Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([C:22]#[N:23])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1.[I-].[Zn+2].[I-].O>[NH2:23][CH2:22][C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)([OH:17])[CH3:16]
Reactant: C[Si](C)(C)C#N
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(CN)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
A mixture of 1-(4-benzyloxy-phenyl)-ethanone (18.50 g; 81.8 mmol), zinc iodide (0.52 g; 1.6 mmol), and trimethylsilyl cyanide (33.8 mL; 269.8 mmol) was stirred overnight at RT. Subsequently, the excess trimethylsilyl cyanide was removed in vacuo, and the residue dissolved in THF (100 mL). The resulting solution was added, dropwise, to a mixture of lithium aluminum hydride (12.7 g; 335.2 mmol) in THF (200 mL). The resulting mixture was heated under reflux for 2 h. Next, the mixture was cooled to 0° C. and treated successively with water (13 mL), 2M aqueous NaOH (26 mL), and water (13 mL). Thereafter the mixture was heated under reflux for 15 minutes, cooled again to RT, filtered over Kieselguhr, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, MeOH) to afford 1-Amino-2-(4-benzyloxy-phenyl)-propan-2-ol (18.15 g).
Reaction SMILES: C(OC1C(=O)N=C(CC2(C3C=CC=CC=3)CCCC2)N2CCN(C3CC3)C(=O)C=12)C1C=CC=CC=1.O[CH2:37][CH2:38][N:39]([CH:69]1[CH2:74][CH2:73][O:72][CH2:71][CH2:70]1)[C:40]([C:42]1[C:47]([O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[C:46]([OH:56])[N:45]=[C:44]([CH2:57][C:58]2([C:63]3[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=3)[CH2:62][CH2:61][CH2:60][CH2:59]2)[N:43]=1)=[O:41]>>[CH2:49]([O:48][C:47]1[C:46](=[O:56])[N:45]=[C:44]([CH2:57][C:58]2([C:63]3[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=3)[CH2:59][CH2:60][CH2:61][CH2:62]2)[N:43]2[CH2:37][CH2:38][N:39]([CH:69]3[CH2:70][CH2:71][O:72][CH2:73][CH2:74]3)[C:40](=[O:41])[C:42]=12)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C(c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CCOCC1
Agent: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CC1
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccccc4)CCCC3)n2CCN1C1CCOCC1
Yield: 56.2 %

Procedure:
This compound was prepared following the same method as described for 9-benzyloxy-2-cyclopropyl-6-(1-phenyl-cyclopentylmethyl)-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (286) from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-(tetrahydro-pyran-4-yl)-amide (309) (440 mg, 0.90 mmol). The product was obtained as a white solid (260 mg, 56.1%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C(Cl)Cl>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(Cl)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2ccc(Cl)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-chloro-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:17]([NH2:19])=[O:18])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[CH2:20]([C:22]1[CH:23]=[C:24]([N:28]=[C:29]=[O:30])[CH:25]=[CH:26][CH:27]=1)[CH3:21]>C1COCC1.C(OCC)(=O)C>[CH2:20]([C:22]1[CH:23]=[C:24]([NH:28][C:29]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]([C:17]([NH2:19])=[O:18])[C:10]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][CH:11]=4)=[CH:4][CH:3]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)[CH3:21]
Reactant: NC(=O)n1c(-c2ccc(N)cc2)cc2ccccc21
Reactant: CCc1cccc(N=C=O)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCc1cccc(NC(=O)Nc2ccc(-c3cc4ccccc4n3C(N)=O)cc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The reaction mixture of 2-(4-amino-phenyl)-indole-1-carboxylic acid amide (125.5 mg, 0.5 mmol, 1 eq) and 3-ethylphenyl isocyanate (0.073 mL, 1 eq) in anhydrous THF (4 mL) was stirred at room temperature for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous NH4Cl, saturated aqueous NaHCO3, brine, and dried with anhydrous sodium sulfate. The upper liquor was decanted, concentrated, and the solid residue was triturated with EtOAC-Hex (1:1). 2-[4-({[(3-ethylphenyl)amino]carbonyl}amino)phenyl]-1H-indole-1-carboxamide was obtained as white solid upon filtration in amount of 156 mg (78%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=2)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=1[CH2:8][CH3:9].[NH2:24][CH2:25][C:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.CN1C(=O)CCC1.C(OCC)(=O)C>O>[NH2:32][C:26]1([CH2:25][NH:24][C:2]2[N:3]=[C:4]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:15]=3)[C:5]([C:10]([NH2:12])=[O:11])=[N:6][C:7]=2[CH2:8][CH3:9])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCc1nc(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)nc1Cl
Reactant: NCC1(N)CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1nc(C(N)=O)c(Nc2cccc(S(C)(=O)=O)c2)nc1NCC1(N)CCCCC1
Temperature: 180 °C
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A mixture of 5-chloro-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Preparation Example 353) (150 mg), 1-(aminomethyl)cyclohexaneamine (163 mg) and NMP (1 mL) was heated at 180° C. for 20 minutes using a microwave reaction system. The reaction liquid was cooled, and ethyl acetate and water were added and stirred for 30 minutes. Thereafter, the precipitated powder was collected by filtration. This powder was heated with ethanol-water (1:1) and washed to give 5-{[(1-aminocyclohexyl)methyl]amino}-6-ethyl-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (112 mg) as a white solid.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=1)(=O)=O.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>CC#N>[CH3:20][S:17]([C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:8]=[C:7]([C:21]([F:24])([F:23])[F:22])[N:6]=[C:5]([NH:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[N:10]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: NCc1ccccn1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(S(C)(=O)=O)n2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)nc(NCc3ccccn3)n2)cc1
Yield: 80 %

Procedure:
To a stirred solution of 2-(methylsulfonyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyrimidine (0.10 g, 0.26 mmol) in MeCN (4 ml) was added 2-(aminomethyl)-pyridine (0.14, 5 eq) and the resultant solution heated under reflux for 3 h. The cooled reaction mixture was concentrated in vacuo and purified by SPE chromatography using chloroform, diethyl ether, ethyl acetate, acetone and methanol as the eluotropic series of solvents. Concentration in vacuo of the combined fractions containing pure product gave the title compound as a colourless solid (0.086 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:15])[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH2:10][CH2:11][CH:12]=2)[N:7]=1.Cl.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23]Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH2:10][CH2:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:15][CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[N:3]=1
Reactant: N#Cc1c(C2=CCCO2)nc(N)[nH]c1=O
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1c(OCc2ccccn2)nc(N)nc1C1=CCCO1

Procedure:
From 2-amino-4-(4,5-dihydro-furan-2-yl)-6-oxo-1,6-dihydro-pyrimidine-5-carbonitrile, 2-picolyl chloride hydrochloride and caesium carbonate in DMF. ES-MS m/e (%): 296 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][CH2:10][CH2:11]Br>>[Br:9][CH2:10][CH2:11][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: BrCCBr
Reactant: Oc1ccccc1Cl
Product: Clc1ccccc1OCCBr

Procedure:
2-Chlorophenol was reacted with 1,2-dibromoethane according to the procedure described in Step 2A to yield the titled compound.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH2:12][N:13]2[C:34](=[O:35])[N:16]3[CH:17]=[CH:18][C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[C:20]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[C:15]3=[N:14]2)=[CH:10][CH:9]=[C:8]([C:36]([F:39])([F:38])[F:37])[N:7]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:19]2[CH:18]=[CH:17][N:16]3[C:34](=[O:35])[N:13]([CH2:12][C:11]4[C:6]([CH2:5][OH:4])=[N:7][C:8]([C:36]([F:38])([F:39])[F:37])=[CH:9][CH:10]=4)[N:14]=[C:15]3[C:20]=2[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[CH:32][CH:31]=1
Reactant: CC(=O)OCc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2CO)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)ccn12
Yield: 76.8 %

Procedure:
A solution of (3-((7-(4-chlorophenyl)-3-oxo-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)methyl)-6-(trifluoromethyl)pyridin-2-yl)methyl acetate (220 mg, 0.397 mmol) and 1.0 M aqueous K2CO3 solution (3.1 mL, 3.1 mmol) in methanol (7 mL) was stirred at room temperature for 30 min, then concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (12 g) eluted with a gradient of ethyl acetate (50-100%) in hexanes to afford 156 mg (77%) of the title compound as a yellow foam. A portion of the product (110 mg) was further purified using preparative reverse phase HPLC (Phenomenex Luna 5 μm C-18 21.2×100 mm column eluted with a linear gradient of 50% to 100% B over 8 min (A=90% water, 10% methanol and B=90% methanol, 10% water) with flow rate at 20 mL/min and UV detection at 220 nm). The desired fractions were concentrated under reduced pressure. The residue was dissolved in acetonitrile, frozen and lyophilized to afford 97 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.67 min, [M+H]+=512.0.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[CH2:5]([NH2:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O>[Cl:1][CH2:2][CH:3]=[N:12][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=CCCl
Reactant: NCc1ccccc1
Solvent: O
Product: ClCC=NCc1ccccc1

Procedure:
A solution of 4 ml of chloroacetaldehyde in 20 ml of demineralized water was cooled and a solution of 2.14 g of benzylamine in 10 ml of water was added thereto with stirring. After stirring for 5 minutes at 10° to 15° C., a gum was obtained and a turbid solution which was extracted with 30 ml and then with 20 ml of benzene. The organic solution was dried, filtered, rinsed and the filtrate was evaporated to dryness under vacuum to obtain 3.34 g of 2chloro-N-benzylethanimine which was used as is for the next step.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21](Cl)=[O:22]>CCOCC>[Cl:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[Cl:27])[C:21]([N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]2)=[N:9]1)=[O:22]
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Solvent: CCOCC
Product: CN1CCC(c2nn(C(=O)c3ccc(Cl)c(Cl)c3)c3ccccc23)CC1
Temperature: 100 °C
Yield: 57 %

Procedure:
A mixture of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole and 8 ml of 3,4-dichlorobenzoyl chloride was heated at 100° C. in a steam bath for 4 hrs. After the reaction mixture cooled to ambient temperature, ether was added and the salt was collected. The salt was mixed with water and ammonium hydroxide solution was added until the mixture was basic. The mixture was warmed on the steam bath for about 5 mins, cooled and extracted with dichloromethane. Evaporation of the dichloromethane in vacuo provided the free base. The base was recrystallized from methanol-trichloromethane (with concentration of the mother liquor) to yield 3.0 g (57%) of product, mp 187°-189° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].C(N(CC)CC)C.[C:26]1([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:26]1([N:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][CH2:4][N:5]3[C:9]4[CH:10]=[CH:11][CH:12]=[C:13]5[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=45)[S:6]3(=[O:18])=[O:17])[CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CCN(c2ccccc2)CC1
Temperature: 20 °C

Procedure:
The experiment is carried out as in Example 1, starting with 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.5 g), triethylamine (4.2 cc) and N-phenylpiperazine (4.8 cc) in toluene (80 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (30 cc), 2-[3-(4-phenyl-1-piperazinyl)propyl]naphtho[1,8-cd]isothiazole 1,1-dioxide (5.7 g) is obtained, m.p. 126° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:10]([NH2:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C@H:10]([NH:20][CH3:21])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C1CN(Cc2ccccc2)CC1N
Reactant: O=C([O-])[O-]
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CN[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccccc1C
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 35.1 %

Procedure:
To a solution of rac-(3S,4R)-1-benzyl-4-o-tolyl-pyrrolidin-3-ylamine (0.73 g, 2.74 mmol) in THF (15 ml) was added a solution of K2CO3 (0.75 mg, 5.48 mmol) in H2O (5 ml). After 10 minutes, ethyl chloroformate (0.27 ml, 2.87 mmol) was added and stirring was continued at RT for an additional 2 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (10 ml) and a solution of borane in THF (1M) was added (11 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with conc. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (60 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.27 g (35%) of rac-((3S,4R)-1-benzyl-4-o-tolyl-pyrrolidin-3-yl)-methyl-amine as a colorless oil. ES-MS m/e: 281.3 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[CH3:14][N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CCN(CC)CC>ClCCl>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([N:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C(Br)c1cccnc1
Reactant: CN1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(c1cccnc1)N1CCN(C)CC1
Yield: 28.1 %

Procedure:
Bromo-pyridin-3-yl-acetic acid ethyl ester (2.54 g; 10.2 mmol), was reacted in refluxing dichloromethane, overnight with 1-methylpiperazine (4.54 mL; 41.0 mmol; 4 equiv) and Et3N (5.8 mL; 41.0 mmol; 4 equiv). The reaction solution was evaporated to dryness, dissolved in CH2Cl2, washed five times with saturated NaHCO3 (aq), washed once with saturated NaCl (aq), dried with Na2SO4, filtered, and concentrated in vacuo. The resulting brown oil was purified with silica gel chromatography in a 3×17 cm glass column using a 2% methanol/chloroform (v/v) mobile phase. A second column eluted with 30% EtOAc/hexanes (v/v) followed by a step gradient of 0.5-3% methanol/CH2Cl2 (v/v) produced the desired product as a yellow oil (756 mg; 28% yield). MS(ES) calc'd: [M+H]+=263.1 m/z. Found: 263.1 m/z.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][O:5][CH3:6].Cl.[C:9]([C:12]1[C:13]([CH:23]2[CH2:26][CH2:25][CH2:24]2)=[CH:14][C:15]([CH3:22])=[C:16]([CH:21]=1)[C:17]([O:19][CH3:20])=[O:18])(=[NH:11])[NH2:10].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH:23]1([C:13]2[C:12]([C:9]3[NH:10][C:3]([CH2:4][O:5][CH3:6])=[CH:2][N:11]=3)=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:22])[CH:14]=2)[CH2:24][CH2:25][CH2:26]1
Reactant: COC(=O)c1cc(C(=N)N)c(C2CCC2)cc1C
Reactant: COCC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCc1cnc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a round-bottom flask was added a solution of 1-bromo-3-methoxypropan-2-one (compound 246.2, 505 mg, 1.81 mmol, 1.00 equiv, 60%) in CH3CN (16 mL). Methyl 5-carbamimidoyl-4-cyclobutyl-2-methylbenzoate hydrochloride (compound 245.1, 450 mg, 1.59 mmol, 1.00 equiv) and potassium carbonate (554 mg, 3.61 mmol, 3.00 equiv, 90%) were added to the reaction. The resulting solution was stirred overnight at 80° C. under nitrogen. After cooling to ambient temperature, the reaction was carefully quenched by the addition of water. The resulting mixture was extracted with 2×50 mL of ethyl acetate. The combined organic layers were dried (Na2SO4), and concentrated in vacuo. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:2) as eluent to furnish 170 mg (24%) of methyl 4-cyclobutyl-5-(5-(methoxymethyl)-1H-imidazol-2-yl)-2-methylbenzoate as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N+:11]([O-])=O>CO>[CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH2:11]
Reactant: COC(=O)Cc1ccccc1[N+](=O)[O-]
Solvent: CO
Product: COC(=O)Cc1ccccc1N
Reaction time: 25.5 h

Procedure:
The title A compound, (2-nitro-phenyl)-acetic acid methyl ester (5.0 g, 25.6 mmol) is dissolved in MeOH (125 mL) in a Parr Bottle. It is purged with nitrogen, then added PtO2 (185 mg), then placed on a Parr Shaker under 50 to 55 psi of hydrogen with shaking for 25.5 h. The reaction is opened and filtered through celite, and concentrated to yield (2-amino-phenyl) acetic acid methyl ester as an amber oil: [M+1]+=166.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:24][CH2:25][OH:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:30]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:24][CH2:25][O:26][CH3:30])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1

Procedure:
2-[1-(4-Benzyloxyphenyl)-1H-indol-2-yl]ethanol (0.675 mmol) was dissolved in tetrahydrofuran (5 mL) under N2, and sodium hydride (81 mg, 60% dispersion in mineral oil, 2.03 mmol) was added. The reaction was heated to reflux, at which time iodomethane (0.42 mL, 6.75 mmol) was added. The reaction was stirred at reflux for 3 hours, then carefully quenched with water. The mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated. The residue was purified by SiO2 chromatography (5-20% ethyl acetate/hexanes) to give the desired product, 0.14 g. LC-MS (C24H23NO2 calc'd 357) m/z 358 (M+H).
Reaction SMILES: [CH2:1]([N:8]([CH:12]1[CH2:14][CH2:13]1)[C:9]([Cl:11])=[O:10])[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.C1(NCC2CC[O:23]CC2)CC1.C(NCC1CC1)C1C=CC=CC=1>C(Cl)Cl.CO>[CH:12]1([N:8]([CH2:1][CH:2]2[CH2:7][CH2:6][O:23][CH2:4][CH2:3]2)[C:9]([Cl:11])=[O:10])[CH2:14][CH2:13]1
Reactant: C1CC(CNC2CC2)CCO1
Reactant: O=C(Cl)N(Cc1ccccc1)C1CC1
Agent: c1ccc(CNCC2CC2)cc1
Solvent: ClCCl
Solvent: CO
Product: O=C(Cl)N(CC1CCOCC1)C1CC1

Procedure:
The title compound is prepared analogously as described for benzyl-cyclopropyl-carbamoyl chloride starting from cyclopropyl-(tetrahydro-pyran-4-ylmethyl)-amine (prepared analogously as described for benzyl-cyclopropylmethyl-amine). TLC, Rf (CH2Cl2/MeOH 95:5)=0.9.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C@H:11]([NH:13][C:14]2[C:15]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=4)[NH:20][C:16]=3[N:17]=[CH:18][N:19]=2)[CH3:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[Cl:3][CH2:29][C:26]1[CH:25]=[CH:24][C:23]([C:21]2[NH:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C@@H:11]([C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH3:12])[C:15]=3[CH:22]=2)=[CH:28][CH:27]=1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CO)cc3)cc12)c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CCl)cc3)cc12)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of thionyl chloride (25.7 ml, 0.328 mol) in 180 ml of toluene is cooled to −10° C. Solid {4-[4-((R)-1-phenyl-ethylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol (11.3 g, 0.0328 mol) is added in 8 portions over a range of 1 h. The temperature is then increased slowly to 0° C. and the mixture stirred for 2 h. The cold reaction mixture is filtered and the solid washed with toluene and ether. The crude product is suspended in water and treated with saturated sodium bicarbonate solution until the mixture turns basic. The mixture is stirred well for about 10 min and filtered. The solid is thoroughly washed with water and dried under reduced pressure to give the title compound; m.p.>320° C.; Rf (dichloromethane/ethanol 9:1)=0.46; HPLC tR=10.63 min; MS-ES+: (M+H)+=363.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][O:2]1.[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH:23]=[O:24])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O.C(OCC)(=O)C>O1CCCC1.C([Li])CCC>[CH2:10]([N:17]1[CH2:22][CH2:21][CH:20]([CH:23]([CH:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][O:2]2)[OH:24])[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2c(c1)COC2
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: OC(C1CCN(Cc2ccccc2)CC1)C1OCc2ccccc21
Temperature: -70 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
After dissolving 591 mg of 1,3-dihydroisobenzofuran in 10 ml of tetrahydrofuran, 3.9 ml of n-butyllithium (1.5 M, n-hexane solution) was added thereto at −70° C. under a nitrogen atmosphere, the mixture was stirred for 1 hour, and then a solution of 1 g of 1-benzylpiperidine-4-carboxaldehyde in tetrahydrofuran (5 ml) was added dropwise and the mixture was stirred for 1 hour. Water was added to the reaction solution, extraction was performed with ethyl acetate, the extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Purification was performed by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain 597 mg of (1-benzylpiperidin-4-yl)-(1,3-dihydroisobenzofuran-1-yl)methanol.