Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][CH2:28][CH3:29].[CH3:30][N:31]([CH3:46])[C:32]1[CH:41]=[CH:40][CH:39]=[C:38]2[C:33]=1[CH:34]=[CH:35][CH:36]=[C:37]2[S:42](Cl)(=[O:44])=[O:43].C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O.O>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][CH2:28][CH3:29])[N:12]([CH2:11][CH2:10][CH2:9][NH:8][S:42]([C:37]3[C:38]4[C:33](=[C:32]([N:31]([CH3:46])[CH3:30])[CH:41]=[CH:40][CH:39]=4)[CH:34]=[CH:35][CH:36]=3)(=[O:44])=[O:43])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1cccc2c(N(C)C)cccc12
Yield: 65.8 %

Procedure:
Under a nitrogen atmosphere triethylamine (765 mg, 7.56 mmol) was added to a solution of 1-(3-aminopropyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.5 g, 5.04 mmol) in 1-methyl-2-pyrrolidinone (75 mL). A solution of 5-dimethylamino-1-naphthalenesulfonyl chloride (1.5 g, 5.55 mmol) in 1-methyl-2-pyrrolidinone was added. The reaction was monitored by HPLC. The reaction mixture was combined with water (500 mL) and the pH was adjusted to 10 with solid potassium carbonate. The resulting yellow precipitate was isolated by filtration, rinsed with water and then purified by column chromatography (silica gel eluting with 1–5% methanol in chloroform). The purified material was recrystallized from acetonitrile to provide 1.76 g of N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-5-(dimethylamino)naphthalene-1-sulfonamide as a solid, m.p. 216.5–217.5° C. Analysis: Calculated for C29H34N6O2S: % C, 65.64; % H, 6.46; % N, 15.84. Found: % C, 65.52; % H, 6.44; % N, 15.90.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[NH3:24]>>[NH2:24][C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]3[O:20][CH2:21][O:22][C:16]=3[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1
Reactant: N
Reactant: Clc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Product: Nc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Reaction time: 18 h

Procedure:
2.0 g of 2.6-dichloro-4-(3,4-methylenedioxybenzyl)aminoquinazoline was heated to 120° C. in 50 ml of ethanolic ammonia put in a pressure vessel for 18 hours, cooled and concentrated under a reduced pressure. The obtained residue was introduced to a silica gel column and eluted with a chloroform/methanol (9:1) mixture to give 830 mg of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([C:7]=32)[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[O:1]=[C:2]1[C:8]2=[CH:9][N:10]([S:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:30])=[O:29])[C:11]3[CH:12]=[CH:13][CH:14]=[C:6]([C:7]=32)[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)c2c[nH]c3cccc(c23)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)c2cn(S(=O)(=O)c3ccccc3)c3cccc(c23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-Butyl 3-oxo-1,3,4,6-tetrahydro-5H-azepino[5,4,3-cd]indole-5-carboxylate, Intermediate 17 (50 mg, 0.17 mmol), tetrabutylammonium hydrogensulfate (8 mg, 0.01 mmol) and benzenesulfonyl chloride (25 μl, 0.19 mmol) were dissolved in DCM (2 ml). 2.5 M NaOH (77 μl) was added. The mixture was stirred for 1 h at room temperature. The DCM phase was collected and washed with NaHCO3(sat.) and water. Evaporation gave a residue that was purified on silica 8-66% EtOAc in petroleum ether 45-60°. Obtained 42.4 mg of the title compound as a clear glass. MS (ESI+) m/z 371 [M+H-isobutene]+.
Reaction SMILES: O[C:2]1[C:3](=[O:37])[N:4]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)=[CH:28][CH:27]=2)[CH:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[C:6]=1[C:7]([C:9]1([CH3:17])[CH2:14][O:13]C(C)(C)[O:11][CH2:10]1)=O.O.[NH2:39][NH2:40].Cl.CO>C(O)(=O)C>[OH:11][CH2:10][C:9]([C:7]1[C:6]2[CH:5]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])[N:4]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4[CH:36]=[CH:35][S:34][CH:33]=4)=[CH:30][CH:31]=3)[C:3](=[O:37])[C:2]=2[NH:39][N:40]=1)([CH2:14][OH:13])[CH3:17]
Reactant: COc1ccccc1C1C(C(=O)C2(C)COC(C)(C)OC2)=C(O)C(=O)N1c1ccc(-c2ccsc2)cc1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccccc1C1c2c(C(C)(CO)CO)n[nH]c2C(=O)N1c1ccc(-c2ccsc2)cc1
Yield: 73.6 %

Procedure:
A mixture of 3-hydroxy-4-(2,2,5-trimethyl-1,3-dioxane5-yl)carbonyl-5-(2-methoxyphenyl)-1-(4-thiophene-3-ylphenyl)-1,5-dihydropyrrole-2-one (0.15 g, 0.3 mmol), hydrazine hydrate (0.07 mL, 1.4 mmol) and acetic acid (1 mL) was heated at reflux overnight. After the reaction mixture was concentrated in vacuo, to the resulting residue was added 2 mol/L hydrochloric acid/methanol solution (2.89 mL, 5.8 mmol) and the resulting mixture was heated at reflux for 6 hours. After the reaction mixture was concentrated in vacuo, saturated sodium bicarbonate solution was added to the residue and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting residue was purified on a silica gel column chromatography (methanol/chloroform). The resulting compound was triturated with ethyl acetate and n-hexane to give 3-(1,1-dihydroxymethylethyl) 4-(2-methoxyphenyl)-5-(4-thiophene-3-ylphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (0.105 g, yield: 77%) as colorless solid.
Reaction SMILES: [CH3:1][CH2:2][N:3](C(C)C)C(C)C.[Br:10][C:11]1[C:12]([F:19])=[CH:13][C:14]([CH3:18])=[C:15]([CH:17]=1)[NH2:16].BrCC#N>C1COCC1>[Br:10][C:11]1[C:12]([F:19])=[CH:13][C:14]([CH3:18])=[C:15]([NH:16][CH2:1][C:2]#[N:3])[CH:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(F)c(Br)cc1N
Agent: N#CCBr
Solvent: C1CCOC1
Product: Cc1cc(F)c(Br)cc1NCC#N
Temperature: 25 °C

Procedure:
Hunig's Base (6.15 mL) was added to 5-bromo-4-fluoro-2-methylaniline (Example 318a, 3.59 g) in THF (50 mL) at room temperature followed by bromoacetonitrile (2.451 mL). The reaction was heated to reflux overnight. The reaction was cooled to room temperature and concentrated. 2N HCl and DCM were added. The organic layer was separated and dried (MgSO4) and concentrated to give the subtitle compound as a solid (6.61 g). 1H NMR δ (CDCl3) 6.92 (d, 1H), 6.80 (d, 1H), 4.13 (d, 2H), 3.78 (s, 1H), 2.13 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:17][S:18]([CH2:20][CH:21]([CH2:23]C)[CH3:22])=[O:19])([C:11]2[N:12](C)[CH:13]=[N:14][CH:15]=2)C)=[CH:5][C:4]=1[F:25])#[N:2].[CH:26]1([C:29]#[C:30][Mg]Br)[CH2:28][CH2:27]1.C1(C#C)CC1.C([Mg]Br)C>C1COCC1.CCOCC>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[N:12]([C:30]#[C:29][CH:26]3[CH2:28][CH2:27]3)[CH:13]=[N:14][CH:15]=2)=[N:17][S:18]([CH2:20][CH:21]([CH3:23])[CH3:22])=[O:19])=[CH:5][C:4]=1[F:25])#[N:2]
Reactant: Br[Mg]C#CC1CC1
Reactant: CCC(C)CS(=O)NC(C)(c1ccc(C#N)c(F)c1)c1cncn1C
Agent: C#CC1CC1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)CS(=O)N=C(c1ccc(C#N)c(F)c1)c1cncn1C#CC1CC1

Procedure:
To a solution of N-[1-(4-cyano-3-fluoro-phenyl)-1-(3-methyl-3H-imidazol-4-yl)-ethyl]-2ethylpropanesulfinamide (Example 1, Step I) (0.50 g, 1.50 mmol) in THF (12 mL) at 0° C. in an ice-H2O bath was added cyclopropylethynyl magnesium bromide (3 mL of a 2M solution in Et2O prepared from cyclopropyl acetylene and ethyl magnesium bromide). Grignard reagent was added until the reaction mixture color remained dark brown/black. After 1 h the reaction mixture was quenched with H2O, diluted with CH2Cl2 and aqueous saturated NaHCO3 solution, layers separated, the aqueous layer washed with CH2Cl2 (2×), the organics combined, and dried (MgSO4). Filtration and concentration in vacuo gave the title compound as a 77/22 ratio of diastereomers.
Reaction SMILES: Br.C[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)=[CH:6][CH:5]=1>C(OC(=O)C)(=O)C>[OH:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc(C2CCCC(=O)C2)cc1
Agent: Br
Solvent: CC(=O)OC(C)=O
Product: O=C1CCCC(c2ccc(O)cc2)C1
Temperature: 0 °C

Procedure:
2.12 ml of 48% aqueous hydrobromic acid are added slowly to 1.28 g of 3-(4-methoxyphenyl)cyclohexanone in 6.4 ml of acetic anhydride. After 4 hours at reflux, the reaction mixture is poured into ice-water and extracted with diethyl ether. After concentration of the organic phase and purification over silica gel, 3-(4-hydroxyphenyl)cyclohexanone is obtained in the form of an oil.
Reaction SMILES: [CH2:1]([N:8]([CH3:24])[C@@H:9]1[C:13]2=[CH:14][C:15]3[CH:16]=[C:17]([Br:21])[CH:18]=[CH:19][C:20]=3[N:12]2[CH2:11][C@@H:10]1[CH2:22][OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:23][CH2:22][C@H:10]1[CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][C:17]([Br:21])=[CH:16][C:15]=3[CH:14]=[C:13]2[C@H:9]1[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:24])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1ccccc1)[C@@H]1c2cc3cc(Br)ccc3n2C[C@@H]1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1ccccc1)[C@@H]1c2cc3cc(Br)ccc3n2C[C@@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Step 2 (690 mg, 1.8 mmol) was dissolved in CH2Cl2 (10 mL) with N,N-diisopropylethylamine (0.94 mL, 5.4 mmol). The mixture was cooled to 0° C., before adding methanesulfonyl chloride (0.21 mL, 2.7 mmol). After 30 min, the mixture was washed with water, dried over Na2SO4 and concentrated. The crude mixture was carried on without further purification.
Reaction SMILES: [N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6](O)=[O:7])=[N+:2]=[N-:3].S(Cl)([Cl:13])=O>ClC(Cl)C>[N:1]([C:4]([CH3:10])([CH3:9])[CH2:5][C:6]([Cl:13])=[O:7])=[N+:2]=[N-:3]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(CC(=O)O)N=[N+]=[N-]
Solvent: CC(Cl)Cl
Product: CC(C)(CC(=O)Cl)N=[N+]=[N-]
Temperature: 50 °C

Procedure:
To a stirred solution of 3-azido-3-methylbutanoic acid (10 g, 69.8 mmol) in anh. dichloroethane (50 mL) was added thionyl chloride in one portion (10.0 mL, 2 equiv, 0.14 mol). The flask was fitted with a condenser and the reaction was heated in a 50° C. oil bath for 2 h. The reaction was concentrated to a brown-black suspension. The residue was vacuum distilled through a short path distillation apparatus. The forerun was discarded and the major fraction distilled at 66° C. at 18 mbar as a pale yellow liquid (9.66 g, 85.6%). 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2 H).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.P(Br)(Br)[Br:11]>ClCCl>[Br:11][CH2:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1
Reactant: OCc1cccc(O)c1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: Oc1cccc(CBr)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged 15 mL of dichloromethane. To the stirred solvent was added 3-hydroxymethyl-phenol (0.5 g, 4.03 mmol). The RM was brought to 0° C. and phosphorous tribromide (1.6 g, 0.56 mL, 6.04 mmol) was added drop wise. After addition, the RM was stirred at RT for 1 h. After 1 h, the RM was diluted with dichloromethane (25 mL) and the organic layer was washed with water (20 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as brown solid. (0.65 g, yield: 86.3%); MS (ESI, 120 eV): m/z=187.0 (M+H)+; 1H NMR (300 MHz, CDCl3): δ 7.10-7.15 (t, 1H), 6.86-6.89 (d, 1H), 6.80 (d, 1H), 6.67-6.71 (m, 1H), 4.35-4.36 (d, 2H), 3.80-3.94 (bro s, 1H).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[CH2:9][C@@H:8]([S:10][C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][NH:6]1)=[N+:2]=[N-:3].[CH2:30]([N:34]=[C:35]=[O:36])[CH2:31][CH2:32][CH3:33]>C1COCC1>[CH2:30]([NH:34][C:35]([N:6]1[CH2:7][C@H:8]([S:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:9][C@H:5]1[CH2:4][N:1]=[N+:2]=[N-:3])=[O:36])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCN=C=O
Reactant: [N-]=[N+]=NC[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1
Solvent: C1CCOC1
Product: CCCCNC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 79.5 %

Procedure:
280 mg (0.7 mmol) (2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine were treated with 87 μM (0.77 mol, 1.1 eq) butyl isocyanate in 5 ml THF at 0° C., and the solution was stirred at RT for 45 min. The solvent was evaporated, and the residue was purified by flash chromatography yielding 278 mg (80%) (2S,4R)-2-azidomethyl-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid butylamide as white foam.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:23]=[C:22]2[O:24][CH2:25][CH2:26][O:27][C:21]2=[CH:20][C:7]=1[CH2:8][N:9]1C(=O)C2=CC=CC=C2C1=O)[CH3:2].NN.C(OCC)C>C(O)C>[CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:23]=[C:22]2[O:24][CH2:25][CH2:26][O:27][C:21]2=[CH:20][C:7]=1[CH2:8][NH2:9])[CH3:2]
Reactant: CCOCOc1cc2c(cc1CN1C(=O)c3ccccc3C1=O)OCCO2
Agent: NN
Solvent: CCOCC
Solvent: CCO
Product: CCOCOc1cc2c(cc1CN)OCCO2

Procedure:
N-(2-ethoxymethoxy-4,5-ethylenedioxybenzyl)phthalimide (625 mg, 1.69 mmol) was mixed with 0.2 mL (6.4 mmol) hydrazine in 30 mL ethanol and refluxed for three hr. The reaction mixture was cooled, 30 mL ethyl ether was added to the mixture, and a white precipitate was removed by filtration. The filter cake was washed three times with diethyl ether and the combined organic solutions were evaporated to yield a residue that was partitioned between ethyl ether and 10% sodium hydroxide. The organic phase was washed three times with 10% sodium hydroxide, and the aqueous washes were combined and back-extracted twice with dichloromethane. The organic solutions were combined and washed with brine and dried over sodium sulfate/potassium carbonate. Subsequent evaporation of solvent gave 2-ethoxymethoxy-4,5-ethylenedioxybenzylamine as a light yellow oil (346 g, 86% crude), which solidified upon standing. IR: 3375 cm-1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[C:7]([O:11]C(=O)C)[C:6]=2[CH:15]=1.Cl>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH3:10])[C:7](=[O:11])[C:6]=2[CH:15]=1
Reactant: CC(=O)Oc1c(C)oc2ccc(Br)cc12
Agent: Cl
Solvent: CO
Product: CC1Oc2ccc(Br)cc2C1=O
Temperature: 75 °C
Yield: 91.9 %

Procedure:
A suspension of acetic acid 5-bromo-2-methyl-benzofuran-3-yl ester (18.9 g, 70.4 mmol) in methanol (232 mL) and a I M aqueous HCl solution (44 mL) is heated under reflux (75° C.) for 7 h. After cooling to room temperature the reaction mixture is concentrated by rotary evaporation. The residue is diluted with water and extracted three times with diethyl ether. The combined organic layers are washed with water, brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford the title compound as a yellow oil (14.7 g, 64.7 mmol, 92%). MS (ES+): 227 (M(C9H779BrO2)+H)+.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:5]1([N:9]([CH3:11])[CH3:10])[CH2:8][NH:7][CH2:6]1)[CH3:4].N1CC[CH2:14][CH2:13]1>>[ClH:1].[ClH:1].[CH2:3]([C:5]1([N:9]2[CH2:11][CH2:14][CH2:13][CH2:10]2)[CH2:8][NH:7][CH2:6]1)[CH3:4]
Reactant: C1CCNC1
Reactant: CCC1(N(C)C)CNC1
Agent: Cl
Product: CCC1(N2CCCC2)CNC1

Procedure:
1-(3-Ethyl-3-azetidinyl)pyrrolidine dihydrochloride was prepared according to the procedure described for the preparation of 3-ethyl-N,N-dimethyl-3-azetidinamine dihydrochloride (Example 211), utilizing pyrrolidine in place of dimethylamine in Part A. LCMS: (M+H)+ 155.1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.I[CH2:14][CH:15]([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1
Reactant: OCCNCc1ccc(Cl)nc1
Reactant: CC(C)CI
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(CCO)Cc1ccc(Cl)nc1
Yield: 80.6 %

Procedure:
A stirred mixture of 2.0 grams (0.007 mole) of 2-{[(6-chloro(3-pyridyl))methyl]amino}ethan-1-ol (known compound), 1.29 gram (0.007 mole) of 1-iodo-2-methylpropane and 0.9 gram (0.007 mole) if diisopropylethylamine in 50 mL of acetonitrile was heated at reflux for 16 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, eluting with a mixture of diethyl ether and hexanes. The appropriate fractions were combined and concentrated under reduced pressure, yielding 1.37 grams of 2-{[(6-chloro(3-pyridyl))methyl](2-methylpropyl)amino}ethan-1-ol. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][CH2:2][CH:3]([OH:6])[CH2:4][Br:5].N1C=CN=C1.[C:12]([Si:16](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:15])([CH3:14])[CH3:13]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)C>[Br:1][CH2:2][CH:3]([CH2:4][Br:5])[O:6][Si:16]([C:12]([CH3:15])([CH3:14])[CH3:13])([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: OC(CBr)CBr
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)[Si](OC(CBr)CBr)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 100.3 %

Procedure:
To a solution of 1,3-dibromo-2-propanol (20.00 g, 91.79 mmol) in methylene chloride (DCM) (100 mL) cooled to 0° C. was added 1H-imidazole (6.56 g, 96.4 mmol) followed by tert-butylchlorodiphenylsilane (25.1 mL, 96.4 mmol) and 4-dimethylaminopyridine (1.12 g, 9.18 mmol). The reaction was stirred with warming to room temperature overnight. The reaction mixture was diluted with diethyl ether, washed with water, and the aqueous layer was again extracted once with ether. The combined organic extracts were washed with water, followed by brine, dried over sodium sulfate, decanted and concentrated. Flash chromatography (eluting with a gradient from 0-15% ethyl acetate/hexanes) afforded desired product (42 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.72-7.66 (m, 4H), 7.51-7.37 (m, 6H), 4.00-3.91 (m, 1H), 3.49-3.45 (m, 4H), 1.09 (s, 9H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].Br[CH2:19][C:20]1[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([CH3:31])[C:21]=1[O:22][CH2:23][C:24]#[N:25]>>[Cl:30][C:28]1[CH:27]=[C:26]([CH2:31][O:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:21]([O:22][CH2:23][C:24]#[N:25])=[C:20]([CH3:19])[CH:29]=1
Reactant: Cc1cc(Cl)cc(CBr)c1OCC#N
Reactant: OCCCCOCc1ccc2ccccc2n1
Product: Cc1cc(Cl)cc(COCCCCOCc2ccc3ccccc3n2)c1OCC#N

Procedure:
MS (ESI) 424 (M+H)+. Prepared from 4-(quinolin-2-ylmethoxy)-butan-1-ol (EXAMPLE-34b) and (2-bromomethyl-4-chloro-6-methyl-phenoxy)-acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)/[CH:14]=[CH:15]/[CH3:16])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[F:45][C@H:46]1[CH2:50][CH2:49][NH:48][CH2:47]1.CCN(C(C)C)C(C)C>ClCCl>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[CH:21][CH:22]=1)[CH:14]=[CH:15][CH3:16])[C:10]([N:48]1[CH2:49][CH2:50][C@H:46]([F:45])[CH2:47]1)=[O:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C/C=C/[C@@H](c1ccc(-c2ccc(F)cc2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: F[C@H]1CCNC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC=C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 2.11 g (5.49 mmol) of the acid from Step F dissolved in anhydrous dichloromethane (100 mL) was added EDC (1.34 g, 7.0 mmol), HOBT (0.95 g, 7.0 mmol), (3S)-3-fluoropyrrolidine hydrochloride (880 mg, 7.0 mmol) and N,N′-diisopropylethylamine (1.1 mL, 7.0 mmol). After stirring for 48 h at room temperature, the reaction mixture was concentrated and diluted with 100 mL of 10% aqueous hydrochloric acid. The resultant mixture was then extracted with three 150-mL portions of ethyl acetate, the organic phases combined and washed sequentially with 5% hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous brine (100 mL each). The organic phase was then dried over magnesium sulfate, filtered, and evaporated in vacuo to yield the crude material as a viscous oil. The crude material was purified by flash chromatography on a Biotage® system (silica gel, 0 to 40% ethyl acetate/hexanes gradient) to give the title compound as a colorless solid. LC/MS 471.3 (M+1).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=N[C:34]2[CH:35]=[CH:36][CH:37]=[N:38][C:33]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCCC)C>CN(C=O)C>[CH2:33]([N:38]([CH2:37][CH2:36][CH3:35])[C:5]([C:4]1[CH:8]=[C:9]([CH:10]=[C:2]([I:1])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7])[CH3:34]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CCCNCC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(CC)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Iodo-5-(methoxycarbonyl)benzoic acid (1 g, 3.3 mmol) is dissolved in DMF (10 mL), and diisopropylethylamine (1.7 mL, 9.8 mmol), HATU (1.5 g, 3.9 mmol), and N-ethylpropylamine (572 μL, 4.9 mmol) are added. The reaction stirred at room temperature 16 h. The reaction is partitioned between ethyl acetate and water. The organic layer is washed with saturated sodium bicarbonate, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 40% ethyl acetate/hexane) provides the title compound. ESI MS m/z 376.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](SC)=[C:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>CO>[NH2:11][C:10]1[NH:20][N:19]=[C:8]([NH:7][CH2:6][C:5]2[CH:16]=[CH:17][C:2]([NH2:1])=[CH:3][CH:4]=2)[C:9]=1[C:12]#[N:13]
Reactant: NN
Reactant: CSC(NCc1ccc(N)cc1)=C(C#N)C#N
Solvent: O
Solvent: CO
Product: N#Cc1c(NCc2ccc(N)cc2)n[nH]c1N
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A mixture of 15.71 g (64.3 mmol) of 3-(4-amino-benzylamino)-2-cyano-3-methylmercapto-acrylonitrile, 3.35 ml (67.5 mmol) of hydrazine hydrate and 90 ml of methanol is stirred for 1 hour at 20° C., heated under reflux for 4 hours and then concentrated by evaporation in vacuo. Digestion of the crystalline residue in 70 ml of diisopropyl ether, filtering and digestion again in 100 ml of isopropanol yield the title compound; m.p. 168-170° C.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].Br[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=1>>[CH3:22][C:19]1[CH:20]=[CH:21][C:16]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])=[N:17][CH:18]=1
Reactant: Cc1ccc(Br)nc1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Product: Cc1ccc(C#Cc2c(-c3ccccc3)noc2C)nc1
Yield: 55 %

Procedure:
As described for example 11c, 4-ethynyl-5-methyl-3-phenyl-isoxazole (92 mg, 0.50 mmol) was converted (using 2-bromo-5-methylpyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 75 mg, 55%) which was obtained as a light brown solid. MS: m/e=275.2 [M+H]+.