Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:5]2[CH:13]=[C:14]([C:16]([O:18]CC)=O)[N:15]=[C:4]2[CH:3]=1.O.[NH2:22][NH2:23]>CCO>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][CH:10]=[N:9]2)[N:5]2[CH:13]=[C:14]([C:16]([NH:22][NH2:23])=[O:18])[N:15]=[C:4]2[CH:3]=1
Reactant: NN
Reactant: CCOC(=O)c1cn2c(-n3cccn3)cc(Br)cc2n1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1cn2c(-n3cccn3)cc(Br)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of ethyl 7-bromo-5-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylate (3.96 g, 11.8 mmol) in EtOH (100 mL) was added hydrazine hydrate (5.91 mL, 0.118 mmol) and the mixture stirred overnight at rt. After 3 days, the reaction was almost complete by LCMS so stirring was maintained for 1 more night. The mixture was diluted with EtOH (50 mL), filtered and the solids washed with EtOH (2×50 mL), EtOAc (2×50 mL) and heptane (50 mL) before being air dried. The yield was 3.56 g (94%) LCMS MS: 321.01, 322.98 [M+H]+.
Reaction SMILES: [N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][CH:18]([C:23]([O:25]C)=[O:24])[C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.C1COCC1.O.[OH-].[Na+]>CO>[N:1]1([CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]([CH2:17][CH:18]([C:23]([OH:25])=[O:24])[C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1
Reactant: COC(=O)C(Cc1ccc(OCCn2ccc3cccnc32)cc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C(Cc1ccc(OCCn2ccc3cccnc32)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The compound obtained in Example 30 (274 mg) is dissolved in 5 ml of methanol, 2.5 ml of THF and 5 ml of water. A 2M solution of sodium hydroxide is added (1.8 ml) and the reaction mixture is stirred for 4 days at ambient temperature. The solvents are then evaporated off under reduced pressure, and the resulting residue is taken up in water and extracted with ethyl acetate. The aqueous phase is cooled to 0° C. and acidified with a 2M hydrochloric acid solution, and the resulting solid is filtered off.
Reaction SMILES: [NH:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:11][CH:12]\2[OH:13])[CH:3]=[N:2]1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[CH3:38][O:37][C:35]([CH2:34][N:1]1[CH:5]=[C:4](/[CH:6]=[C:7]2\[CH2:8][N:9]([C:14]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:10][CH2:11][CH:12]\2[OH:13])[CH:3]=[N:2]1)=[O:36]
Reactant: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cn[nH]c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)cn1
Temperature: 25 °C
Yield: 39 %

Procedure:
To a solution of (E)-3-[(1H-pyrazol-4-yl)methylidene]-1-(triphenylmethyl)piperidin-4-ol (10.31 g) and methyl bromoacetate (7.0 ml) in N,N-dimethylformamide (150 ml) were added potassium carbonate (10.20 g) and potassium iodide (12.30 g) with stirring at room temperature, and the resulting mixture was refluxed for 1 hour. After water was added, the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate, hexane, and dichloromethane (2:1:1) as the eluent to afford the title compound (4.74 g, yield: 39%) as a pale yellow amorphous solid.
Reaction SMILES: C(OC([NH:11][CH:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:13]([O:16][CH3:17])[O:14][CH3:15])=O)C1C=CC=CC=1.[ClH:24].O1CCOCC1>CO.[H][H].[Pd]>[ClH:24].[CH3:17][O:16][CH:13]([O:14][CH3:15])[CH:12]([NH2:11])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: COC(OC)C(NC(=O)OCc1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(OC)C(N)c1ccccc1
Yield: 91 %

Procedure:
1-Benzyloxycarbonylamino-2,2-dimethyloxy-1-phenylethane (1.21 g, 3.84 mmol) was dissolved in methanol (38.4ml), and 4 N hydrogen chloride/1,4-dioxane (0.96 ml, 3.84 mmol) and palladium black (121 mg) were added to it and hydrogenolyzed overnight at room temperature in hydrogen atmosphere. After the palladium black was removed by filtration, the filtrate was concentrated under reduced pressure, and methylene chloride and diethyl ether were added to the resulting residue. The precipitated solid was collected by filtration whereby the title compound (760.3 mg, 91% yield) was obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[N:7][C:6]=12.[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH3:33])=[C:22](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH3:33])=[C:22]([C:2]2[CH:3]=[N:4][N:5]3[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[N:7][C:6]=23)[CH:23]=1)=[O:18]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)s1
Reactant: FC(F)(F)c1cnc2c(Br)cnn2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cnn3cc(C(F)(F)F)cnc23)c(C)s1
Temperature: 85 °C
Yield: 46.8 %

Procedure:
3-Bromo-6-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine (200 mg, 0.752 mmol), methyl-5-methyl-4-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophene-2-carboxylate (297 mg, 1.05 mmol), Pd(PPh3)4 (43.4 mg, 0.038 mmol), and 2 M sodium carbonate (aq) (750 μL, 1.50 mmol) were placed in a sealed tube. 1,4-dioxane (3.75 mL) was added and the reaction purged with N2 for 5 min. The reaction was heated to 85° C. for 7 h. After consumption of starting material, the reaction was cooled to room temperature, diluted with water and extracted 3× with ethyl acetate. The organic layers were combined, washed with brine, dried with sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-70% EtOAc/Hex) to afford the title compound (120 mg, 0.352 mmol). LRMS (APCI) calc'd for (C14H10F3N3O2S) [M+H]+, 342.0; found 342.0.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:33])[CH:11]=1>>[F:33][C:12]1[CH:11]=[C:10]([N:4]2[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]2(=[O:8])=[O:7])[CH:15]=[CH:14][C:13]=1[C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=2)[CH2:22][CH2:23]1)=[O:17]
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cc3F)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3F)CC2)nc1C
Yield: 32.4 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (152 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (305 mg) described in Preparation Example 128 and by the reaction and treatment in the same manner as in Example 4, the title compound (112 mg) was obtained.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:6][CH2:5][NH:4][CH2:3]1.C[O:9][C:10]([C:12]1[C:16]([NH:17][C:18]([C:20]2[C:25]([NH:26][C:27]3[CH:28]=[N:29][CH:30]=[N:31][CH:32]=3)=[CH:24][CH:23]=[C:22]([CH:33]3[CH2:35][CH2:34]3)[N:21]=2)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=1)=O>>[F:1][C:2]1([F:7])[CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:16]([NH:17][C:18]([C:20]3[C:25]([NH:26][C:27]4[CH:28]=[N:29][CH:30]=[N:31][CH:32]=4)=[CH:24][CH:23]=[C:22]([CH:33]4[CH2:35][CH2:34]4)[N:21]=3)=[O:19])=[CH:15][N:14]([CH3:36])[N:13]=2)=[O:9])[CH2:3]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Reactant: FC1(F)CCNC1
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)N2CCC(F)(F)C2)n1
Yield: 14 %

Procedure:
According to the general method described in step 5 of example 27, reaction of 3,3-difluoropyrrolidine with 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester provided the title compound (14%) as sticky yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)=O.[NH:18]=[N+]=[N-].S(=O)(=O)(O)O>C1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:18]
Reactant: [N-]=[N+]=N
Reactant: O=Cc1ccc(C2CCCc3cncn32)cc1
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: N#Cc1ccc(C2CCCc3cncn32)cc1
Reaction time: 2 h

Procedure:
A solution of 2.01 g of 5-(p-formylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine and 0.96 g of hydrazoic acid in 30 ml benzene is maintained by external cooling at room temperature, while 0.8 ml of concentrated sulfuric acid is added dropwise. The reaction mixture is stirred for 2 h and neutralized. The organic phase is separated, dried over sodium sulfate and evaporated to yield an oil which is chromatographed on silica gel with ethyl acetate to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[C:69]([O:71][CH2:72][CH3:73])=[O:70].FC(F)(F)C(O)=O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH:64]1[C:69]([O:71][CH2:72][CH3:73])=[O:70])=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCOC(=O)C1CCCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and ethyl piperidine-2-carboxylate in DMSO at ambient temperature and subsequent treatment with trifluoroacetic acid.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][NH:28][CH2:27]2)[CH2:19][CH2:18]1)[CH3:4].O[C:38]1[CH:46]=[CH:45][C:41]([C:42](O)=[O:43])=[C:40]([O:47][CH3:48])[CH:39]=1.CN(C)CCCN=C=NCC.O.[OH:61]N1C2C=CC=CC=2N=N1>ClCCl>[CH2:3]([O:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[N:17]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH2:25][C@:26]2([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:30][CH2:29][N:28]([C:42]([C:41]3[CH:45]=[C:46]([OH:61])[CH:38]=[CH:39][C:40]=3[O:47][CH3:48])=[O:43])[CH2:27]2)[CH2:19][CH2:18]1)[CH3:4]
Reactant: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: On1nnc2ccccc21
Reactant: COc1cc(O)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(O)ccc4OC)C3)CC2)nc2ccccc21
Yield: 31.1 %

Procedure:
Stir a mixture of 1-(2-ethoxy-ethyl)-2-{4-[2-((S)-3-phenyl-pyrrolidin-3-yl)-ethyl]-[1,4]diazepan-1-yl}-1H-benzoimidazole dihydrochloride (0.53 g, 1 mmol, Preparation 12.1, named as 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl) [1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine), 4-hydroxy-2-methoxybenzoic acid (0.34 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (0.19 g, 1 mmol, Aldrich Chemical Company), 1-hydroxybenzotriazole hydrate (0.14 g, 1 mmol, Aldrich Chemical Company), diisopropyoethylamine (3.4 mL) and dichloromethane (10 mL) overnight at room temperature. Dilute the reaction mixture with dichloromethane, wash with saturated brine, dry (MgSO4) the organic phase, filter and concentrate the filtrate in vacuo. Purify the residue by column chromatography on silica gel eluting sequentially with ethyl acetate, 3% methanol in dichloromethane and 10% methanol in dichloromethane. Concentrate the appropriate fractions to afford 1-[(R)-3-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-[1,4]diazepan-1-yl}-ethyl)-3-phenyl-pyrrolidin-1-yl]-1-(5-hydroxy-2-methoxy-phenyl)-methanone (0.19 g), Rf=0.38 (silica gel, 10% methanol in dichloromethane).
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:13][CH2:14][N:15]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]1[CH3:23].[NH:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27](=[O:34])[NH:26][C:25]1=[O:35].[OH-].[K+]>CN(C)C=O.CO.C1(C)C=CC=CC=1>[CH3:23][C:16]1[N:15]([CH2:14][CH2:13][N:26]2[C:27](=[O:34])[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:24][C:25]2=[O:35])[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=1
Reactant: O=c1[nH]c(=O)c2ccccc2[nH]1
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ncc([N+](=O)[O-])n1CCn1c(=O)[nH]c2ccccc2c1=O

Procedure:
A mixture of 15.0 parts of 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole tosylate and 7.5 parts of 2,4(1H,-3H)-quinazolinedione is dissolved in 190 parts of warm dimethylformamide. 2.9 Parts of potassium hydroxide is dissolved in 80 parts of methanol and diluted with about 95 parts of dimethylformamide. The methanol is removed under reduced pressure, the residual solution added to the quinazolinedione solution, and the resulting mixture heated on a steam bath for 4 hours. The crude solution is cooled, filtered, and diluted with 100 parts of water. The precipitate which forms is separated by filtration and the solvent is evaporated from the filtrate to leave a residue which is stirred with 630 parts of toluene and filtered. The solvent is evaporated from the filtrate to leave a yellow residue. This is dissolved in toluene and dimethylformamide and then concentrated. A precipitate forms and it is separated by filtration to give 3-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-2,4-(1H,3H)quinazolinedione melting at about 261°-264° C.
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].C(OCC)C>CN(C)C=O.O>[N:3]1([CH2:9][C:10]2[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=2)[O:16][CH2:18][CH2:19][CH2:20][N:21]2[C:25](=[O:26])[C:24]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]3[C:22]2=[O:31])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
In an argon stream, 2.2 g of 60% sodium hydride was suspended in 20 ml of N,N-dimethylformamide. The suspension was added dropwise to a solution of 9.6 g of the 3-(1-piperidinomethyl)phenol obtained in Reference Example 1 in 30 ml of N,N-dimethylformamide, followed by stirring at room temperature for 30 minutes. Next, a solution of 14.7 g of N-(3-bromopropyl)phthalimide in 50 ml of N,N-dimethylformamide was added dropwise to the mixture, and the resulting mixture was stirred at 65° C. for 8 hours. After cooling the mixture, a mixture of diethyl ether and water (1:1) was added thereto for extraction, and the organic layer was concentrated under reduced pressure. To the concentrate was added 6N hydrochloric acid for extraction into the aqueous layer, which was then made alkaline with potassium hydroxide, followed by extraction with diethyl ether. The organic layer was dried over magnesium sulfate and distilled under reduced pressure to remove the solvent, giving 16.3 g of transparent oily N-[3-[3-(piperidinomethyl)-phenoxy]propyl]phthalimide (yield 86% ).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1)(=[O:19])=[O:18])=O)(C)(C)C.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(OCC)C.CCCCCC>C(OCC)(=O)C>[N:27]1([C:23]2[CH:22]=[CH:21][C:20]([S:17]([C:9]3[NH:8][C:16]4[C:11]([CH:10]=3)=[CH:12][CH:13]=[CH:14][CH:15]=4)(=[O:18])=[O:19])=[CH:25][CH:24]=2)[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1
Reactant: C1CNCCN1
Reactant: CC(C)(C)OC(=O)n1c(S(=O)(=O)c2ccc(F)cc2)cc2ccccc21
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=S(=O)(c1ccc(N2CCNCC2)cc1)c1cc2ccccc2[nH]1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
The Boc-protecting group on 0.530 g, 1.41 mmol of the 2-(4-Fluorobenzenesulfonyl)-indole-1-carboxylic acid tert-butyl ester from Step 1 was removed by stirring at room temperature in 3 mL of neat TFA. The reaction mixture turned a light burgundy color while stirring. The TFA was removed by adding 25 mL of toluene and removing the solvent/TFA as an azeotrope. This was repeated and the oily residue was then transferred to a sealed tube using 5 mL of DMSO. Solid piperazine (0.61 g, 7.06 mmol, 5 eq.) was added, the tube was sealed, and the reaction mixture heated at 100° C. (bath temp.) for a period of 16 h. The reaction mixture was allowed to cool to room temperature, diluted with 400 mL of ethyl acetate, then washed sequentially with saturated NaHCO3 solution, water, brine, and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave an amber glass which was treated with anhydrous diethyl ether. Hexane (25 mL) was added to the solution, causing a small amount of solid to precipitate out of solution. The mixture cooled was to 0° C. in an ice-water bath, followed by vacuum-filtration of the off-white solid. After drying, 0.150 g, 0.44 mmol, 31.1% yield of 2-(4-Piperazin-1-yl-benzenesulfonyl)-1H-indole was obtained, with a melting point range of 246–248.5° C. and M+H of 342.
Reaction SMILES: Cl.C([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:35])[CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:11][CH2:10]1)C1C=CC=CC=1.CO.O1CCCC1.[H][H]>C1(C)C=CC=CC=1.[Pd]>[OH:35][CH:16]([CH2:17][O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][N:12]1[CH2:13][CH2:14][NH:9][CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CCCCCCCCCCCCCCCCOCC(O)CN1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCOCC(O)CN1CCNCC1
Reaction time: 8 h

Procedure:
1-Benzyl-4-(2-hydroxy-3-n-hexadecyloxypropyl)-piperazine hydrochloride (8 g, 0.0146 mol) was dissolved in toluene (100 ml), methanol (100 ml) and tetrahydrofuran (700 ml) and divided into three 300 ml portions. Each portion was hydrogenated overnight at room temperature on a Parr shaker using a 10% palladium on carbon catalyst (2 g) and 50 p.s.i.g. hydrogen. The catalyst was filtered off and the filtrate evaporated under reduced pressure to a solid, which was triturated under acetone and filtered to give a total yield of product of 2.9 g (43%), mp 230° C. (dec).
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8](OC(=O)CC)(=[O:11])[CH2:9]C.C(OC(=O)CCC)(=O)CCC.C(OC(=O)CCCC)(=O)CCCC.C(OC(=O)CCCCC)(=O)CCCCC>>[CH3:6][C:5]([O:4][CH2:1][CH2:2][CH2:9][CH2:8][OH:11])=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(=O)OC(=O)CC
Agent: CCCC(=O)OC(=O)CCC
Agent: CCCCC(=O)OC(=O)CCCC
Agent: CCCCCC(=O)OC(=O)CCCCC
Product: CC(=O)OCCCCO

Procedure:
The anhydride may be, but not limited to, acetic acid anhydride, propionic anhydride, butyric anhydride, pentanoic anhydride or hexanoic anhydride. Preferably, the anhydride is acetic acid anhydride. According to an embodiment, the esterification of 1,4-bunediol is performed with acetic acid anhydride to form CH3C(O)O—(CH2)4—OH.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20]2[N:25]=[CH:24][C:23]([Br:26])=[CH:22][N:21]=2)[CH2:16]1)(C)(C)C.[Cl:28]CCl>>[ClH:28].[Br:26][C:23]1[CH:22]=[N:21][C:20]([N:17]2[CH2:18][CH2:19][C@H:15]([NH2:14])[CH2:16]2)=[N:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ncc(Br)cn2)C1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@H]1CCN(c2ncc(Br)cn2)C1
Reaction time: 2 h
Yield: 85 %

Procedure:
Add trifluoroacetic acid (20 mL) to a solution of (S)-[1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (3.66 g, 10.7 mmol) in dichloromethane (20 mL). Stir 2 h and concentrate. Dissolve the residue in methanol and pass through a column of Amberjet® 4400 resin (OH-form). Wash the column with methanol and concentrate the eluant. Dissolve the residue in methanol/acetonitrile and add 1 N HCl (25 mL) in methanol. Collect the resulting solid by filtration, wash with acetonitrile and dry the solid to give (S)-1-(5-bromopyrimidin-2-yl)-pyrrolidin-3-ylamine hydrochloride as a tan solid (2.55 g, 85%).
Reaction SMILES: C(OC([NH:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]([CH2:27][C:28]2[C:33](C(O)=O)=[CH:32][CH:31]=[CH:30][N:29]=2)[C:10]1=[O:37])=O)(C)(C)C.O.ON1C2C=CC=C[C:43]=2N=N1.[OH-].[NH4+].N1C(=O)C=NC=C2C=CC=CC=12>O1CCCC1>[NH2:8][CH:9]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C:13]2[CH:23]=[CH:24][CH:25]=[CH:26][C:12]=2[N:11]([CH2:27][C:28]2[CH:33]=[C:32]([CH3:43])[CH:31]=[CH:30][N:29]=2)[C:10]1=[O:37]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)NC1N=C(c2ccccc2F)c2ccccc2N(Cc2ncccc2C(=O)O)C1=O
Agent: O=c1cncc2ccccc2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccnc(CN2C(=O)C(N)N=C(c3ccccc3F)c3ccccc32)c1
Reaction time: 2 h

Procedure:
A solution of (3RS)-3-tert-butoxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1-(3-hydroxycarbonylpyridin-2-yl) methyl-1H-1,4-benzodiazepin-2-one (0.71 g) in tetrahydrofuran (20 ml) was treated with dicyclohexylcalbodiimide (0.29 g) and 1-hydroxybenzotriazole monohydrate (0.215 g) at room temperature. The mixture was stirred for 2 hours at the same condition. To the mixture was added dropwise a solution of ammonium hydroxide (28% ammonia in water, 0.359 g) in tetrahydrofuran (1 ml) at ambient temperature under stirring. The mixture was stirred overnight at ambient temperature. The resultant mixture was concentrated in vacuo, and the residue was taken up with ethyl acetate. The organic layer was washed with a brine and dried over sodium sulfate. Filtration and evaporation gave a crude product. The crude product was purified by column chromatography on silica gel with a mixture of chloroform and methanol to afford (3RS)-1-(3-aminocarbonylpyridin-2-yl)methyl-3-tert-butoxycarbonyl-amino-2,3-dihydro-5-(2-fluorophenyl)-1H,-1,4-benzodiazepin-2-one (0.32 g) as a yellow form.