Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:15][C@H:16]1[CH2:40][CH2:39][C@@:38]2([CH3:41])[C:18](=[CH:19][CH2:20][C@@H:21]3[C@@H:37]2[CH2:36][CH2:35][C@@:34]2([CH3:42])[C@H:22]3[CH2:23][C@H:24]([O:43][Si:44]([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45])[C@@H:25]2[C@H:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:17]1)(=O)C1C=CC=CC=1.O>C(OCC)C>[Si:44]([O:43][C@H:24]1[CH2:23][C@@H:22]2[C@:34]([CH3:42])([CH2:35][CH2:36][C@H:37]3[C@H:21]2[CH2:20][CH:19]=[C:18]2[C@:38]3([CH3:41])[CH2:39][CH2:40][C@H:16]([OH:15])[CH2:17]2)[C@H:25]1[C@H:26]([CH3:33])[CH2:27][CH2:28][CH2:29][CH:30]([CH3:32])[CH3:31])([C:47]([CH3:48])([CH3:49])[CH3:50])([CH3:45])[CH3:46]
Reactant: CC(C)CCC[C@@H](C)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 108 %

Procedure:
To a suspension of lithium aluminium hydride (4.5 g, 120 mmol) in diethyl ether (700 mL) was added, dropwise 16β-(tert-butyldimethylsilyloxy)cholest-5-en-3β-yl benzoate (8.1 g, 12 mmol) in diethyl ether (50 mL). After stirring at room temperature for 15 minutes and at 40° C. for 0.5 hour, water was added. The inorganic impurities were removed by filtration through Celite, and after removal of solvent under reduced pressure the residue was purified by flash chromatography to give 16β-(tert-butyldimethylsilyloxy)cholest-5-en-3β-ol (6.7 g).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH3:23])[C:20]([NH2:22])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32](Cl)(=[O:34])[CH3:33].[OH-].[NH4+]>N1C=CC=CC=1>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH3:23])[C:20]([NH:22][C:32](=[O:34])[CH3:33])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(=O)Cl
Reactant: Cn1c(N)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 4.1 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-amine and 25 parts of pyridine are added dropwise 0.79 parts of acetyl chloride while cooling at 0°-5° C. Upon completion, stirring is continued for one hour at 80° C. The reaction mixture is cooled to room temperature, poured onto ice-water and alkalized with ammonium hydroxide. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol. The product is filtered off, washed with 2-propanol and 2,2'-oxybispropane, and dried, yielding 3 parts of N-{5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-yl}acetamide; mp. 202.5° C.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:20][CH2:21][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[C:22]1([C:21]2[NH:20][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:2]=2)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: NCc1cccc2ccccc12
Product: CCOC(=O)c1nc(-c2cccc3ccccc23)[nH]c1-c1ccc([N+](=O)[O-])cc1
Yield: 24.7 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-nitrophenyl)-3-oxopropionate (10.0 g) and 1-aminomethylnaphthalene (6.4 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 2-(1-naphthyl)-5-(4-nitrophenyl)imidazole-4-carboxylate (3.6 g). 3.0 g therefrom was dissolved in ethyl alcohol (100 ml) and 1 M sodium hydroxide solution (20 ml) was added. The mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 2-(1-naphthyl)-5-(4-nitrophenyl)imidazole-4-carboxylic acid (3.4 g), melting point 161° C. (decomposition).
Reaction SMILES: [NH2:1][CH:2]([C:31]([F:34])([F:33])[F:32])[CH2:3][C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]=[C:9]([N:18]2[CH2:24][C:23]3[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=3[S:21](=[O:30])(=[O:29])[CH2:20][CH2:19]2)[CH:8]=1)=O.Cl>CSC>[O:30]=[S:21]1(=[O:29])[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH2:24][N:18]([C:9]2[CH:8]=[C:7]([NH:6][CH2:4][CH2:3][CH:2]([NH2:1])[C:31]([F:34])([F:33])[F:32])[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)CC(N)C(F)(F)F)c2c1
Agent: Cl
Solvent: CSC
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCC(N)C(F)(F)F)c2c1
Temperature: 85 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
To a solution of 3-amino-N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-4,4,4-trifluorobutanamide (120 mg, 0.245 mmol) was added a solution of borane-methyl sulfide complex in methyl sulfide (5 M, 1.0 mL). The resulting solution was heated at 85° C. for 2 hours. After being cooled to room temperature, the mixture was acidified by careful addition of an aqueous solution of hydrochloric acid (1 M) to about pH 4, and then stirred at room temperature overnight. The resulting mixture was concentrated in vacuo. The residue was neutralized with a 10% aqueous solution of sodium hydroxide to pH >9, and then extracted with dichloromethane (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to afford 60 mg of the title product as a solid (yield was 65%). MS obsd. (ESI+) [(M+H)+] 479, 1H NMR (400 MHz, CDCl3) δ ppm 8.04 (d, J=7.6 Hz, 1 H), 7.65 (d, J=7.6 Hz, 1 H), 7.50-7.49 (m, 2 H), 7.38 (t, J=7.2 Hz, 1 H), 7.30 (m, 1 H), 6.06 (s, 1 H), 5.93 (s, 1 H), 5.12 (s, 1 H), 3.63 (m, 3 H), 4.62 (brs, 2 H), 3.45 (m, 1 H), 3.33 (m, 1 H), 2.42 (s, 3 H), 2.22 (m, 1 H), 2.03 (s, 1 H), 1.82 (m, 1 H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1.O.[NH2:33][NH2:34].C(=O)([O-])O.[Na+]>CN(C=O)C>[S:27]1[CH:28]=[CH:29][CH:30]=[C:26]1[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:20])([F:21])[F:22])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:34][N:33]=1
Reactant: NN
Reactant: O=C(Cc1cccs1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3cccs3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 115 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hydroxy-3-(2-thienylacetyl)-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (180 mg, 0.40 mmol) produced in Synthesis Example 41 in DMF (3 mL) was added hydrazine monohydrate (purity of 80%, 97 μL), and the mixture was stirred at 110 to 120° C. for 2 hours. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, washed with water, recrystallized from methanol, and dried to give 3-(2-thienylmethyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (109 mg, yield 61%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23]#[N:24])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH-].[Na+].C(OCC)(=[O:31])C>S(=O)(=O)(O)O>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([C:23](=[O:31])[NH2:24])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Temperature: 0 °C
Yield: 77 %

Procedure:
A solution of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-cyanoindoline (1.0 g) in conc. sulfuric acid (1 l) was heated at 50° C. for 2 hr. After diluting with ice water, the reaction solution was basified with a conc. aqueous solution of sodium hydroxide. Then ethyl acetate was added thereto and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (0.81 g) as a white powder (yield: 77%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[C:7](=[C:8]([O:17][CH3:18])[C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[C:5]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:4]=1.C(N(CC)CC)C.Cl[C:33]1[S:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>C(O)CCC>[S:34]1[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=[C:33]1[N:22]1[CH2:23][CH2:24][N:19]([C:5]2[N:4]=[C:3]([NH2:2])[C:12]3[C:7](=[C:8]([O:17][CH3:18])[C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=2)[CH2:20][CH2:21]1
Reactant: COc1cc2c(N)nc(N3CCNCC3)nc2c(OC)c1OC
Reactant: Clc1nc2ccccc2s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: COc1cc2c(N)nc(N3CCN(c4nc5ccccc5s4)CC3)nc2c(OC)c1OC
Reaction time: 0.25 h
Yield: 48.5 %

Procedure:
A mixture of 4-amino-2-(1-piperazinyl)-6,7,8-trimethoxyquinazoline hydrochloride (4.0 g) and triethylamine (4.1 g) in butanol (250 ml) was stirred for 15 min and 2-chlorobenzthiazole (1.7 g) was added. The resulting mixture was refluxed for 20 hr, concentrated to about 150 ml, cooled and filtered. The precipitate was washed with water, dried and crystallized from methanol to give the title compound (2.2 g): mp>250° C.; ir (nujol) 3370, 3300 and 3610 cm-1 ; uv max (MeOH) 225 (ε=45,900), 250 (ε=56,700), 277 (ε=45,200) and 353 nm (ε=5,100); nmr (DMSO-d6) δ3.7 (m, 8H), 3.8 (s, 6H), 3.95 (s, 3H) and 7.3 (m, 7H); and Anal. Calcd. for C22H24N6O3S: C, 58.40% H, 5.30% N, 18.58% and Found: C, 58.22% H, 5.50% N, 18.62%.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[CH2:7][O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:11][CH:10]=1.[OH-].[Na+].[C:24]([O:28]C)(=[O:27])[CH:25]=[CH2:26].Cl>O1CCOCC1.ClCCl>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:13][C:12]1[CH:20]=[CH:21][C:9]([O:8][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH2:26][CH2:25][C:24]([OH:28])=[O:27])=[CH:10][CH:11]=1
Reactant: c1ccc(Oc2ccc(OC[C@H]3CCCN3)cc2)nc1
Reactant: C=CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)CCN1CCCC1COc1ccc(Oc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
The product from Example 167 (125 mg, 0.37 mmol) was treated with 20% NaOH (10 mL) and extracted with EtOAc, dried over Na2SO4 and dried down to give the free base. Dichloromethane (3 mL) and methyl acrylate (1 mL, 7 mmol) were added and the mixture was stirred at ambient temperature overnight. The reaction mixture was dried down to give oil. 4.0M HCl in dioxane was added and the mixture was stirred overnight at ambient temperature. The solvent was evaporated to give the title compound (61 mg, 57%); LC/MS; m/z 343 (M+H) 99%
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:14]1=2)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2].I.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](SC)=[NH:33]>CCO.[Pd]>[CH2:1]([N:3]([CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([NH:23][C:32]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[NH:33])[CH:21]=[CH:22][C:14]1=2)[C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH3:2]
Reactant: CCN(CCN1CCOc2cc([N+](=O)[O-])ccc21)C(=O)OC(C)(C)C
Reactant: CSC(=N)c1cccs1
Agent: [Pd]
Agent: I
Solvent: CCO
Product: CCN(CCN1CCOc2cc(NC(=N)c3cccs3)ccc21)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.6 %

Procedure:
A suspension of tert-butyl ethyl(2-(7-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl)carbamate (7 g, 19.92 mmol) and Pd—C (2.11 g, 1.992 mmol, 10% wt) in anhydrous EtOH (100 mL) was purged with hydrogen gas. The reaction was stirred at room temperature for 16 hours under a hydrogen atmosphere (balloon pressure). The reaction mixture was filtered through a Celite pad and washed with EtOH (50 mL). The filtrate containing tert-butyl 2-(7-amino-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethyl(ethyl)carbamate was treated with methyl thiophene-2-carbimidothioate hydroiodide (11.36 g, 39.8 mmol) and stirred overnight at room temperature. The reaction was concentrated and then partitioned between saturated NaHCO3 solution (150 mL) and CH2Cl2 (75 mL). The mixture was transferred to a separatory funnel, and the product was extracted into CH2Cl2 (2×100 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was subjected to flash chromatography on silica gel using a sequence of eluents (CH2Cl2; 1:99 (2M NH3 in MeOH):CH2Cl2; 1.75:98.25 (2M NH3 in MeOH):CH2Cl2; and 2.5:97.5 (2M NH3 in MeOH):CH2Cl2) to give a brown solid (4 g, 46.7%). 1H-NMR (CDCl3) δ 7.43-7.41 (m, 2H), 7.11-7.05 (m, 1H), 6.72-6.69 (m, 1H), 6.54-6.51 (m, 2H), 4.23-4.20 (m, 2H), 3.39-3.25 (m, 8H), 1.47 (s, 9H), 1.11-1.10 (m, 3H); ESI-MS (m/z, %): 431 (MH+, 100).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH2:29][N:30]2[CH2:34][CH2:33][O:32][C:31]2=[O:35])[N:24]=1.BrC1C=CN=C(CN2CCOC2=O)N=1>>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:27]2[CH:28]=[CH:23][N:24]=[C:25]([CH2:29][N:30]3[CH2:34][CH2:33][O:32][C:31]3=[O:35])[N:26]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: O=C1OCCN1Cc1nccc(Cl)n1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Agent: O=C1OCCN1Cc1nccc(Br)n1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccnc(CN4CCOC4=O)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (85 mg, 0.27 mmol) and the mixture of 3-[(4-chloropyrimidin-2-yl)methyl]-1,3-oxazolidin-2-one (21.5 mg, 0.10 mmol) and 3-[(4-bromopyrimidin-2-yl)methyl]-1,3-oxazolidin-2-one (44.2 mg, 0.17 mmol) as the starting materials.
Reaction SMILES: [C:1]([CH2:9][C:10]1([OH:16])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.[I-].[K+]>[ClH:17].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:13]2[CH2:14][CH2:15][C:10]([CH2:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)([OH:16])[CH2:11][CH2:12]2)=[CH:20][CH:19]=1
Reactant: O=C(CC1(O)CCNCC1)c1ccccc1
Reactant: Clc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cl
Product: O=C(CC1(O)CCN(Cc2ccc(Cl)cc2)CC1)c1ccccc1
Yield: 70.5 %

Procedure:
4-benzoylmethyl-4-piperidinol (II) is firstly prepared according to the method of synthesis and post-treatment in General Method one. Thereafter, 1.76 g (8.8 mmol) of p-chlorobenzyl bromide and 1.75 g (8.0 mmol) of 4-benzoylmethyl-4-piperidinol (II), 0.03 g (0.2 mmol) of potassium iodide and 3.53 g (25.6 mmol) of anhydrous K2CO3 is placed in anhydrous acetone (60 ml), and reacting at reflux for 8 hours. Operating according to the post-treatment procedure in General Method two obtains 2.25 g of a white crystal, with yield of 70.5%.
Reaction SMILES: [CH3:1][Al](C)C.[NH2:5][C@H:6]([C:14]([OH:16])=O)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C[O:18][C:19](=[O:25])[C@H:20]([CH:22]([CH3:24])[CH3:23])[NH2:21].Cl.[OH-].[Na+]>CCCCCC.C(Cl)Cl.O>[CH3:1][N:21]([C:14](=[O:16])[C@H:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH2:5])[C@H:20]([C:19]([OH:18])=[O:25])[CH:22]([CH3:24])[CH3:23]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C[Al](C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCCCCC
Solvent: ClCCl
Product: CC(C)[C@@H](C(=O)O)N(C)C(=O)[C@@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 34 %

Procedure:
A solution of trimethylaluminum (136.2 mL of a 2M solution in hexane, 272.4 mmol) was added dropwise to a stirring suspension of L-phenylalanine (15.0 g, 90.79 mmol) in 150 mL of methylene chloride at 0° C. (ice-bath). The resultant clear solution was allowed to warm to room temperature and stirred for 23 h. A solution of the free base of L-valine methyl ester (15.22 g, 90.79 mmol) in 100 mL of methylene chloride was added dropwise and the resultant clear solution was stirred at room temperature for 72 h. The reaction mixture was then cooled to 0° C. and with stirring, 6N HCl was dropwise until the pH was 2. The mixture was stirred for an additional 0.5 h followed by addition of 40 mL of 50% aqueous NaOH until the pH was 13. To this mixture was added 800 mL of methylene chloride and 100 mL of water. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to provide a residue which was chromatographed on silica gel using 5% methanol in methylene chloride as the eluting solvent. The desired fractions were collected and evaporated under reduced pressure to yield 5.0 g (34%) of the title product as a colorless oil. IR (neat, cm-1), C=O (1665.8, 1742.0), N--H (3366.6). 1H NMR and 13C NMR (CDCl3) spectra were both consistent with the title product. Analysis calculated for C15H22ClN2Oe ·1/4H2O: C, 56.41; H, 7.42; N, 8.77; Cl, 11.10; Found: C, 56.34; H, 7.65; N, 8.61; Cl, 10.62.
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[C@@H:9]([CH2:11][C@H:12](OS(C)(=O)=O)[CH3:13])[CH3:10])(=O)=O.[C:19](#[N:21])C>>[CH3:10][C@@H:9]([CH2:11][C@H:12]([CH3:13])[C:19]#[N:21])[C:1]#[N:2]
Reactant: CC#N
Reactant: C[C@H](C[C@@H](C)OS(C)(=O)=O)OS(C)(=O)=O
Reactant: [C-]#N
Agent: [K+]
Product: C[C@H](C#N)C[C@H](C)C#N
Reaction time: 8 h

Procedure:
A suspension of potassium cyanide (36 g) in a solution of (2R,4R)-2,4-pentanediol dimethanesulfonate (36 g) dissolved in acetonitrile (77 mL) is stirred overnight under reflux. The mixture is partitioned between dichloromethane (200 mL) and water (150 mL). The organic layer is extracted six times with dichloromethane. The combined organic extracts are dried over magnesium sulphate, concentrated under reduced pressure and purified by chromatography over silica gel using a gradient heptane/ethyl acetate from 4/1 to 2/1 to give 8.3 g of (2S,4S)-2,4-dimethylpentanedinitrile as a yellow solid used without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:16][N:17]([CH3:20])[C:18]#[N:19]>C1C(O)=CC=CC=1C>[CH3:16][N:17]([CH3:20])[C:18]([NH:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[NH:19]
Reactant: CN(C)C#N
Reactant: Cc1cccc(-c2ccccc2)c1N
Agent: Cl
Solvent: Cc1cccc(O)c1
Product: Cc1cccc(-c2ccccc2)c1NC(=N)N(C)C

Procedure:
A mixture of 2-amino-3-methylbiphenyl hydrochloride (2.65 g), N,N-dimethylcyanamide (1.3 g) and m-cresol (20 ml) was heated at 90°-95° C. for 18 hours to give N,N-dimethyl-N'-(3-methyl-2-biphenylyl)guanidine as a colourless solid (m.p. 144°-145° C.) which was recrystallised from hexane.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([N:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:24]N1C(=O)CCC1=O>CN(C)C=O>[Br:24][C:10]1[N:9]=[C:8]([C@H:11]2[CH2:12][CH2:13][C@H:14]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[CH2:15][CH2:16]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn2c1cnc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Solvent: CN(C)C=O
Product: Cc1nccn2c1c(Br)nc2[C@H]1CC[C@H](N2CCN(C)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (2.086 mmol, 654 mg) in N,N-dimethylformamide (10 mL) was added N-bromosuccinimide (2.295 mmol, 408 mg) and the mixture was stirred at room temperature for one hour. The reaction mixture was evaporated to dryness. The residue was dissolved in dichloromethane/methanol 9/1 (100 mL) and this solution was washed with a mixture of water (2 ml), of saturated aqueous sodium hydrogencarbonate (2 mL) and a few drops of 2 N sodium hydroxide, the organic layer dried (sodium sulfate) and evaporated to dryness to yield crude 1-bromo-8-methyl-3-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)imidazo[1,5-a]pyrazine (1.04 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:5]([N:21]2[CH2:22][CH2:23][CH2:24][C:19]([OH:25])([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=3)[CH2:20]2)=[O:6])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cccc(F)c3)C2)c1

Procedure:
The compound of Example 2 was prepared according to the general preparation protocol A from 3-fluorobenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: C[O:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH3:16])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].B(Cl)(Cl)Cl>C(Cl)Cl>[OH:2][C:3]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([CH3:16])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1c(C)cc(OC)cc1OC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1c(C)cc(OC)cc1O
Temperature: -78 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
To a solution of ethyl 2,4-dimethoxy-6-methylbenzoate (5.73 g, 25.6 mmol) in 200 mL of methylene chloride at −78° C. was added boron trichloride (28.1 mL of a 1.0 M solution in methylene chloride, 28.1 mmol) via an addition funnel over 15 min. The solution was allowed to stir at −78° C. for 2 h. The cooling bath was removed, the reaction was allowed to warm for 15 min. and then was carefully quenched with 1N HCl. Most of the methylene chloride was removed by rotary evaporator and the reaction was diluted with ethyl acetate. The organics were washed with 1N HCl and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (elution with 8:1 hexane/ethyl acetate) to afford 3.8 g (70%) of the title compound as a tan solid. 1H NMR (CDCl3): δ 11.85 (s, 1H), 6.31 (d, 1H, J=2.2 Hz), 6.25 (d, 1H, J=2.6 Hz), 4.37 (q, 2H, J=7.2 Hz), 3.77 (s, 3H), 2.49 (s, 3H), 1.39 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9]([CH:12]=[O:13])=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]2[C:9]([CH2:12][OH:13])=[CH:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2occ(C=O)c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1cccc2occ(CO)c12
Reaction time: 2 h

Procedure:
The aldehyde 123 from above (4.34 g, 24.63 mmol) is dissolved in 10 ml of methanol and cooled in an ice-bath. Solid sodium borohydride (4.9 g, 123.2 mmol) is added in portions and the mixture is stirred for 2 hours. It is then poured onto ice-cold HCl, extracted three times with DCM, dried and evaporated. The crude material is purified by chromatography on silicagel using hexane and EtOAc (from 20% to 50%).