosuccinimide (4.2 g, 18.7 mmol) at 10 minute intervals. Stir over the weekend at room temperature. Strip off the acetonitrile and dilute the oil with dichloromethane (100 mL). Wash with saturated ammonium chloride solution (2×50 mL). Collect the organic phase, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure to yield a dark red oil. Purify the oil using flash chromatography, eluting with 100% hexane/0% (20% ethyl acetate/hexane) to 0% hexane/100% (20% ethyl acetate/hexane) in a step gradient of 50% increments to give an orange oil (10.97 g, 87%).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O-:11].[Na+]>CN(C)C=O>[CH3:10][O:11][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: COc1cccnc1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccnc1OC
Yield: 29 %

Procedure:
The 2-chloro-3-methoxypyridine (2) (13 g, 90.6 mmol), from Step I, was stirred with 3-equivalents of sodium methoxide (14.7 g, 271.8 mmol) in dimethylformamide (100 mL) at 100° C. until completion of the reaction. The reaction mixture was then quenched with water and extracted with dichloromethane. The combined extracts were washed with water, concentrated and distilled (74° C.; 5 mm Hg) to give the product, 2,3-dimethoxypyridine (3), as a clear oil (7 g; 29% yield for two steps).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]([CH2:44][CH3:45])[CH2:20][C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([O:42]C)=[O:41])[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:30])[CH2:25][C:26](=[O:28])[OH:27])=[O:22])=[O:18])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].Cl>CO.O>[C:1]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][C:17]([N:19]([CH2:44][CH3:45])[CH2:20][C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([OH:42])=[O:41])[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:30])[CH2:25][C:26](=[O:27])[OH:28])=[O:22])=[O:18])[CH2:12][CH2:13]1)([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: CCN(CC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1CCCCC1)C(=O)OC)C(=O)CCCC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCN(CC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](CC1CCCCC1)C(=O)O)C(=O)CCCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-[N-[N-(4-(N-BOC-piperidin-4-yl)butanoyl)-N-ethylglycyl]aspartyl(b-benzyl ester)]-b-cyclohexylalanine, methyl ester (1.79 g) is dissolved in methanol (40 ml) and 10% palladium/carbon (0.25 g) is added. The mixture is shaken under hydrogen at 50 psi for about 18 hours. The mixture is filtered through a Celite pad and the filtrate evaporated in vacuo to give N-[N-[N-(4-(N-BOC-piperidin-4-yl)butanoyl)-N-ethylglycyl]aspartyl]-b-cyclohexylalanine, methyl ester. The ester is dissolved in methanol (20 ml) and 1N aqueous sodium hydroxide solution (10 ml) is added. The mixture is stirred at room temperature for about 4 hours, diluted with water (25 ml), and acidified to pH 2 with 1N HCl. The mixture is extracted with ethyl acetate (3×100 ml) and the ethyl acetate solution dried over magnesium sulfate, filtered and evaporated in vacuo to give N-[N-[N-(4-(N-BOC-piperidin-4-yl)butanoyl)-N-ethylglycyl]aspartyl]-b-cyclohexylalanine.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][C@@H:15]2[O:20][C:19]3[C:21]([NH2:26])=[C:22]([NH2:25])[CH:23]=[CH:24][C:18]=3[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.[F:27][C:28]([F:36])([F:35])[C:29]([F:34])([F:33])[C:30](O)=O>C(Cl)Cl>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][CH2:14][CH:15]2[O:20][C:19]3[C:18](=[CH:24][CH:23]=[C:22]4[NH:25][C:30]([C:29]([F:34])([F:33])[C:28]([F:36])([F:35])[F:27])=[N:26][C:21]4=3)[O:17][CH2:16]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc(N)c(N)c3O2)cc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2COc3ccc4[nH]c(C(F)(F)C(F)(F)F)nc4c3O2)cc1

Procedure:
A solution of 1.0 g (2.4 mmole) of [(2R)-7,8-diamino-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate dihydrochloride in 30 mL of pentafluoropropionic acid was refluxed under nitrogen for 6 hours. The mixture was diluted to 400 mL with methylene chloride, washed with 400 mL of water and with 400 mL of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated to a crude foam in vacuum. The crude product was column chromatographed on silica gel with 1% methanol in chloroform and the product fractions combined and concentrated in vacuum to give 0.90 g of the (R)-enantiomer of the title compound as a yellow oil. 1H-NMR (CDCl3): doublet 7.75 δ(2H); doublet 7.3 δ(2H); doublet 7.15 δ(1H); doublet 6.9 δ(1H); multiplet 4.5 δ(1h); doublet of doublets 4.25 δ(1H); multiplet 4.2 δ(2H); doublet of doublets 4.1 δ(1H); singlet 2.4 δ(3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C.Cl.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl[C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=[CH:28][C:27]=1[N+:36]([O-:38])=[O:37]>C(Cl)(Cl)Cl>[N+:36]([C:27]1[CH:28]=[N:29][C:30]2[C:35]([C:26]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:34][CH:33]=[CH:32][CH:31]=2)([O-:38])=[O:37]
Reactant: CCOC(=O)CCCCN
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCCNc1c([N+](=O)[O-])cnc2ccccc12
Reaction time: 4 h
Yield: 99.3 %

Procedure:
Potassium carbonate (66.23 g, 479.3 mmol), triethylamine (167 mL, 1.20 mol), and ethyl 5-aminovalerate hydrochloride (104.4 g, 575.2 mmol) were added to a solution of 4-chloro-3-nitroquinoline (100.0 g, 479.3 mmol) in chloroform (1000 mL) according to the method described in Part B of Example 6. The reaction was run for four hours and provided 151 g of ethyl 5-(3-nitroquinolin-4-ylamino)pentanoate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:23])[C:13]([N:15]([CH3:22])[N:16]=[C:17]([CH3:21])[CH2:18][S:19][CH3:20])=[O:14])[CH3:2].[OH:24]O>CO>[CH2:10]([C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([CH2:1][CH3:2])[C:4]=1[C:12](=[O:23])[C:13]([N:15]([CH3:22])[N:16]=[C:17]([CH3:21])[CH2:18][S:19]([CH3:20])=[O:24])=[O:14])[CH3:11]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CSC
Reactant: OO
Solvent: CO
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.2 %

Procedure:
To a 50 ml volume three-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfanyl-2-propylidene)hydrazine ((4-4)-(1)-39) (5.60 g) and methanol (14 ml) were added, and cooled on ice-bath. 33% of aqueous hydrogen peroxide solution (2.1 g) was added dropwise thereto. Then, the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to chloroform) to give 1.95 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfinyl-2-propylidene)hydrazine ((4-19)-(1)-39).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].[CH3:10][O:11][CH2:12][C:13](Cl)=[O:14]>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:13](=[O:14])[CH2:12][O:11][CH3:10])[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: COCC(=O)Cl
Reactant: C#Cc1cccc(N)c1
Solvent: ClCCl
Product: C#Cc1cccc(NC(=O)COC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a cooled solution of 3-ethynylphenylamine (7.02 g, 60 mmol) in methylene chloride is added a solution of methoxyacetyl chloride (7.8 g, 72 mmol) in methylene chloride (10 mL) dropwise over a period of 30 min at 0° C. After addition, the reaction mixture is allowed to warm-up to room temperature and stirred overnight. The solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is washed with saturated NaHCO3, H2O, dried (MgSO4) and concentrated to afford the title compound as a colorless oil 10.2 g (90%). 1HNMR (CDCl3): δ (ppm) 3.04 (s, 1H,), 3.48 (s, 3H), 3.98 (s, 2H), 7.24 (m, 2H), 7.61 (d, 1H), 7.66 (s, 1H), 8.21 (s, b, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[NH2:35][C:36]([CH3:49])([CH3:48])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:35][C:36]([CH3:49])([CH3:48])[CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])=[O:23])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC(C)(N)CCCNC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)CCCNC(=O)OC(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
To a stirred solution of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.32 mmol) in 6 mL of DMF was added EDCI (123 mmol, 0.64 mmol), DMAP (110 mg, 0.90 mmol) and tert-butyl 4-amino-4-methylpentylcarbamate (139 mg, 0.64 mmol) in one portion at room temperature and the mixture stirred at room temperature for 16 hours. The reaction mixture was poured into 40 mL of water, filtered, the filter cake washed with petroleum ether then dried to give crude tert-butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylpentylcarbamate (75 mg, 46%) as a yellow solid. MS: (M+H)+=510.2.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Br[CH2:11][C:12](=O)[CH3:13]>C(COC)OC.C(O)C>[CH3:13][C:12]1[N:1]=[C:2]2[C:3]([CH:4]=[O:5])=[CH:6][CH:7]=[CH:8][N:9]2[CH:11]=1
Reactant: CC(=O)CBr
Reactant: Nc1ncccc1C=O
Solvent: COCCOC
Solvent: CCO
Product: Cc1cn2cccc(C=O)c2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-aminonicotinaldehyde (92.8 g, 0.76 mol) and bromoacetone (114.5 g, 0.84 mol) in dimethoxyethane (980 ml) is stirred for 2 hours at room temperature and then heated at 65° with stirring for 14 hours.The solid which separates is isolated by filtration, dissolved in 800 ml absolute ethanol and heated under a reflux for 6 hours. The ethanol solvent is removed under reduced pressure and the residue treated with 138ml 6 N hydrochloric acid in 750 ml water for 0.5 hour. The acidic aqueous layer is washed with ether (2×300 ml) and basified with cooling (78 ml) 50% sodium hydroxide and 25 g sodium bicarbonate). The aqueous layer is extracted with dichloromethane. The extracts are combined and dried over anhydrous sodium sulfate. Following filtration, the solvent is removed under reduced pressure to afford 2-methyl-8-formyl-imidazo[1,2-a]pyridine, mp 136°-139.5° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[C@H:9]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH2:8][N:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6]1.Br[CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[OH:1][CH2:2][CH2:3][CH2:4][C@H:5]1[C@H:9]([N:10]([CH2:31][CH2:32][CH:33]([CH3:35])[CH3:34])[S:11]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)(=[O:13])=[O:12])[CH2:8][N:7]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:6]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCCO)[C@H](NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)C1
Reactant: CC(C)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCN([C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1CCCO)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Reaction time: 3.5 h

Procedure:
To a mixture of tert-butyl (3R*,4S*)-3-(3-hydroxypropyl)-4-{[(4-nitrophenyl)sulfonyl]amino}pyrrolidine-1-carboxylate (0.82 g, 1.91 mmol) and 1-bromo-3-methylbutane (0.30 g, 2.0 mmol) in 8 mL DMF, Cs2CO3 (0.93 g, 2.86 mmol) was added and the mixture was stirred at 3.5 hours at 85° C. The mixture was diluted with H2O, extracted with CH2Cl2, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 1→5% MeOH in CH2Cl2 giving the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:6]1=[O:25].C(N(CC)CC)C.[Cl:33][C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39](Cl)=[O:40]>ClCCl>[Cl:33][C:34]1[CH:38]=[CH:37][S:36][C:35]=1[C:39]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([C:17]3=[CH:18][C:19]4[O:23][CH2:22][O:21][C:20]=4[CH:24]=[C:16]3[O:15][CH2:14]2)[C:6]1=[O:25])=[O:40]
Reactant: O=C(Cl)c1sccc1Cl
Reactant: NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21)c1sccc1Cl
Reaction time: 2 h
Yield: 69 %

Procedure:
To a solution of 1′-(3-aminopropyl)spiro[furo[2,3-f]-[1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.05 g, 0.13 mmol) in dichloromethane (4.00 mL) was added triethylamine (0.03 g, 0.26 mmol) and 3-chlorothiophene-2-carbonyl chloride (0.02 g, 0.12 mmol) at 0° C. The mixture was stirred for 2 h, washed with 15% HCl solution and water. The organic layer was dried over MgSO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was dissolved in ethyl acetate, and the product was precipitated with the addition of hexane. The white solid was collected by filtration and dried in vacuo to yield the title compound (0.04 g) in 67% yield: 1H NMR (300 MHz, CDCl3) δ 7.60 (t, 1H), 7.41 (d, 1H), 7.33-7.27- (m, 1H), 7.17 (d, 1H), 7.08-7.03- (m, 1H), 6.93 (t, 1H), 6.49 (s, 1H), 6.11 (s, 1H), 5.95 (m, 2H), 4.90 (d, 1H), 4.65 (d, 1H), 3.96-3.79- (m, 2H), 3.53-3.36- (m, 2H), 2.04-1.93- (m, 2H); 13C NMR (75 MHz, CDCl3) 178.3, 160.6, 156.0, 149.0, 142.4, 141.8, 132.5, 129.4, 129.2, 129.1, 124.2, 123.7, 123.6, 119.2, 108.5, 102.9, 101.6, 93.7, 80.5, 58.3, 37.4, 36.5, 27.3; MS (ES+) m/z 483 (M+1).