Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[CH3:14][S:15]([N:1]1[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6]1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: C1=CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=CCC1
Reaction time: 2.5 h

Procedure:
To a stirred solution of 1,2,3,6-tetrahydropyridine (1.5 g, 18.04 mmol, Aldrich) and triethylamine (36.12 mmol, 5.05 mL) in methylene chloride (60 mL) at 0° C., methane sulfonyl chloride (1.82 mL, 23.45 mmol, Aldrich) was added and the mixture was stirred for 2.5 hours. The reaction was quenched with water and the mixture was extracted with methylene chloride. The extracts were dried with MgSO4 and the solvent was removed under reduced pressure to give the desired product as an off-white solid. 2.20 g, 76%. MS (ES) MH+=162.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]([Si:13]([CH3:29])([CH3:28])[O:14][C:15]1[CH:23]=[C:22]2[C:18]([CH:19]=[C:20]([C:24]([O:26][CH3:27])=[O:25])[NH:21]2)=[CH:17][CH:16]=1)([CH3:12])[CH3:11]>CN(C=O)C>[Br:8][C:19]1[C:18]2[C:22](=[CH:23][C:15]([O:14][Si:13]([C:10]([CH3:9])([CH3:11])[CH3:12])([CH3:28])[CH3:29])=[CH:16][CH:17]=2)[NH:21][C:20]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1cc2ccc(O[Si](C)(C)C(C)(C)C)cc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: COC(=O)c1[nH]c2cc(O[Si](C)(C)C(C)(C)C)ccc2c1Br
Reaction time: 8 h
Yield: 17 %

Procedure:
NBS (0.670 g, 3.77 mmol) was added to a solution of methyl 6-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1H-indole-2-carboxylate (1.15 g, 3.77 mmol) in DMF (6 mL) and stirred overnight. The reaction was partitioned between EtOAc and water. The organic layer was separated, dried over MgSO4, filtered and concentrated. The residue was adsorbed onto silica gel and purification was accomplished by silica gel column chromatography (EtOAc/hexanes) to afford the title compound (0.246 g, 17%). 1H NMR (400 MHz, CDCl3): δ ppm 9.31 (br. s., 1H), 7.48 (d, 1H), 6.76-6.84 (m, 2H), 3.98 (s, 3H), 0.99 (s, 9H), 0.21 (s, 6H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:11]1([C@H:16]([N:20]2[CH:24]=[C:23](B3OC(C)(C)C(C)(C)O3)[CH:22]=[N:21]2)[CH2:17][C:18]#[N:19])[CH2:15][CH2:14][CH2:13][CH2:12]1.O1CCOCC1.O.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:11]1([C@H:16]([N:20]2[CH:24]=[C:23]([C:2]3[C:3]4[CH:10]=[CH:9][NH:8][C:4]=4[N:5]=[CH:6][N:7]=3)[CH:22]=[N:21]2)[CH2:17][C:18]#[N:19])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC1(C)OB(c2cnn([C@H](CC#N)C3CCCC3)c2)OC1(C)C
Reactant: Clc1ncnc2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#CC[C@H](C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 95 °C
Reaction time: 17 h
Yield: 64.3 %

Procedure:
Method C. To a 25 mL round bottom flask equipped with a stir bar, condenser, and three-way valve connected to nitrogen and vacuum was charged 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 154 mg, 1.00 mmol), (3R)-3-cyclopentyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanenitrile ((R)-24, 445 mg, 1.41 mmol, 1.41 equiv), 1,4-dioxane(2.78 mL, 35.6 mmol), water (1.39 mL, 77.2 mmol), and potassium carbonate (K2CO3, 693 mg, 5.02 mmol, 5.0 equiv) at room temperature. The resulting mixture was degassed three times back filling with nitrogen each time before being charged tetrakis(triphenylphosphine)palladium(0) (207 mg, 0.180 mmol, 0.18 equiv). The resulting reaction mixture was degassed four times back filling with nitrogen each time and then warmed to 95° C. The reaction mixture was stirred at 95° C. for 17 hours. When the reaction was deemed complete, the reaction mixture was cooled to room temperature before being diluted with ethyl acetate (20 mL) and 20% aqueous brine (11 mL). The mixture was stirred vigorously at room temperature until the majority of solids had gone into solution. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic extracts were washed with saturated brine (10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was then purified by flash chromatography (SiO2, 0-100% ethyl acetate/hexanes gradient elution) to afford (3R)-3-cyclopentyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile ((R)-12, 197 mg, 306.4 mg theoretical, 64.3% yield) as colorless oil, which was solidified upon standing at room temperature. For (R)-12: 1H NMR (DMSO-d6, 400 MHz) δ ppm 12.1 (bs, 1H), 8.80 (d, 1H, J=0.42 Hz), 8.67 (s, 1H), 8.37 (s, 1H), 7.59 (dd, 1H, J=2.34, 3.51 Hz), 6.98 (dd, 1H, J=1.40, 3.44 Hz), 4.53 (td, 1H, J=19.5, 4.63 Hz), 3.26 (dd, 1H, J=9.77, 17.2 Hz), 3.18 (dd, 1H, J=4.32, 17.3 Hz), 2.40 (m, 1H), 1.79 (m, 1H), 1.65 to 1.13 (m, 7H); C17H18N6(MW, 306.37) LCMS (EI) m/e 307 [M++H].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[N:19][C:18]=3[C:17]([O:33][CH3:34])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:32])[C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)=[N:19][C:18]=3[C:17]([O:33][CH3:34])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)c2sc(NC(=O)c3ccc(F)cc3)nc12
Reaction time: 4 h
Yield: 23 %

Procedure:
To a solution of 0.14 g (0.94 mmol) of 4-[2-(4-fluoro-benzoylamino)-4-methoxy-benzothiazol-7-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester in 6.0 ml of methanol and 6.0 ml THF 90.0 mg of Pd/C (10%) were added. The reaction mixture was hydrogenated at 60° C. for 4 h, then filtered and evaporated to dryness in vacuo. The residue was crystallized from diethyl ether to yield 0.105 g (75%) 4-[2-(4-fluoro-benzoylamino)-4-methoxy-benzothiazol-7-yl]-piperidine-1-carboxylic acid tert-butyl ester as a white solid. F.p.: 222-223° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[F:11].[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:22]2[CH2:23][CH2:24][N:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:20][CH2:21]2)=[O:8])=[CH:4][C:3]=1[F:11]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Nc1ccc(C(=O)O)cc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)N2CCN(Cc3ccccc3)CC2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
4-Amino-3-fluorobenzoic acid (28.4 mmol, 4.40 g), 1-benzylpiperazine (28.4 mmol, 4.93 mL, 5 g) and triethylamine (85 mmol, 11.86 mL, 8.61 g) were stirred in dichloromethane at room temperature. 1-Propanephosphonic acid cyclic anhydride (42.6 mmol, 25.2 mL, 27.1 g, 50% solution in ethyl acetate) was added and the reaction mixture stirred at room temperature for 1 hour. The reaction mixture was washed with saturated sodium bicarbonate solution and concentrated under reduced pressure to afford the title compound (7.51 g). MS (ESI) m/z 314.1 [M+H]+
Reaction SMILES: [CH:1]1([Si:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16]([OH:21])([CH2:19][CH3:20])([CH3:18])[CH3:17].[O-]CC.[Na+].C[Si](C)(C)Cl>>[C:16]([O:21][Si:6]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])([CH2:19][CH3:20])([CH3:18])[CH3:17]
Reactant: CCC(C)(C)O
Reactant: CCO[Si](OCC)(OCC)C1CCCC1
Agent: CC[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Product: CCO[Si](OCC)(OC(C)(C)CC)C1CCCC1
Yield: 78.6 %

Procedure:
In a 100 ml three-neck flask provided with a magnetic stirrer and a reflux condenser were charged 20.5 g (0.0882 mole) of cyclopentyl triethoxysilane, 128 g (1.46 mole) of tert-amyl alcohol and 0.953 g (14.0 m mole) of sodium ethoxide, which were then reacted with each other in an oil bath of 105° C. for 24 hours under stirring. Subsequently, trimethylchlorosilane was added to neutralize the alkali. Then, 19.0 g (0.0693 mole) of tert-amyloxy cyclopentyl diethoxysilane were obtained by vacuum distillation. Its structure was confirmed as in Example 1. The yield was 79%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[CH:5]=[C:4]([CH:18]=[CH:19][CH3:20])[C:3]=1[OH:21].ClC1C=C(C=CC=1)C(OO)=[O:27]>C(Cl)Cl>[Cl:8][C:7]1[C:6]([C:9](=[O:17])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:5][C:4]2[CH2:18][CH:19]([CH2:20][OH:27])[O:21][C:3]=2[C:2]=1[Cl:1]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC=Cc1cc(C(=O)c2ccccc2F)c(Cl)c(Cl)c1O
Solvent: ClCCl
Product: O=C(c1ccccc1F)c1cc2c(c(Cl)c1Cl)OC(CO)C2
Reaction time: 96 h

Procedure:
A mixture of 2,3-dichloro-6-propenyl-4-(2-fluorobenzoyl)phenol (62.5 g., 0.192 mole) and m-chloroperoxybenzoic acid (47.6 g., 0.22 mole in 550 ml. of methylene chloride was stirred at room temperature for 24 hours. The precipitated m-chlorobenzoic acid was removed by filtration and the filtrate was washed successively with 5% aqueous sodium sulfite and 10% aqueous sodium bicarbonate. The methylene chloride was kept at room temperature for 4 days and then washed with 0.5N NaOH solution. After drying over MgSO4, the solvent was evaporated to give 45 g. of solid product, m.p. 148°-150° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.[C:19]([O:23][C:24]([N:26]([C:34]1[N:39]=[C:38]2[N:40]([CH2:46][C:47]3[C:52]([CH3:53])=[C:51]([O:54][CH3:55])[C:50]([CH3:56])=[CH:49][N:48]=3)[N:41]=[C:42]([CH2:43][CH2:44][OH:45])[C:37]2=[C:36]([Cl:57])[N:35]=1)[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:45][CH2:44][CH2:43][C:42]2[C:37]3[C:38](=[N:39][C:34]([N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:25])[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:35][C:36]=3[Cl:57])[N:40]([CH2:46][C:47]3[C:52]([CH3:53])=[C:51]([O:54][CH3:55])[C:50]([CH3:56])=[CH:49][N:48]=3)[N:41]=2)(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: COc1c(C)cnc(Cn2nc(CCO)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(Cn2nc(CCOS(=O)(=O)c3ccc(C)cc3)c3c(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc32)c1C
Reaction time: 12 h
Yield: 91 %

Procedure:
Triethylamine (0.048 mL), p-toluenesulfonyl chloride (43 mg) and 4-dimethylaminopyridine (0.7 mg) were added to a mixture composed of di-tert-butyl{4-chloro-3-(2-hydroxyethyl)-1-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}imidodicarbonate of 8) above (64 mg) and dehydrated dichloromethane (1 mL) under cooling in an ice bath. The ice bath was removed and the mixture was stirred for 12 hours. The reaction mixture was diluted with ethyl acetate and sequentially washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (74 mg, 91%) as an amorphous substance.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:30])[C:5]1[C:6](=[CH:11][C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22]C(OC(C)(C)C)=O)=[CH:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8]>C(OCC)C.CO>[CH3:2][O:3][C:4](=[O:30])[C:5]1[C:6](=[CH:11][C:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH2:22])=[CH:13][CH:14]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1ccc(Cc2ccccc2NC(=O)OC(C)(C)C)cc1C(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1ccc(Cc2ccccc2N)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
2N hydrogen chloride in diethyl ether (1 ml) was added to a solution of 4-(2-(tert-butoxycarbonylamino)benzyl)phthalic acid dimethyl ester (100 mg, 0.25 mmol) in methanol (1 ml). The mixture was stirred for 2 hours at room temperature and evaporated to dryness in vacuo. The crude product was recrystallized from diethyl ether/ethyl acetate to give light, golden crystals of 4-(2-aminobenzyl)phthalic acid dimethyl ester (yield: 69 mg (86%)). 1H—NMR (CDCl3) in ppm: δ 7.74 (1H,d); 7.60 (1H,s); 7.54 (1H,d); 7.27 (2H,d); 7.13 (1H,m); 7.05 (1H,d); 4.12 (2H,s); 3.8 (6H,2xs); 2.5 (3H,s). LC-MS: m/e 322 (M+Na), 300 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25](I)[CH2:26][CH3:27].[H-].[Na+].O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[CH2:25][CH2:26][CH3:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCI
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCN(C(=O)OCc1ccccc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.8 %

Procedure:
To 110 mg (0.32 mmol) 4-benzyloxycarbonylamino-1-t-butoxycarbonylpiperidine from Step C and 0.16 mL (1.6 mmol) of n-propyl iodide in 2 mL of DMF under nitrogen was added 26 mg (0.65 mmol) of 60% sodium hydride in mineral oil. The reaction was stirred at rt for 16 h and was then poured into water and extracted twice with ether. The organic layers were each washed with a portion of brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC eluting with 20% ethyl acetate in hexanes to afford 90 mg of title compound.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[N:8]=1)=O.[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34]N)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1>>[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([N:34]3[C:5]([C:7]4[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]5[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=5)[C:17]#[N:18])[N:8]=4)=[CH:4][CH:3]=[N:2]3)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: NNc1ccnc2cc(Cl)ccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(C#N)c2)ccc1=O
Product: N#Cc1cccc(-n2ccc(=O)c(-c3ccnn3-c3ccnc4cc(Cl)ccc34)n2)c1

Procedure:
The product was obtained starting from 3-[3-((E)-3-Dimethylamino-acryloyl)-4-oxo-4H-pyridazin-1-yl]-benzonitrile (A-19) and (7-chloro-quinolin-4-yl)-hydrazine according to the method described for example 91. MS: M=425.1 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[H-].[Na+].[CH2:29](I)[CH2:30][CH2:31][CH3:32]>CN(C=O)C.[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[C:8]([CH2:24][CH3:25])=[C:9]([C:22]#[N:23])[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:18]([CH2:29][CH2:30][CH2:31][CH3:32])[N:19]=[N:20][N:21]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCCCI
Reactant: CCOC(=O)c1c(-c2ccc(-c3nnn[nH]3)cc2)c(C#N)c(CC)n1C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1nnnc1-c1ccc(-c2c(C#N)c(CC)n(C)c2C(=O)OCC)cc1
Temperature: 0 °C
Yield: 33.9 %

Procedure:
Into a round bottom flask containing a solution of 4-cyano-5-ethyl-1-methyl-3-[4-(1H-tetrazol-5-yl)-phenyl]-1H-pyrrole-2-carboxylic acid ethyl ester (0.150 g, 0.428 mmol, prepared in example E-242) in DMF (2 mL) cooled to 0° C. while stirring add NaH (0.019 g, 0.479 mmol, 60% in mineral oil). Let stir for 1 h, then add butyl iodide (0.054 mL, 0.479 mmol) and let stir for 2.5 h. Dilute the mixture with brine (20 mL) and extract the mixture with EtOAc (3×15 mL). Combine the organic layers and wash with brine (2×20 mL), aqueous NH4Cl (1×20 mL), aqueous NaHCO3 (1×20 mL) and water (1×20 mL). Dry the organic layer over anhydrous Na2 SO4, filter, and concentrate under reduced pressure. Purify the residue via silica gel chromatography (eluent: 20 to 98% EtOAc in hexanes). Concentrate under reduced pressure the purified fractions and place under vacuum to provide the title compound as a colorless oil (0.059 g); mass spectrum (m/e): 407.4 (M+H)
Reaction SMILES: [F:1][CH:2]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4][CH:3]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C.Cl[C:27]1[N:31]([CH3:32])[N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>CCO>[F:1][CH:2]1[CH2:8][CH2:7][N:6]([C:27]2[N:31]([CH3:32])[N:30]=[CH:29][C:28]=2[N+:33]([O-:35])=[O:34])[CH2:5][CH2:4][CH:3]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14]
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCCC1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCC(F)C(NC(=O)OC(C)(C)C)CC1
Temperature: 130 °C
Yield: 13.6 %

Procedure:
To a solution of tert-butyl 5-fluoroazepan-4-ylcarbamate (310 mg, 1.34 mmol) in EtOH (4 mL) was added DIPEA (1 ml, 5.7 mmol) and 5-chloro-1-methyl-4-nitro-1H-pyrazole (216 mg, 1.34 mmol). The reaction mixture was heated at 130° C. in a microwave for 8 hr. The solvent was removed under reduced pressure and the residue was purified via silica gel column chromatography (30-40% EtOAc/isohexane) to give the two trans (anti) isomers, tert-butyl 5-fluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate as a yellow glass (65 mg) contaminated with some of the cis (syn) isomer.
Reaction SMILES: C(O[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:4][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13]2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)N1CCC(n2ccc3ccccc32)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCC(n2ccc3ccccc32)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To an ice cooled solution of 4-indol-1-yl-piperidine-1-carboxylic acid ethyl ester (50 g, 0.18 mol) in dry THF (400 mL) was added LAH in small portions (7 g, 0.18 mol). After 2 hours, the mixture was quenched by successive addition of water (7 mL) 15% of sodium hydroxide (7 mL) and water (21 mL). The reaction mixture was filtered. The filtrate was dried and evaporated. The residue crystallized on standing and was recrystallized from a small amount of di-i-propyl ether to give the title compound (25 g, 63% of theory). M.Pt.: 58° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:13]=[CH:12]2)C1C=CC=CC=1>CO.ClCCl.[Pd]>[CH2:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCn1ccc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCn1ccc2cc(O)ccc21
Reaction time: 12 h

Procedure:
0.5 g (1.55 mmol) 5-benzyloxy-1-heptylindole is dissolved in a Schlenk flask in 10 ml methanol and 4 ml dichloromethane. 0.06 g Pd (10%)/C is added and the mixture is rinsed with nitrogen for 15 minutes. Thereafter, a balloon filled with hydrogen is placed on the Schlenk piston and hydrogenation is carried out at room temperature for 12 h. The batch is filtrated on a frit and the solvent is removed in vacuo. The residue is purified on silica gel by means of column chromatography (flow agent: hexane/ethyl acetate 9:1). The product accrues as an oil.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([N:22]([CH:32]([CH3:34])[CH3:33])[C:23]1[N:24]=[C:25]([Cl:31])[C:26]([CH:29]=O)=[N:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:35]([NH:42][CH2:43][CH2:44][OH:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])O.[Na+]>C(#N)C.C(O)(=O)C>[CH2:35]([N:42]([CH2:29][C:26]1[C:25]([Cl:31])=[N:24][C:23]([N:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:32]([CH3:34])[CH3:33])=[CH:28][N:27]=1)[CH2:43][CH2:44][OH:45])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)N(Cc1ccccc1)c1cnc(C=O)c(Cl)n1
Reactant: OCCNCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)N(Cc1ccccc1)c1cnc(CN(CCO)Cc2ccccc2)c(Cl)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
Sodium triacetoxyborohydride (2.65 g) was added to a solution of 5-[benzyl(1-methylethyl)amino]-3-chloropyrazine-2-carbaldehyde (2.42 g), N-benzylethanolamine (1.42 g) and acetic acid (1.43 mL) in acetonitrile (14 mL), and the mixture was stirred at room temperature for 16 hr. The reaction mixture was basified with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 20→50% ethyl acetate/hexane) to give the title compound (3.32 g, 94%) as a pale-yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=[CH:8]2)[CH:2]=1.ClN1C(=[O:22])CCC1=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:22])[CH:2]=1
Reactant: c1cncc(-n2ccc3ccccc32)c1
Reactant: O=C1CCC(=O)N1Cl
Product: O=C1Cc2ccccc2N1c1cccnc1
Yield: 59 %

Procedure:
1-(pyridin-3-yl)-1H-indole is reacted with N-chlorosuccinimide as described in Example 12 to give 1-(pyridin-3-yl)-1,3-dihydroindol-2-one (59% yield) as a light brown solid.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].C[Li].C1C[O:17][CH2:16]C1>>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:16][O:17]1
Reactant: C1CCOC1
Reactant: C#CCCOC1CCCCO1
Agent: [Li]C
Product: C1CCC(OC2CCCCO2)OC1
Temperature: -30 °C
Reaction time: 4 h

Procedure:
2-(3-Butynyloxy)tetrahydro-2H-pyran (112.5 g, 0.729 mole) was added dropwise to a solution of methyllithium (500 mL of MeLi 1AM in ether, 0.7 mole) in 1 L of anhydrous THF at -30° C. under argon atmosphere in a 5 L round bottom flask. After this addition was completed, the cooling bath was removed and the solution was allowed to stand at room temperature for 4 hours. The solution was cooled again at -30° C. and a solution of ketone 3 (75 g, 0.2 mole) in 2.5 L of anhydrous TTh was added dropwise. After completing this addition, the cooling bath was removed and the mixture was allowed to stand at room temperature for 16 h. To this mixture, 100 mL of brine were added and the solution was diluted with ethyl acetate, washed with brine and dried with anhydrous MgSO4. The solvent was then evaporated and crystallization took place after a short period of time. Hexane was added to complete the precipitation. The solid was then filtered and washed with hexane. The compound 4 was used in the next step without further purification. Yield: 95.8 g (90%). 1H NMR δ (CDCl3, 300 MHz, TMS): 0.82 (s, 3H, 18CH3), 1.01 (s, 3H, 19CH3), 2.52 (t, 2H, J=6.8 Hz, CCCH2), 3.15-3.44 (m, 4H, SCH2), 3.50-3.56 (m, 2H, CH2OTHP), 3.75-3.90 (m, 2H, pyran OCH2), 4.66 (s, 1H, OCHO), 5.47 (s, 1H, C-4H.