Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24]O)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[NH:39]1[CH:43]=[N:42][CH:41]=[N:40]1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[C:1]1(/[CH:7]=[CH:8]/[C:9]2[O:10][CH:11]=[C:12]([CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][N:39]4[CH:43]=[N:42][CH:41]=[N:40]4)=[CH:18][CH:17]=3)[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1nc[nH]n1
Reactant: OCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: O
Solvent: C1CCOC1
Product: C(=C/c1nc(COc2ccc(CCCn3cncn3)cc2)co1)\c1ccccc1
Yield: 61.7 %

Procedure:
To a solution of 3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propanol (760 mg), tributyl phosphine (1.01 g) and 1,2,4-triazole (280 mg) in tetrahydrofuran (15 ml) was added dropwise, at 0° C., diethyl azodicarboxylate (700 mg). The mixture was heated for one hour under reflux, poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated. The residue was subjected to a silica gel column chromatography. The crystals obtained from the fraction eluted with ethyl acetate-hexane (2:1, v/v) were recrystallized from ethyl acetate-hexane to give 1-[3-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]propyl]-1,2,4-triazole (540 mg, 70%) as colorless prisms, mp 108-109° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][OH:21].[C:22](Cl)(=[O:25])[CH2:23][CH3:24].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][CH2:20][O:21][C:22]([CH2:23][CH3:24])=[O:25]
Reactant: CCC(=O)Cl
Reactant: Cc1cc2c(cc1C)C(CCO)N(c1cccnc1)C2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCCC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Yield: 70.6 %

Procedure:
A solution of 5,6-dimethyl-2-(3-pyridyl)-3-(2-hydroxyethyl)isoindolin-1-one (50 mg, 0.18 mmol), propionyl chloride (16 mg, 0.18 mmol) and triethylamine (18 mg, 0.18 mmol) in dichlorometane was stirred at 25° C. for 3 hrs. The reaction solution was washed with water, dried, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel chromatography (chloroform:methanol=20:1) to give 43 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:49]=[CH:48][CH:47]=[CH:46][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([CH:38]=[CH2:39])=[C:34]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH:33]=2)=[CH:13][CH:12]=1>C(N(CC)CC)C.CO.[Pd]>[CH2:38]([C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:30][CH:18]2[CH:17]([C:14]3[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]4[CH:46]=[CH:47][CH:48]=[CH:49][C:3]=4[O:2][CH3:1])=[CH:16][CH:15]=3)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]2)=[CH:33][C:34]=1[O:40][CH2:41][CH2:42][CH2:43][O:44][CH3:45])[CH3:39]
Reactant: C=Cc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1OCCCOC
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1OCCCOC

Procedure:
The solution of 0.090 g of tert-butyl 4-{4-[3-(2-methoxybenyloxy)propoxy]phenyl}-3-[3-(3-methoxypropoxy)-4-vinylbenzyloxy]piperidine-1-carboxylate in 0.090 ml of triethylamine and 5.0 ml of methanol is hydrogenated in the presence of 10 mg of 10% Pd/C over 16 hours. The reaction mixture is clarified by filtration and the filtrate is concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.23 (1:2 EtOAc-heptane); Rt=30.02 (II).
Reaction SMILES: CC1(C)[NH:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:11]([O:13][CH2:14][C:15](=O)[CH3:16])=[CH:12][C:4]=2[O:3]1.[NH3:19].[H][H]>[Ni].CO>[NH2:19][CH:15]([CH3:16])[CH2:14][O:13][C:11]1[CH:12]=[C:4]([OH:3])[C:5](=[CH:9][CH:10]=1)[C:6]([NH2:7])=[O:8]
Reactant: CC(=O)COc1ccc2c(c1)OC(C)(C)NC2=O
Reactant: [H][H]
Reactant: N
Agent: [Ni]
Solvent: CO
Product: CC(N)COc1ccc(C(N)=O)c(O)c1

Procedure:
After adding about 5 g of Raney nickel catalyst, a solution of 25 g of 2,3-dihydro-2,2-dimethyl-7-(2-oxo-propoxy)-4H-1,3-benzoxazin-4-one in 500 ml of methanol is introduced into an autoclave and ammonia gas is then injected until the pressure is 5 bars. The solution is then hydrogenated at 50° and a hydrogen pressure of 100 bars until the reaction has ceased. After filtering off the catalyst and evaporating the solution, crude 4-(2-amino-propoxy)-salicylamide is obtained, which after recrystallisation from methanol melts at 185°-187°.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1.C(C1C=CC=CC=1CO)CC1C=CC=CC=1.[NH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.C([O-])([O-])=O.[K+].[K+]>>[C:18]1([CH2:17][CH2:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([N:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:3]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Clc1cncc(OCc2ccccc2CCc2ccccc2)n1
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: OCc1ccccc1CCc1ccccc1
Agent: [K+]
Product: c1ccc(CCc2ccccc2COc2cncc(N3CCNCC3)n2)cc1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-{[2-(2-phenylethyl)benzyl]oxy}pyrazine (1.72 g, 5.30 mmol; obtained according to the procedure of example 50, step 1, starting from 2-phenethylbenzyl alcohol), piperazine (1.37 g, 16.0 mmol) and K2CO3 (0.73 g, 5.3 mmol). The yield of the title compound was 1.38 g (69%) which was obtained as an oil. Purity 100% (HPLC). MS m/z 375 (M+H)+. HRMS m/z calcd for C23H26N4O (M)+ 374.2107, found 374.2113.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[Cl:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)=[O:6])=[CH:25][N:24]=1
Reactant: OB(O)c1cnc(Cl)nc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(I)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cccc(-c2cnc(Cl)nc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described infashion to that described in Example 13 using 3-iodo-N-(4-(trifluoromethoxy)phenyl)benzamide (Stage 1.1) and 2-chloropyrimidin-5-ylboronic acid to afford the title compound as a white powder. UPLC-MS (Condition 1) tR=2.93 min, m/z=394.0 [M+H]+, m/z=392.0 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.40 (d, J=8.6 Hz, 2H) 7.72 (t, J=7.7 Hz, 1H) 7.90 (d, J=9.0 Hz, 2H) 8.00-8.09 (m, 2H) 8.36 (s, 1H) 9.24 (s, 2H) 10.52 (s, 1H)
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH3:35])[C:13]([CH2:33][CH3:34])=[C:14]([C:31]#[N:32])[C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:27]([N+:28]([O-])=O)=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:18][CH:17]=1)=[O:10])[CH3:7]>C(O)C>[CH2:6]([O:8][C:9]([C:11]1[N:12]([CH3:35])[C:13]([CH2:33][CH3:34])=[C:14]([C:31]#[N:32])[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[C:27]([NH2:28])=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:20][CH:21]=1)=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(-c2ccc(-c3ncccc3[N+](=O)[O-])cc2)c(C#N)c(CC)n1C
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(-c2ccc(-c3ncccc3N)cc2)c(C#N)c(CC)n1C
Temperature: 90 °C
Yield: 60.1 %

Procedure:
Add tin (II) chloride dihydrate (669 mg, 3.54 mmol) into a solution of 3-[4-(3-nitro-pyridin-2-yl)-phenyl]-4-cyano-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (275 mg, 0.681 mmol, prepared in example E-38) in ethanol. Heat the mixture at 90° C. for 3 hours. Concentrate the reaction to remove ethanol. Dilute the residue with methylene chloride and H2O. Adjust the pH to 8 by adding saturated aqueous NaHCO3 solution. Extract with methylene chloride (2×30 mL) and EtOAc (2×30 mL). Combine the organic extracts, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the residue by flash chromatography (elution with 17% acetone in hexanes) to provide the title compound as yellow solid (153 mg, 0.409 mmol, 60%). Mass spectrum (m/e): 375.1 (M+1). Rf=0.1 (17% of acetone in hexanes).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:3]=1[CH2:4][N:5]=[N+:6]=[N-:7].Cl[C:14](=[CH2:17])[C:15]#[N:16]>CCCCCCC>[C:15]([C:14]1[N:7]=[N:6][N:5]([CH2:4][C:3]2[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:8]=2[F:12])[CH:17]=1)#[N:16]
Reactant: [N-]=[N+]=NCc1c(F)cccc1F
Reactant: C=C(Cl)C#N
Solvent: CCCCCCC
Product: N#Cc1cn(Cc2c(F)cccc2F)nn1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A mixture of 2,6-difluorobenzyl azide (34.2 g), 2-chloroacrylonitrile (26.6 g) and n-heptane (125 ml) is stirred at about 80° C. for 24 hours, whereby a suspension results. Unreacted 2-chloroacrylonitrile and 2,6-difluorobenzyl azide as well as n-heptane are distilled off (distillate 25 ml) by raising the external temperature to about 130° C. The mixture is cooled to about 20° C. and the suspension is stirred at about 20° C. for about 2 hours. The product is isolated by filtration, washed with n-heptane (100 ml) and dried in vacuo at about 60° C. Yield: 20.45 g=46.4% (beige powder).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH2:8](N(CC)CC)[CH3:9].[C:15]([OH:18])(=[O:17])[CH3:16].O1CC1C=C>COCCOCCOC>[C:15]([O:18][CH:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH:8]=[CH2:9])(=[O:17])[CH3:16]
Reactant: CC(=O)O
Reactant: CCN(CC)CC
Reactant: CC(=O)OC(C)=O
Agent: C=CC1CO1
Solvent: COCCOCCOC
Product: C=CC(COC(C)=O)OC(C)=O
Temperature: 125 °C
Reaction time: 0.02 h
Yield: 93 %

Procedure:
A 100-mL autoclave was charged with 45.25 g (0.44 mol) acetic anhydride, 1.62 g (0.016 mol) of triethylamine, 1.94 g (0.032 mol) acetic acid and 3.44 g of diglyme. The autoclave was purged with helium twice, then the vessel was pressurized to 6.2 bars (75 psig) with helium followed by agitation. The reaction mixture was heated to 125° C. Then 31.35 mL (0.40 mol) of 3,4-epoxy-1-butene was introduced to the reactor via syringe pump over 10 seconds. A first sample was taken at 1 min, then sequential samples were obtained every 15 min during the course of 2.25 hrs for analysis by GC. GC analysis of the crude mixture after 2.25 hrs revealed a 93% yield of 3,4-diacetoxy-1-butene with a 95% selectivity and 1.9% 3,4-epoxy-1-butene. The reaction was observed to be first order in 3,4-epoxy-1-butene with a first order rate constant of 0.029 min-1 (Table A). This example demonstrates the catalytic effect of a tertiary amine with two molar equivalents of acetic acid as a co-catalyst (Table B).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25]C(=O)OC(C)(C)C)[CH2:20]1.C(O)(C(F)(F)F)=O.C(Cl)[Cl:41]>CCCCO>[ClH:41].[NH2:25][C@@H:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])[C:4]=23)[CH2:20]1
Reactant: CC(C)(C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCCCO
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](N)C3)c12
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pivalamide (0.128 g, 0.407 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (0.245 g, 1.22 mmol) in n-BuOH (2 mL) were stirred at 143° C. (bath) for 24 hours. The solvent was removed, and the residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL) and dried over sodium sulfate. After removal of the solvent, the residue was purified by C-18 reverse phase flash chromatography (Biotage SP4 unit, C-18 25M column, 30-80% CH3CN/water gradient; 30 CV) to give a solid. The solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL), and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give (R)—N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)pivalamide hydrochloride (66 mg, 32% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 11.78 (s, 1H), 9.03 (s, 1H), 8.25 (s, 1H), 8.18-8.07 (m, 3H), 3.49-3.31 (4H), 3.10-3.03 (m, 1H), 2.17-2.07 (m, 1H), 1.93-1.85 (m, 1H), 1.77-1.65 (m, 1H), 1.55-2.42 (m, 1H), 1.28 (s, 91-1); LCMS (APCI+) m/z 394 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][C:8]1[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[F:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[S:36][C:35]([CH3:37])=[N:34][C:33]=2[C:38](Cl)=[O:39])=[CH:28][CH:27]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[S:36][C:35]([CH3:37])=[N:34][C:33]=2[C:38]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][C:8]2[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:39])=[CH:30][CH:31]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]2[S:36][C:35]([CH3:37])=[N:34][C:33]=2[C:38]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]2[CH2:7][C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:39])=[CH:30][CH:31]=1
Reactant: C[Si](C)(C)CCOCn1c(CC2CCCCN2)cc2ccccc21
Reactant: Cc1nc(C(=O)Cl)c(-c2ccc(F)cc2)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3ccccc3[nH]2)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3ccccc3n2COCC[Si](C)(C)C)c(-c2ccc(F)cc2)s1

Procedure:
(RS)-1-[5-(4-Fluoro-phenyl)-2-methyl-thiazol-4-yl]-1-{2-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-indol-2-ylmethyl]-piperidin-1-yl}-methanone (130 mg) was prepared from (RS)-2-piperidin-2-ylmethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indole, D68 (520 mg) and 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carbonyl chloride (512 mg) according to a procedure similar to that for Example 1. A stirring solution of the above amide (125 mg) in dry THF (5 ml) was treated with a solution of tetrabutylammonium fluoride (2.2 mmol) in THF (5 ml). Once tlc indicated the reaction had gone to completion, the reaction mixture was poured into water and the product extracted with ethyl acetate. The combined organics were washed with brine, dried (Na2SO4) and the solvent removed in vacuo. Chromatography (silica gel, 0-100% pentane-ethyl acetate followed by preparative tlc, 40% ethyl acetate-pentane) afforded the title compound as a white solid (2.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([NH:19]C(=O)C)[CH2:15][CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([NH2:19])[CH2:17][CH2:18]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CCC(NC(C)=O)CC2)cc1OC
Agent: Cl
Product: COc1ccc(CCN2CCC(N)CC2)cc1OC

Procedure:
The acetamido compound of Example 3 (2.5 g.) in 2 N hydrochloric acid (25 ml.) was heated under reflux for 3.5 hours. The cooled solution was basified and extracted with chloroform. Evaporation of the washed and dried extracts gave an oil which was treated with ethanolic hydrogen chloride to provide 1.67 g. of the title compound as its dihydrochloride, m.p. 260°-263° C. (Found: C, 53.4; H, 7.7; N, 8.3. C15H24N2O2.2HCl requires C, 53.3; H, 7.8; N, 8.3%).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C(N(CC)CC)C>C(O)CCC>[CH3:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:3]=1
Reactant: Cc1nc(Cl)c2[nH]cnc2n1
Reactant: COc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cccc(Nc2nc(C)nc3nc[nH]c23)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 2-methyl-6-chloropurine (1.69 g; 0.01 mol) and m-anisidine (1.23 g; 0.01 mol) in n-butanol (20 ml), triethylamine (3.5 ml; 0.025 mol) was added. The resulting thick suspension was stirred at 110° C. for 3 hours, when TLC showed the absence of starting material and the presence of desired product. The reaction mixture was then cooled to room temperature. The white precipitate was filtered off, rinsed with n-butanol (2×10 ml) and water (3×10 ml) and dried into constant weight. Yield: 1.92 g (75%). The crude product was purified as hydrochloride salt by the crystallization from 2.5 M methanolic hydrochloric acid. TLC (chloroform-methanol-NH4OH; 4:1:0.05): one single spot, free of starting material. HPLC purity: 99+%.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]3[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][CH2:18][C:17]=23)=[O:12])=[CH:4][C:3]=1[CH3:25].[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:8][C:7]1[CH:6]=[C:5]([CH2:9][CH2:10][C:11]([C:13]2[S:14][C:15]([CH3:24])=[C:16]3[CH2:21][C:20]([CH3:22])([CH3:23])[CH2:19][CH2:18][C:17]=23)=[O:12])[CH:4]=[C:3]([CH3:25])[C:2]=1[O:1][CH2:26][CH:28]1[CH2:29][O:30]1
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1O
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Product: Cc1cc(CCC(=O)c2sc(C)c3c2CCC(C)(C)C3)cc(C)c1OCC1CO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.3 %

Procedure:
A solution of 3-(4-hydroxy-3,5-dimethyl-phenyl)-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (200 mg, 0.561 mmol) in isopropanol (5 mL) and 3 N aq. NaOH (2 mL) is treated with epichlorohydrine (210 mg, 1.68 mmol) and the mixture is stirred at rt for 6 h before it is diluted with diethyl ether, washed with sat. aq. NaHCO3 solution followed by water, dried over MgSO4 and evaporated. The crude product is purified on prep. TLC plates with heptane:EA 1:1 to give 3-(3,5-dimethyl-4-oxiranylmethoxy-phenyl)-1-(3,5,5-trimethyl-4,5,6,7-tetrahydro-benzo[c]thiophen-1-yl)-propan-1-one (135 mg) as a yellow oil; LC-MS: tR=1.19 min, [M+1]=413.26.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[NH:14][C:13]([NH2:15])=[N:12][C:11]2[C:7]=1[N:8]=[CH:9][N:10]=2.[H-].[Na+].[N+:18]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Br)([O-:20])=[O:19].O>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:14]=[C:13]([NH2:15])[N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:24][C:23]1[CH:26]=[CH:27][CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: Nc1nc2ncnc-2c(-c2ccco2)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(-c2ccco2)c2ncn(Cc3cccc([N+](=O)[O-])c3)c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
An ice-cold solution of 6-(2-furyl)1H-purine-2-amine (201 mg, 1 mmol) in DMF (6 mL) was treated with NaH (44 mg, 1.1 mmol), stirred for 30 min, treated with 3-nitrobenzyl bromide (238 mg, 1.1 mmol), stirred at room temperature for 3 h, treated with water and the resulting solid filtered, suspended in methanol, stilled for 30 min, and filtered to give the title compound (201 mg, 60%) as a yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:7][C:8]1[O:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][N:29]=3)=[O:32])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CCO1
Reactant: O=C(O)c1ccc(F)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(F)cn3)ccc2F)CCOC(N)=N1

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-carbamic acid tert-butyl ester from experiment F1 (R3=Me) and 5-fluoro-pyridine-2-carboxylic acid followed by deprotection using procedure H yielded the title compound. MS (ESI): m/z=347.0 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][C:3]([CH:5]1[CH:10]2[CH:8]([C:9]2([CH3:12])[CH3:11])[C:7](=[O:13])[O:6]1)=[O:4].C(Cl)Cl.C(Cl)(Cl)Cl.[Br:21]Br>O>[Br:1][CH:2]([Br:21])[C:3]([CH:5]1[CH:10]2[CH:8]([C:9]2([CH3:11])[CH3:12])[C:7](=[O:13])[O:6]1)=[O:4]
Reactant: BrBr
Reactant: CC1(C)C2C(=O)OC(C(=O)CBr)C21
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1(C)C2C(=O)OC(C(=O)C(Br)Br)C21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
0.125 g of (1R-(1 α, 4 β, 5α))-4-(bromoacetyl)-6,6-dimethyl-3-oxabicyclo [3.1.0] hexan-2-one of Example 3 were mixed under an inert ga atmosphere with 1 ml of methylene chloride and 1 ml of chloroform. 50 μl of bromine were added slowly at +25° to 30° C. and the mixture was stirred for 48 hours at ambient temperature. Water was added, followed by decanting and extracting with methylene chloride. The organic phase was dried and the solvent was evaporated under reduced pressure to obtain 0.199 g of the crude expected product in the form of an oil.
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][CH: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][N:30]([CH3:32])[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][CH: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][N:30]([CH3:32])[CH3:31])=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: COc1ccccc1C1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Product: COc1ccccc1C1CCN(C(=O)c2cn(CCN(C)C)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-methoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) (2-chloro-ethyl)-dimethyl-amine gave the title compound.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])=[CH:7][C:6]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.C(N(CC)C(C)C)(C)C.[NH2:37][CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>CN(C)C(=O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:37][CH:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[C:6]([C:22]2[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=2)[CH:7]=1)=[O:21]
Reactant: NC1CCOCC1
Reactant: Cn1nccc1-c1cc(NC(=O)c2ccc(F)cc2F)ccc1OCCBr
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1-c1cc(NC(=O)c2ccc(F)cc2F)ccc1OCCNC1CCOCC1
Temperature: 120 °C
Yield: 71.2 %

Procedure:
To a solution of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4-difluoro-benzamide (0.050 g, 0.12 mmol) in N,N-dimethylacetamide (2.0 mL) was added N,N-diisopropylethylamine (0.040 mL, 0.23 mmol) and 4-aminotetrahydropyran (0.032 mL, 0.32 mmol) in a heavy-walled sealed tube. The solution was heated under microwave irradiation at 120° C. for 1 h. The solution was concentrated and purified by RP-HPLC. Lyophilization afforded a TFA salt as a brown solid (0.039 g, 59%). LCMS m/z (%)=457 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ 10.45 (s, 1H), 7.81 (dd, J=2.6, 9.0 Hz, 1H), 7.79-7.72 (m, 1H), 7.66 (d, J=2.6 Hz, 1H), 7.52 (d, J=1.8 Hz, 1H), 7.48-7.40 (m, 1H), 7.28-7.20 (m, 2H), 6.34 (d, J=1.8 Hz, 1H), 4.28-4.23 (m, 2H), 3.84 (dd, J=4.0, 11.4 Hz, 2H), 3.69 (s, 3H), 3.40-3.32 (m, 2H), 3.32-3.14 (m, 2H), 3.14-3.03 (m, 1H), 1.85 (m, 2H), 1.48-1.36 (m, 2H).