Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[O:12]1[CH:14]([CH3:15])[CH2:13]1>>[OH:12][CH:14]([CH3:15])[CH2:13][NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: CC1CO1
Reactant: Nc1cccc(C(F)(F)F)c1
Product: CC(O)CNc1cccc(C(F)(F)F)c1
Yield: 61.5 %

Procedure:
3-Trifluoromethylaniline is reacted with 1,2-epoxy-propane as described in Example 3, Method (b), point (a) to obtain N-(β-hydroxypropyl)-3-trifluoromethyl-aniline with a yield of 61.5%; b.p.: 112°-118° C./0.5 mm Hg.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([C:18]2[CH:22]=[C:21]([NH2:23])[N:20]([C:24]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[N:29]4)[N:19]=2)[CH2:17][CH2:16]1.ClCCl.[OH-].[Na+]>N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:23][C:21]2[N:20]([C:24]3[CH:33]=[CH:32][CH:31]=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[N:29]4)[N:19]=[C:18]([CH:15]3[CH2:17][CH2:16]3)[CH:22]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(C2CC2)nn1-c1cccc2ncccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(C3CC3)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 35 %

Procedure:
A mixture of 4-t-butylbenzenesulfonyl chloride (0.061 g, 0.26 mmol) and 3-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.05 g, 0.20 mmol) in pyridine (1 mL) was heated at 80° C. for 15 h with stirring. After cooling to room temperature, dichloromethane was added to the reaction mixture and washed with 1 M aqueous sodium hydrogen sulfate (1 mL). The aqueous layer was further extracted with dichloromethane (2×5 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude residue was dissolved in methanol (3 mL) and 1 M aqueous sodium hydroxide (1.0 mL, 1.0 mmol) and stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between dichloromethane (3 mL) and 1 M aqueous sodium hydrogen sulfate (3 mL). The phases were separated and the aqueous layer was extracted with dichloromethane (2×5 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.031 g, 0.070 mmol, 35%). 1H NMR (400 MHz, CDCl3) δ 8.84 (d, J=4.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.55-7.51 (m, 5H), 7.41 (s, 1H), 7.39 (s, 1H), 6.94 (d, J=7.2 Hz, 1H), 6.12 (s, 1H), 1.99-1.93 (m, 1H), 1.36 (s, 9H), 1.01-0.92 (m, 2H), 0.84-0.79 (m, 2H); MS: (ES) m/z calculated for C25H27N4O2S [M+H]+ 447.2. found 447.2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:8](S(CCCCl)(=O)=O)[C:9]1[CH:17]=[C:16]([C:18]([O:20]C)=[O:19])[CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:22][CH3:23])(=[O:7])=[O:6].[OH-].[Na+]>CO>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([NH:8][C:9]1[CH:17]=[C:16]([C:18]([OH:20])=[O:19])[CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:22][CH3:23])(=[O:6])=[O:7]
Reactant: CCn1ccc2c(N(S(=O)(=O)CCCCl)S(=O)(=O)CCCCl)cc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1ccc2c(NS(=O)(=O)CCCCl)cc(C(=O)O)cc21
Reaction time: 1 h
Yield: 74.9 %

Procedure:
To a solution of methyl 4-{bis[(3-chloropropyl)sulfonyl]amino}-1-ethyl-1H-indole-6-carboxylate (D236) (1.8 g, 3.6 mmol, 1 equiv) in MeOH (100 ml) was added a 2N aqueous NaOH solution (20 ml, 40 mmol, excess) and the resulting mixture was stirred for 1 h. Most of MeOH was removed in vacuo and the residue partitioned between AcOEt and a 2N aqueous HCl solution. The two layers were separated and the aqueous phase was dried over MgSO4 and concentrated in vacuo to give 4-{[(3-chloropropyl)sulfonyl]amino}-1-ethyl-1H-indole-6-carboxylic acid (D240) (930 mg, 75%) as a brown oil which was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[NH2:19][CH2:20][CH2:21][C:22]([N:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH3:25])=[O:23].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH3:25][N:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22](=[O:23])[CH2:21][CH2:20][NH:19][CH2:6][C:5]1[CH:8]=[C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CN(C(=O)CCN)C1CCCCC1
Reactant: O=Cc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CN(C(=O)CCNCc1cc(Oc2ccccc2)ccc1[N+](=O)[O-])c1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
2-Nitro-5-phenoxy-benzaldehyde (2.14 g, 0.00882 mol) was added to a solution of 3-amino-N-cyclohexyl-N-methyl-propionamide (1.5 g, 0.00882 mol) in 100 mL of 1,2-dichloroethane, and the mixture was stirred at 80° C. for 1 hour. Sodium triacetoxyborohydride (2.87 g, 0.00882 mol) was added at room temperature, and the reaction mixture was stirred for 15 h. Additional sodium triacetoxyborohydride (1 g) was added, and the reaction mixture was stirred another 20 h at room temperature. To the reaction mixture was added 10% aqueous NaOH solution (50 mL), and the mixture was extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered, and concentrated to yield a residue which was purified by column chromatography over silica gel using 97:3 CH2Cl2:MeOH as the eluent. The product containing fractions were combined and evaporated to yield a side product (MW 638). The residue was further purified by column chromatography over silica gel using 97:3 CH2Cl2:MeOH. The product containing fractions were combined and evaporated to yield a residue. The fractions containing impure product were combined and evaporated to yield a second residue, which was purified by silica gel chromatography to yield additional desired product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:21]([S:22][CH2:23][CH2:24][CH3:25])=[CH:20][C:19](=[O:26])[N:18]([CH2:27][CH2:28][CH3:29])[C:17]2=[O:30])=[CH:11][CH:10]=1)#[N:2].[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(Cl)Cl>[CH2:27]([N:18]1[C:19](=[O:26])[CH:20]=[C:21]([S:22][CH2:23][CH2:24][CH3:25])[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:33][N:32]=[N:31][N:2]=3)=[CH:14][CH:13]=2)[C:17]1=[O:30])[CH2:28][CH3:29]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 115 °C
Yield: 48.3 %

Procedure:
A mixture of 1-(2'-cyanobiphenyl-4-yl)methyl-3-propyl-6-propylthiopyrimidine-2,4(1H,3H)-dione (0.77 g), sodium azide (1.8 g) and ammonium chloride (1.48 g) in dimethylformamide (10 ml) was heated at 115° C. for 84 hours. The reaction mixture was diluted with methylene chloride and then the precipitate was filtered. The filtrate was concentrated to dryness in vacuo. The resulting residue was extracted with methylene chloride water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give yellow amorphous powders (0.41 g, 46%).
Reaction SMILES: Cl.Cl.Cl.Cl.Cl.[CH3:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[C:17]([N:19]3[CH:28]([CH3:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)=[CH:24][CH:25]=4)[CH2:20]3)[N:16]=[C:15]([NH2:36])[N:14]=2)[CH2:9][CH2:8]1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>>[CH:37]1([C:40]([N:33]2[CH2:32][CH2:31][CH:30]([C:23]3[CH:22]=[C:21]4[C:26]([CH2:27][CH:28]([CH3:29])[N:19]([C:17]5[CH:18]=[C:13]([N:10]6[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]6)[N:14]=[C:15]([NH2:36])[N:16]=5)[CH2:20]4)=[CH:25][CH:24]=3)[CH2:35][CH2:34]2)=[O:41])[CH2:39][CH2:38]1
Reactant: CC1Cc2ccc(C3CCNCC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: CC1Cc2ccc(C3CCN(C(=O)C4CC4)CC3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 144 starting from 4-(4-methylpiperazin-1-yl)-6-(3-methyl-7-piperidin-4-yl-3,4-dihydroisoquinolin-2(1H)-yl)pyrimidin-2-amine tetrahydrochloride HCl salt (Example 144, Step 3) and cyclopropanecarbonyl chloride. LCMS (M+H)+: m/z=490.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:11])[N:3]=1.Cl.[NH2:13][C@H:14]1[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=2)[CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[C:4]([CH3:11])[N:3]=[C:2]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19](=[O:32])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=3)[CH2:15]2)[N:7]=1
Reactant: N[C@H]1CCN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C1
Reactant: Cc1cc(N(C)C)nc(Cl)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1cc(N(C)C)nc(N[C@H]2CCN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C2)n1
Temperature: 160 °C
Yield: 87.1 %

Procedure:
A mixture of 2-chloro-4-dimethylamino-6-methylpyrimidine (0.20 g), 1-((S)-3-aminopyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone mono hydrochloride (0.38 g), triethylamine (0.30 g), and isopropanol (2.9 mL) was heated at 160° C. in a microwave reaction apparatus for 3.5 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/methanol=95:5) to obtain 1-((S)-3-(4-dimethylamino-6-methylpyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (0.43 g). (2) 1-((S)-3-(4-Dimethylamino-6-methylpyrimidin-2-ylamino)pyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone obtained in (1) was dissolved in ethyl acetate (2.0 mL), followed by addition of a solution (0.58 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred at room temperature for 5 min. The reaction mixture was concentrated under reduced pressure, and the residue was solidified with diisopropyl ether to obtain the title compound (0.10 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[CH3:8].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)[CH3:8]
Reactant: BrCc1ccccc1
Reactant: CCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(OCc2ccccc2)c1
Temperature: 2 °C
Reaction time: 0.83 h
Yield: 92.7 %

Procedure:
To a suspension of potassium carbonate (17 g, 123 mmol) in N,N-dimethylformamide (40 ml) was added a solution of 3-ethyl-phenol (14.8 ml, 123 mmol) in N,N-dimethylformamide (40 ml) at 2° C. under an argon atmosphere. After stirring for 50 min at 2° C., benzyl bromide (14.6 ml, 123 mmol) was added over a period of 15 min at 2° C. The suspension was stirred for additional 30 min at 2° C. and for 12 h at ambient temperature. After adding ice water (250 ml), the solution was extracted two times with diethyl ether. The combined extracts were washed two times with brine and dried over sodium sulfate. Evaporation of the solvent gave a yellow oil which was purified by column chromatography (silica gel, cyclohexane) to yield 24.3 g (114 mmol, 93%) of the title compound as yellow liquid.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)(=[S:3])[NH2:2].[Cl:17][CH2:18][C:19](=O)[CH3:20].Cl>C(O)C>[ClH:17].[CH3:20][C:19]1[N:2]=[C:1]([C@@H:4]2[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5]2)[S:3][CH:18]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=S)C1
Reactant: CC(=O)CCl
Agent: Cl
Solvent: CCO
Product: Cc1csc([C@@H]2CC[C@H](N)C2)n1

Procedure:
To a solution of Example 120B (100 mg, 0.41 mmol) in ethyl alcohol (3 mL) was added chloroacetone (0.036 mL, 0.45 mmol). The reaction mixture was stirred at reflux overnight, then 2 mL of 2N aqueous HCl was and the mixture was stirred at reflux for 4 h. The mixture was concentrated and the residue triturated in diethyl ether to provide the title compound as a 2:1 cis/trans mixture of diastereomers. MS (ESI+) M/Z 145 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][C:21]=1[C:29]([F:32])([F:31])[F:30]>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][C:9]=1[S:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:22]=2)=[S:28])=[CH:7][CH:6]=1
Reactant: Nc1ccc(Sc2ccc3ccccc3n2)cc1
Reactant: FC(F)(F)c1cc(N=C=S)ccc1Cl
Product: FC(F)(F)c1cc(NC(=S)Nc2ccc(Sc3ccc4ccccc4n3)cc2)ccc1Cl
Yield: 55.5 %

Procedure:
2-(4-aminophenylthio)quinoline(3.9 mmoles, 1.0 g) and 4-chloro-3-trifluoromethylphenylisothiocyanate (3.9 mmoles, 0.92 g) were reacted according to procedure A to yield 1.06 g, 56% of the title compound. Mass spec (FD) 490. Calculated for C23H15ClF3 N3S2 : C, 56.38; H, 3.09, N, 8.58. Found: C, 56.60; H, 3.11; N, 8.42.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Li])=[CH:4][N:3]=1.[I:10]I>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([I:10])=[CH:4][N:3]=1
Reactant: [Li]c1cnc(Cl)c(Cl)c1
Reactant: II
Product: Clc1cc(I)cnc1Cl

Procedure:
Briefly, in accordance with the present invention, 2,3-dichloro-5-iodopyridine is prepared by lithiating 5-bromo-2,3-dichloropyridine at a reduced temperature to form 2,3-dichloro-5-lithiopyridine. The 2,3-dichloro-5-lithiopyridine is then reacted with I2 at a reduced temperature to form 2,3-dichloro-5-iodopyridine. The resulting product is then extracted and recovered. 2,3-Dichloro-5-iodopyridine is in the form of a white solid and has a melting point of from 56.5° C. to 57.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[CH3:7][N:8]=[C:9]=[O:10]>CN(C)C=O>[NH2:1][C:2]1[N:3]([C:9]([NH:8][CH3:7])=[O:10])[N:4]=[CH:5][N:6]=1
Reactant: Nc1nc[nH]n1
Reactant: CN=C=O
Solvent: CN(C)C=O
Product: CNC(=O)n1ncnc1N
Yield: 81 %

Procedure:
The synthesis method of Example 1-(3) was applied. 3-Amino-1H-1,2,4-triazole (5.00 g), dimethylformamide (30 ml) and methyl isocyanate (4.0 ml) were used as reagents. The mixture was stirred at room temperature i:or 18 hours and 6.83 g of the resulting solid (yield 81%) was collected by filtration. The obtained solid was recrystallized from ethyl acetate to give colorless transparent crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:8][CH2:7][C:6]2=[O:23].[CH:24](=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH:24](=[C:7]1[C:6](=[O:23])[C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH2:8]1)[CH:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH2:30]1
Reactant: COc1ccc2c(c1)C(=O)CCN2S(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1ccccc1
Product: COc1ccc2c(c1)C(=O)C(=CC1C=CC=CC1)CN2S(=O)(=O)c1ccc(C)cc1
Yield: 62.8 %

Procedure:
By the method of Example 146, 25.0 g (75.5 mmol) of 6-methoxy-1-(p-toluenesulfonyl)-2,3-dihydro-4(1H)quinolinone (J. Am. Chem. Soc., Vol. 71, p. 1901, 1949) and 12.0 g (113 mmol) of benzaldehyde were converted to 20.0 g (63%) of present title product recrystallized from ether-hexane, m.p. 131°-132° C.
Reaction SMILES: CC(C)([O-])C.[C:6]([OH:9])(=[S:8])[CH3:7].[CH2:10]([O:13][C:14]([N:16]1[CH2:20][C@H:19](OS(C)(=O)=O)[CH2:18][C@H:17]1[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][C:28]1=[O:34])=[O:15])[CH:11]=[CH2:12].O>CN(C)C=O>[C:6]([S:8][C@@H:19]1[CH2:20][N:16]([C:14]([O:13][CH2:10][CH:11]=[CH2:12])=[O:15])[C@H:17]([CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][C:28]2=[O:34])[CH2:18]1)(=[O:9])[CH3:7]
Reactant: CC(O)=S
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CN1CCN(C)CC1=O
Agent: CC(C)(C)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN1CCN(C)CC1=O

Procedure:
To a solution of pottasium t-butoxide (1.24 g) in N,N-dimethylformamide (15 ml) was dropwise added thioacetic acid (0.85 ml) under ice cooling with stirring. The mixture was stirred at the same temperature for 30 minutes. To the solution of (2S,4R)-1-allyloxycarbonyl-2-(2-oxo-4-methylpiperazin-1-yl) methyl-4-(methanesulfonyloxy)pyrrolidine (3.19 g) in N,N-dimethylformamide (15 ml) was added the mixture obtained above at ambient temperature with stirring. The mixture was stirred at 80°-90° C. for 1.5 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1 v/v) to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(2-oxo-4-methylpiperazin-1-yl) methylpyrrolidine (3.24 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: CCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f15) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH:15]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([NH:20][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: NC1CCCC1
Product: COc1cccc2cc(C(=O)NC3CCCC3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-Methoxybenzofuran-2-carboxylic acid, and cyclopentylamine to give N-cyclopentyl-7-methoxybenzofuran-2-carboxamide (Compound 299a). Successively, it was formylated to give N-cyclopentyl-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 299b), then compound 299b was reacted with methylamine hydrochloride to give compound 299 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:32].[K+].[K+].OO.CO>CS(C)=O>[CH3:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:24][CH2:23][CH2:22][CH:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:20][CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:32])=[CH:7][N:6]=1
Reactant: Cc1cc(CN2CCCC(c3ccccc3)CC2)ccc1Oc1ccc(C#N)cn1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cc(CN2CCCC(c3ccccc3)CC2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 173.1 %

Procedure:
Using a method similar to Example 371, (±)-6-[2-methyl-4-(4-phenyl-azepan-1ylmethyl)-phenoxy]-nicotinonitrile (compound of example 368) (0.246 g, 0.642 mmol), potassium carbonate (0.0429 g, 0.310 mmol), and 30% hydrogen peroxide Solution (aq) (0.220 mL, 1.94 mmol) in dimethylsulfoxide provide, after ion exchange chromatography (methanol→2 M ammonia/methanol), 0.223 g (87%) of the title compound as a while solid: high resolution mass spectrum (electrospray): m/z calc for C25H25N3O2 402.2182, found 402.2172; 1H NMR (methanol-d4): 8.67 (d, 1H, J=2.0 Hz), 8.36 (dd, 1H, J=2.4, 8.8 Hz), 7.51 (d, 2H, J=8.3 Hz), 7.32-7.22 (m, 4H), 7.20-7.14 (m, 3H), 7.04 (d, 1H, J=8.8 Hz), 3.77 (s, 2H), 2.97 (ddd, 1H, J=3.4, 6.3, 13.2 Hz), 2.92-2.83 (m, 3H), 2.81-2.72 (m, 1H), 2.04-1.76 (m, 6H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][CH:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH3:6].[OH-].[K+].S(OC)(O[CH3:24])(=O)=O>CS(C)=O>[CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][CH:5]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:24])[CH:8]=1)[CH3:6]
Reactant: COS(=O)(=O)OC
Reactant: COC(CC(C)c1c[nH]c2ccccc12)OC
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COC(CC(C)c1cn(C)c2ccccc12)OC
Temperature: 25 °C

Procedure:
(R)-3-(1H-Indol-3-yl)-butanal (236 mg, 1.26 mmol) was dissolved in methanol (15 mL) and treated with trimethyl orthoformate (275 μl, 2.50 mmol) and a catalytic amount of p-TSA. The reaction was stirred at room temperature for 3 hours, at which time H2O (10 mL) was added and the reaction was extracted with ether (3×20 mL). The collected organics were rinsed with brine, dried over Na2SO4, and concentrated in vacuo to provide 3-(3,3-dimethoxy-1-methyl-propyl)-1H-indole (228 mg, 1.17 mmol). 3-(3,3-dimethoxy-1-methyl-propyl)-1H-indole (39.9 mg, 0.171 mmol) was dissolved in a KOH (38.4 mg, 0.684 mmol)/DMSO (2 mL) solution and allowed to stir at 0° C. for 10 min, at which time dimethyl sulfate (32.5 μl, 0.340 mmol) was added and the reaction was allowed to warm to room temperature. The reaction was left to stir at room temperature until it appeared done by TLC. The reaction was quenched with H2O (1 mL) and brought to a neutral pH with dropwise addition of 1M HCl. The solution was extracted with Et2O (3×5 mL), and the collected organics were rinsed with brine, dried over Na2SO4, and concentrated in vacuo to provide 3-(3,3-dimethoxy-1-methyl-propyl)-1-methyl-indole. This crude residual material was dissolved in THF (5 mL) and 1M HCl (1 mL) to give (R)-3-(1-methyl-1H-indol-3-yl)-butanal (1.9 mg, 0.0094 mmol) after preparative TLC (25:75 EtOAc/hexanes). [α]D=−4.1 (c=1.0, CHCl3); reported rotation for (R)-3-(1-methyl-1H-indol-3-yl)-butanal [α]D=−4.2 (c=1.0, CHCl3).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10]/[N:11]=[C:12](\[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])/[C:13]([O:15][CH3:16])=[O:14]>C(Cl)(Cl)(Cl)Cl>[CH3:9][O:10]/[N:11]=[C:12](\[C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:24][Br:1])/[C:13]([O:15][CH3:16])=[O:14]
Reactant: CO/N=C(/C(=O)OC)c1c(C)cccc1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CO/N=C(/C(=O)OC)c1c(C)cccc1CBr
Yield: 10.6 %

Procedure:
A mixture of N-bromosuccinimide (11 g, 0.596 mol), 2,2-azobisisobutyronitrile (89 mg, 0.540 mol) and methyl E-2,6-dimethylphenylglyoxylate O-methyl oxime (12 g, 0.542 mol) in CCl4 (200 mL) was refluxed for 4 hours under 300 W lamp. The cooled reaction mixture was filtered, concentrated in vacuo to give the product (17.2 g, 100%) which was used in the next reaction without further purification: