Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)=[C:5]2[Cl:21].[CH3:22][O:23]C1C=CC(CC(C(O)=O)C(O)=O)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[C:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:23][CH3:22])=[CH:16][CH:15]=1)=[C:5]2[Cl:21]
Reactant: COc1ccc(CC(C(=O)O)C(=O)O)cc1
Reactant: Clc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Product: COc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1

Procedure:
The title compound was prepared by substituting 2-(4-chlorobenzyl)malonic acid (Intermediate 3: step b) with 2-(4-methoxybenzyl)malonic acid (Intermediate 7: step b) then following the procedure described for the preparation of 6-bromo-2,4-dichloro-3-(4-chlorobenzyl)quinoline (Intermediate 3: step c).
Reaction SMILES: Br[CH:2]=[CH:3][CH2:4][CH2:5][CH2:6][CH3:7].[H-].[Na+].[NH:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12].O>CS(C)=O>[CH2:7]([N:10]1[C:21](=[O:22])[C:20]2[N:18]([CH3:19])[CH:17]=[N:16][C:15]=2[N:13]([CH3:14])[C:11]1=[O:12])[CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCCCC=CBr
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 43 h
Yield: 98.2 %

Procedure:
1-(5,6-Oxidohexyl)-3,7-dimethylxanthine was synthesized as follows: A mixture of 1-bromohexene (10.7 g, 66 mmol), sodium hydride (1.58 g, 66 mmol), and theobromine (11.9 g, 66 mmol) in dimethylsulfoxide (100 ml) was stirred for 43 hours. The solution was treated with water (200 ml) and then extracted with dichloromethane (3×80 mL). The combined extracts were washed with water (3×100 ml), dried over magnesium sulfate, and then the solvent was evaporated under vacuum to give 1-(5-hexenyl)-3,7-dimethylxanthine (17 g, 98% yield) as a white powder.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:26])[C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[CH:9]1.Cl[C:28]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[C:29]([C:32]#[N:33])[C:30]#[N:31]>CCO>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:26])[C:18]([N:20]2[CH2:21][CH2:22][N:23]([C:28]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[C:29]([C:32]#[N:33])[C:30]#[N:31])[CH2:24][CH2:25]2)=[O:19])=[CH:9]1
Reactant: O=C(C(=O)N1CCNCC1)c1c[nH]c2ccccc12
Reactant: N#CC(C#N)=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CC(C#N)=C(c1ccccc1)N1CCN(C(=O)C(=O)c2c[nH]c3ccccc23)CC1
Reaction time: 16 h

Procedure:
Triethyl amine (1 ml) was added into a solution of 1-(1H-indol-3-yl)-2-(piperazin-1-yl)ethane-1,2-dione (150 mg) and 2-(chloro(phenyl)methylene)malononitrile (110 mg) in EtOH (20 ml). After 16 hours at 115° C., the reaction mixture was cooled down. Then the solvents were removed to offer a residue which was purified using Shimadzu automated preparative HPLC System to afford 2-((4-(2-(1H-indol-3-yl)-2-oxoacetyl)piperazin-1-yl)(phenyl)methylene)malononitrile.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[CH:12][C:13]([NH:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1)=[O:14].[N+:27]([CH2:30]C(C1C=CC=CC=1)CC(NC1C=CC(C(OCC)=O)=CC=1)=O)([O-:29])=[O:28]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH2:30][N+:27]([O-:29])=[O:28])[CH2:12][C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:25][CH:26]=1)=[O:14]
Reactant: CCOC(=O)c1ccc(NC(=O)CC(C[N+](=O)[O-])c2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(NC(=O)C=Cc2ccc3ccccc3c2)cc1
Product: CCOC(=O)c1ccc(NC(=O)CC(C[N+](=O)[O-])c2ccc3ccccc3c2)cc1
Yield: 70 %

Procedure:
This was prepared from corresponding amide 42 (0.995 g, 2.88 mmol) in a similar manner as described for preparation of 47. Chromatography on silica gel performed using a FlashMaster 3 purification station (75:25 hexanes/ethyl acetate, Rf 0.20) afforded 48 (0.819 g, 2.017 mmol, 70%) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 1.26 (3H, t, J 7.6 Hz), 2.85-2.93 (2H, m), 4.10 (1H, quint, J 8.0 Hz), 4.23 (1H, q, J 7.2 Hz), 5.02-5.10 (2H, m), 7.45-7.48 (2H, m), 7.54 (1H, dd, J 1.6, 8.8 Hz), 7.62 (2H, d, J 8.8 Hz), 7.82-7.87 (6H, m). 13C NMR (400 MHz, CDCl3) δ 14.52, 40.75, 40.79, 61.21, 79.48, 119.21, 124.97, 126.43, 126.65, 126.78, 126.87, 127.92, 128.04, 129.37, 130.94, 133.11, 133.59, 135.89, 141.68, 166.37, 168.54. MS (API-ES): m/z found 407 [M+H]+ (100%), HRMS (API-ES) m/z 407.1607 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]([NH2:19])[NH:16][N:15]=1)(=[O:13])=[O:12].[C:20](Cl)(=[O:25])[CH2:21][C:22](Cl)=[O:23]>C(#N)C>[OH:23][C:22]1[CH:21]=[C:20]([OH:25])[N:16]2[N:15]=[C:14]([S:11]([NH:10][C:3]3[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([CH3:8])[C:2]=3[Cl:1])(=[O:13])=[O:12])[N:18]=[C:17]2[N:19]=1
Reactant: O=C(Cl)CC(=O)Cl
Reactant: Cc1ccc(Cl)c(NS(=O)(=O)c2n[nH]c(N)n2)c1Cl
Solvent: CC#N
Product: Cc1ccc(Cl)c(NS(=O)(=O)c2nc3nc(O)cc(O)n3n2)c1Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 85 %

Procedure:
To a stirred solution of 2.52 grams (g) (0.0078 moles) of N-(3-(((2,6-dichloro-3-methylphenyl)amino)sulfonyl)-1H-1,2,4-triazol-5-yl)amine in 100 milliliters (mL) of dry acetonitrile under nitrogen was added 1.5 g (0.01 moles) of freshly distilled malonyl chloride. The mixture was stirred at ambient temperature overnight (14 hr) and a yellow precipitate formed. The solid product was collected by filtration and dried; mp 280°-282° C. (decomposes). The filtrate was found to contain additional product which was recovered by concentrating the filtrate to dryness. The combined yield of product was 2.58 g (85 percent yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.F[C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc(C=O)cc2)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
20 ml (0.18 mol) of 1-methylpiperazine and 19 ml (0.18 mol) of 4-fluorobenzaldehyde (Fluka, Buchs, Switzerland), in each case in 45 ml of DMSO, are added to 25 g (0.18 mol) of K2CO3 in 90 ml of DMSO and the whole is stirred at 100° C. for 3 h. The reaction mixture is cooled down and poured onto 2l of ice water; this mixture is then extracted twice with ethyl acetate. The organic phases are washed with brine, dried (Na2SO4) and concentrated by evaporation, with the title compound thereby being obtained:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]O)=[CH:17][N:16]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:32])=O>O>[Cl:32][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CO)cn1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.3 %

Procedure:
To a mixture of 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine-5-methanol (12.2 g) and toluene (200 ml) was added thionyl chloride (5.39 g), and the mixture was stirred at room temperature for 1 hr. Iced water was added to the reaction mixture, and after neutralization with saturated aqueous sodium hydrogencarbonate, the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give crystals (11.7 g, yield 90%) of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine from a fraction eluted with ethyl acetate-hexane (1:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 86-87° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C@@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][CH:16]=[CH2:17])[CH:9]=1.[CH3:26][C@H:27]([CH:31]=[CH2:32])[C:28](O)=[O:29].N1C=CC=CC=1>CCOC(C)=O>[CH3:26][C@H:27]([CH:31]=[CH2:32])[C:28]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C@@H:14]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15][CH:16]=[CH2:17])[CH:9]=1)=[O:29]
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccccc2N)ccn1
Reactant: C=C[C@@H](C)C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)c1cc(-c2ccccc2NC(=O)[C@H](C)C=C)ccn1
Temperature: 25 °C
Yield: 84.6 %

Procedure:
To a solution of 45D (1.4 g, 4.12 mmol), (R)-2-methylbut-3-enoic acid (0.58 g, 5.79 mmol) in EtOAc (41.2 ml) was added pyridine (1.001 ml, 12.37 mmol). The reaction was cooled down to 0° C. under Ar and propane phosphonic acid anhydride (4.91 ml, 8.25 mmol) was added dropwise. The reaction was then gradually warmed up to rt over night. The reaction mixture was diluted and washed with sat. aq. NaHCO3, aqueous layer back-extracted with EtOAc, combined EtOAc phase washed with brine, dried over MgSO4, filtered, concentrated. The residue was purified by silica gel chromatography to give the desired product (1.47 g, 85%) as an off white foam. 1H NMR (500 MHz, CHLOROFORM-d) δ 8.65-8.60 (m, 1H), 8.19 (d, J=8.3 Hz, 1H), 7.47-7.36 (m, 2H), 7.24-7.18 (m, 3H), 7.16 (dd, J=5.0, 1.4 Hz, 1H), 5.82-5.62 (m, 3H), 5.10-5.01 (m, 4H), 4.86 (d, J=7.2 Hz, 1H), 3.03 (quin, J=7.2 Hz, 1H), 2.62 (tq, J=14.1, 6.9 Hz, 2H), 1.49-1.36 (m, 9H), 1.25 (d, J=7.2 Hz, 3H). MS (ESI) m/z: 422.1 (M+H)+.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][N:8]=[C:7]([N:14]=[CH:15][N:16]([CH3:18])[CH3:17])[CH:6]=1>C(O)C.[Pd]>[CH3:17][N:16]([CH3:18])[CH:15]=[N:14][C:7]1[CH:6]=[C:5]2[CH:4]=[CH:3][NH:11][C:10]2=[CH:9][N:8]=1
Reactant: CN(C)C=Nc1cc(/C=C/N(C)C)c([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CCO
Product: CN(C)C=Nc1cc2cc[nH]c2cn1
Reaction time: 24 h
Yield: 104.7 %

Procedure:
A suspension of N′-[4-((E)-2-dimethylamino-vinyl)-5-nitro-pyridin-2-yl]-N,N-dimethyl-formamidine (Preparation #10a, 8.36 g, 31.4 mmol) and 10% Pd on carbon (800 mg) in ethanol (120 mL) was shaken in a hydrogenation vessel under an atmosphere of 10-55 psi H2 for about 24 hours. The reaction was filtered through Celite® and concentrated to yield N,N-dimethyl-N′-(1H-pyrrolo[2,3-c]pyridin-5-yl)-formamidine (6.19 g, 105%) as a dark solid. RP HPLC (Table 1, Method e) Rt=0.84, m/z: (MH)+ 189. The crude product was used in the next step without further purification.
Reaction SMILES: O[Li].[OH2:3].C(OC(=O)[CH2:8][CH:9]1[N:14]2[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=[C:13]2[C:12](=[O:21])[NH:11][CH2:10]1)C.O1CCCC1.[OH2:28]>>[N+:18]([C:16]1[CH:17]=[C:13]2[C:12](=[O:21])[NH:11][CH2:10][CH:9]([C:8]([OH:28])=[O:3])[N:14]2[CH:15]=1)([O-:20])=[O:19]
Reactant: O
Reactant: CCOC(=O)CC1CNC(=O)c2cc([N+](=O)[O-])cn21
Agent: [Li]O
Solvent: C1CCOC1
Product: O=C1NCC(C(=O)O)n2cc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
LiOH.H2O (27 mg, 1.12 mmol) was added to a solution of ethyl(7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (V, where R1=OCH2CH3) (0.15 g, 0.56 mmol) in a mixture tetrahydrofuran-water (1:1, 9 mL) and the reaction mixture was stirred at room temperature for 3 h. The organic phase was washed with dichloromethane (2×10 mL). The aqueous phase was acidified with hydrochloric acid (1 M) to reach pH<1 and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated under vacuum to obtain compound 7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (V, where R1=OH) as an off-white solid (101 mg, 75% yield).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)#[CH:2].Br[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([NH:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[O:30])=[CH:24][CH:23]=1.C#C>>[C:36]([O:35][C:33]([NH:32][NH:31][C:29]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:2]#[C:1][C:3]2[N:4]=[C:5]([CH:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]3)[S:6][CH:7]=2)=[CH:27][CH:26]=1)=[O:30])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: C#Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(Br)cc1
Agent: C#C
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(C#Cc2csc(C3CCN(C(=O)OC(C)(C)C)CC3)n2)cc1
Yield: 18 %

Procedure:
Using tert-butyl 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine-1-carboxylate and tert-butyl 2-[(4-bromophenyl)acetyl]hydrazinecarboxylate as starting materials, Sonogashira-Castero-Stephens acetylene coupling was performed under reaction conditions similar to those of Production Example 1, step 4 to give tert-butyl 4-[4-({4-[2-(tert-butoxycarbonyl)hydrazino]carbonylmethylphenyl}ethynyl)-1,3-thiazol-2-yl]piperidine-1-carboxylate (yield 18%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1)[CH3:2]>C(O)C.C(O)(=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16](=[O:19])[O:17][CH3:18])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2cncc(NC(=O)OC)c2)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: CCc1ccc(C2CNCC(NC(=O)OC)C2)cc1

Procedure:
A solution of 1.0 g (3.7 mmol) of methyl [5-(4-ethylphenyl)pyridin-3-yl]carbamate in 100 ml of ethanol and 100 ml of acetic acid was reacted according to General Method 5A. The solution was concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, dichloromethane/methanol 4:1). Yield: 171 mg (16% of theory)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:8]1>C(#N)C>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=2)[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:8]1
Reactant: CS(=O)(=O)c1cn(CC2=NCCN2)c2ccc([N+](=O)[O-])cc12
Solvent: CC#N
Product: CS(=O)(=O)c1cn(CC2=NCCN2)c2ccc(N)cc12

Procedure:
1-(4,5-Dihydro-1H-imidazol-2-ylmethyl)-3-methanesulfonyl-1H-indol-5-ylamine, (mp 215-217° C.) was prepared by reduction of the nitro group of compound 1-(4,5-dihydro-1H-imidazol-2-ylmethyl)-3-methanesulfonyl-5-nitro-1H-indole, with TiCl3 in aqueous acetonitrile.
Reaction SMILES: COC1N=CC(N2CCC([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=4)[CH2:16]3)CC2)=CC=1.[Cl:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][C:47](=O)[CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1.COC1N=CC(N2CCC(=O)CC2)=CC=1>>[Cl:37][C:38]1[CH:39]=[C:40]([N:44]2[CH2:49][CH2:48][CH:47]([N:15]3[CH2:19][CH2:18][C@@H:17]([NH:20][C:21](=[O:36])[CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:34])[F:33])[CH:26]=4)[CH2:16]3)[CH2:46][CH2:45]2)[CH:41]=[CH:42][CH:43]=1
Reactant: O=C1CCN(c2cccc(Cl)c2)CC1
Reactant: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn1
Agent: COc1ccc(N2CCC(=O)CC2)cn1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCN(c3cccc(Cl)c3)CC2)C1

Procedure:
The title compound was synthesized in similar fashion to N-[2-({(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, whereby 1-(3-chlorophenyl)piperidin-4-one was substituted for 1-(6-methoxypyridin-3-yl)piperidin-4-one, and was isolated as a white solid. 1H-NMR (CDCl3) δ: 1.87-2.10 (m, 5H), 2.37-2.44 (m, 1H), 2.66-2.74 (m, 2H), 2.86-2.95 (m, 2H), 3.03-3.09 (m, 1H), 3.55 (d, J=11.7 Hz, 1H), 3.64-3.76 (m, 3H), 4.06-4.23 (m, 2M), 4.79-4.83 (m, 1H), 6.74-6.78 (m, 1H), 6.83-6.85 (m, 2H), 7.13-7.18 (m, 1H), 7.53-7.57 (m, 1H), 7.66-7.75 (m, 2H), 8.09 (m, J=7.5 Hz, 1H), 8.20 (s, 1H), 8.28 (s, 1H), 9.09 (d, J=7.8 Hz, 1H). MS m/z: 509 (M+1).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:10]=[C:9]3SC)[CH2:3][CH2:2]1.ClC1C=CC=C(C(OO)=[O:34])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+].CC1NN=C(N)C=1>C(Cl)Cl.C1COCC1>[CH:1]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]3[C:13]=2[N:12]=[C:11]([C:14]([F:23])([F:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:10]=[C:9]3[OH:34])[CH2:3][CH2:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C3CC3)cccc12
Agent: Cc1cc(N)n[nH]1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: ClCCl
Product: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C3CC3)cccc12
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
To 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline (150 mg, 0.41 mmol) in DCM (5 mL) cooled to 0° C. was added 3-chloroperbenzoic acid (70%, 42 mg, 0.17 mmol) and the mixture stirred for 15 min. The mixture was diluted with DCM and then a sodium thiosulfate solution, followed by a saturated sodium bicarbonate solution was added. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the obtained residue was added THF (4 mL) and 5-methyl-1H-pyrazol-3-amine (185 mg, 1.9 mmol) and the mixture stirred at rt for 30 min. The crude mixture was concentrated under reduced pressure and then purified by preparative HPLC (Varian C-18 reverse phase column, eluted with gradient of solvent B=0.05% formic acid/ACN and solvent A=5% ACN/0.05% formic acid/H2O) to afford 8-cyclopropyl-2-(difluoro(5-fluoropyridin-2-yl)methyl)quinazolin-4-ol (50 mg, 37%). LC-MS (ESI) m/z 332 (M+H)+.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1)#[C:2][CH3:3].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.C(C1CNCCN1)#CC.C(N(CC)CC)C.[S:40]1[CH:44]=[CH:43][CH:42]=[C:41]1[S:45](Cl)(=[O:47])=[O:46]>C(Cl)Cl>[C:1]([CH:4]1[NH:5][CH2:6][CH2:7][N:8]([S:45]([C:41]2[S:40][CH:44]=[CH:43][CH:42]=2)(=[O:47])=[O:46])[CH2:9]1)#[C:2][CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC#CC1CNCCN1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC#CC1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The 2-(1-propyn-1-yl)piperazine bis(trifluoroacetate (110 mg, 0.312 mmol) was dissolved in CH2Cl2 in a 50 mL round-bottomed flask and was then cooled to 0° C. To this solution was added an excess of triethylamine (152 μL, 1.093 mmol) followed by thiophene-2-sulfonyl chloride (57.0 mg, 0.312 mmol, Sigma-Aldrich, St. Louis, Mo.). The mixture was warmed slowly to room temperature and stirred for 2 h. Afterwards, the mixture was concentrated and absorbed onto silica gel. The crude material was purified via column chromatography (about 40 g silica gel, 0% to 10% MeOH in CH2Cl2) to give 3-(1-propyn-1-yl)-1-(2-thiophenylsulfonyl)piperazine (42 mg) as a foamy solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[CH3:12][C:13]([CH3:34])([CH:16]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)OS(C1C=CC(C)=CC=1)(=O)=O)[C:14]#[N:15].[OH-].[Na+]>O1CCCC1.O>[CH3:12][C:13]([CH3:34])([CH2:16][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:14][NH2:15]
Reactant: Cc1ccc(S(=O)(=O)OC(c2ccncc2)C(C)(C)C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(CN)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
Lithium aluminum hydride (345 mg, 9.10 mmol) was put under a nitrogen atmosphere, and anhydrous diethyl ether (10 ml) was added dropwise thereto under ice-cold water-cooling. Next, a solution of 2,2-dimethyl-3-(4-pyridyl)-3-(p-tolylsulfonyloxy)propionitrile (600 mg, 1.82 mmol) in tetrahydrofuran (10 ml) was added dropwise to the mixture. The whole was stirred at room temperature overnight, and water (324 μl), a 15% aqueous sodium hydroxide solution (324 μl) and water (972 μl) were added successively to the reaction mixture under ice-cold water-cooling while stirring it vigorously. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained concentrate was purified by silica gel column chromatography to give the target compound (83.0 mg, 0.505 mmol, 28%) as a pale yellow oily matter.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]1)=[O:7].O[N:28]=[C:29]([NH2:31])[CH3:30]>>[CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH:12]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)[CH2:11][CH:10]([C:24]2[O:25][N:31]=[C:29]([CH3:30])[N:28]=2)[CH2:9]1)=[O:7]
Reactant: CC(N)=NO
Reactant: COCCNC(=O)N1CC(C(=O)O)CC(c2ccc(C(F)(F)F)cc2)C1
Product: COCCNC(=O)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(C)no2)C1
Yield: 42.9 %

Procedure:
100 mg (0.26 mmol) of the compound from Example 105A and 40 mg (0.534 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Diastereomer separation of 62 mg of the cis/trans isomer mixture according to Method 12C gave 46 mg of the title compound and 5.7 mg of the trans isomer.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.C([Li])(C)(C)C.CCCCC.[CH3:20][N:21]([CH3:35])[C:22]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]1>C1COCC1>[S:1]1[C:5]([C:25]2([OH:28])[CH2:26][CH2:27][C:22]([N:21]([CH3:20])[CH3:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][CH2:24]2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CN(C)C1(c2ccccc2)CCC(O)(c2cc3ccccc3s2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
A solution of benzo[b]thiophene (400 mg, 2.98 mmol) in dry THF (20 ml) was cooled to −5° C. under a stream of argon. Tert-butyllithium (3.58 mmol, 2.11 ml of a 1.7 molar pentane solution) was carefully added dropwise, to avoid exceeding a reaction temperature of 0° C. Once all the substance had been added, the reaction mixture was stirred for 2 hours at 0° C. A solution of 4-dimethylamino-4-phenylcyclohexanone (648 mg, 2.98 mmol) in dry THF (5 ml) was then added dropwise at 0° C. The mixture was stirred for 15 minutes at 0° C. and then 6 hours at ambient temperature. The reaction mixture was quenched with saturated ammonium chloride solution (20 ml), the organic phase was separated and the aqueous phase extracted four times with dichloromethane (20 ml). The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed under vacuum. Purification was carried out by flash chromatography over silica gel with cyclohexane/ethylacetate (V:V=1:1). 345 mg 1-benzo[b]thiophen-2-yl-4-dimethylamino-4-phenylcyclohexanol with a melting point of 183–185° C. were obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-].[Na+]>Br>[N:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:10]1[CH2:11][CH2:12][CH2:13][CH:9]1[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(C2CCCN2Cc2ccccn2)c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Oc1cccc(C2CCCN2Cc2ccccn2)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
2-(3-Methoxyphenyl)-1-(2-pyridinylmethyl)pyrrolidine and 48% hydrobromic acid (40 ml) were warmed to 100° C. for 7 hrs, cooled to ambient temperature, and neutralized with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (2 times). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by flash column chromatography (silica gel, 1:1 ethyl acetate/dichloromethane). The appropriate fractions were collected and concentrated to give 2.7 g (69%) of product, mp 96°-98° C.