Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[CH:43]=[CH:44][C:45]2[C:51]3[S:52][C:53]([C:55]([N:57]([C:59]4[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=4[Cl:68])[C:62](O)=[O:63])[CH3:58])=[O:56])=[CH:54][C:50]=3[CH2:49][CH2:48][O:47][C:46]=2[CH:69]=1>C1COCC1.O>[Br:41][C:42]1[CH:43]=[CH:44][C:45]2[C:51]3[S:52][C:53]([C:55]([N:57]([C:59]4[CH:60]=[C:61]([C:62]([N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[O:63])[CH:65]=[CH:66][C:67]=4[Cl:68])[CH3:58])=[O:56])=[CH:54][C:50]=3[CH2:49][CH2:48][O:47][C:46]=2[CH:69]=1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1cc(C(=O)O)ccc1Cl
Reactant: CN1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc(Cl)c(N(C)C(=O)c3cc4c(s3)-c3ccc(Br)cc3OCC4)c2)CC1
Reaction time: 8 h
Yield: 94.3 %

Procedure:
To a mixture of 1-methyl-piperazine (1.22 g, 12.18 mmol), DIPEA (3 mL), HATU (2.78 g, 7.31 mmol) in THF (60 mL) was added 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoic acid (3.0 g, 6.09 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was stirred overnight, diluted with water, extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo to give 8-bromo-N-(2-chloro-5-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (3.3 g, yield 94%) 1H NMR (DMSO-d6, 400 MHz): δ7.74-7.21 (m, 6H, ArH), 6.67 (s, 1H, ═CH), 4.18 (t, J=4.4 Hz, 2H, CH2), 3.31-2.12 (m, 16H, CH3, CH2)
Reaction SMILES: N[C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.N[C@H:23]1[C@H:27]([CH3:28])CNC1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:15]1([N:7]2[C:8]3[C:3](=[CH:2][C:11]([F:12])=[CH:10][C:9]=3[F:14])[C:4](=[O:21])[CH:5]=[CH:6]2)[CH2:17][CH2:16]1.[CH:28]1([C:5]2([C:18]([OH:20])=[O:19])[C:4](=[O:21])[C:3]3[C:8](=[C:9]([F:14])[CH:10]=[C:11]([F:12])[CH:2]=3)[NH:7][CH2:6]2)[CH2:27][CH2:23]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C[C@@H]1CNC[C@H]1N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)C1(C2CC2)CNc2c(F)cc(F)cc2C1=O
Product: O=c1ccn(C2CC2)c2c(F)cc(F)cc12
Yield: 85.5 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.5 g), trans-3-amino-4-methylpyrrolidine (0.76 g), DBU (0.77 g), and acetonitrile (30 ml) was refluxed for 7 hours. The precipitated crystals were collected by filtration after cooling, washed with acetonitrile, and dried. Recrystallization from chloroform-ethanol gave cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.05 g), m.p. 234°-236° C.
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH2:19].[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.[C:30]([BH3-])#[N:31].[Na+].Cl>CO.CC1C(Br)=C(O)C(Br)=CC=1C1(C2C=C(Br)C(O)=C(Br)C=2C)OS(=O)(=O)C2C=CC=CC1=2.C(O)C>[CH3:20][S:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:31][CH2:30][C:25]2[CH:28]=[CH:29][C:22]([S:21][CH3:20])=[CH:23][CH:24]=2)=[CH:24][CH:23]=1
Reactant: CSc1ccc(C=O)cc1
Reactant: NCCCCNCCCCCCCNCCCCN
Reactant: [BH3-]C#N
Agent: Cc1c(C2(c3cc(Br)c(O)c(Br)c3C)OS(=O)(=O)c3ccccc32)cc(Br)c(O)c1Br
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: CSc1ccc(CNCCCCNCCCCCCCNCCCCNCc2ccc(SC)cc2)cc1

Procedure:
Dissolve 1,6,14,19-tetraazanonadecane (1.35 g, 0.005 mol) in methanol (distilled from Mg) (50 mL) and add 4-(methylthio)benzaldehyde (1.52 g, 0.01 mol), sodium cyanoborohydride (0.62 g, 0.010 mol) and 1 drop of 1% bromocresol green in ethanol. Maintain the pH of the reaction with 1N hydrochloric acid in methanol until the indicator no longer changes. Evaporate the solvent in vacuo and partition the residue between 1N sodium hydroxide (50 mL) and ethyl acetate (100 mL). Separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo give the title compound.
Reaction SMILES: [CH3:1][N:2](C=O)C.Br[C:7]1[CH:8]=[C:9]2[C:35](=[CH:36][CH:37]=1)[O:34][C:12]1([CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:29]=[C:28]([O:30][CH3:31])[C:27]4[C:22](=[C:23]([O:32][CH3:33])[CH:24]=[CH:25][CH:26]=4)[N:21]=3)=[O:19])[CH2:14][CH2:13]1)[CH2:11][C:10]2=[O:38]>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.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>[CH3:31][O:30][C:28]1[C:27]2[C:22](=[C:23]([O:32][CH3:33])[CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:18]([N:15]2[CH2:14][CH2:13][C:12]3([CH2:11][C:10](=[O:38])[C:9]4[C:35](=[CH:36][CH:37]=[C:7]([C:1]#[N:2])[CH:8]=4)[O:34]3)[CH2:17][CH2:16]2)=[O:19])[CH:29]=1
Reactant: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(Br)ccc2O3)nc2c(OC)cccc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C#N)ccc2O3)nc2c(OC)cccc12
Temperature: 80 °C
Reaction time: 39 h

Procedure:
118 mg of zinc cyanide, 69.3 mg of Pd(PPh3)4 and 3 mL of DMF were added to 511 mg of the bromo compound obtained in Example 9, and heated under a nitrogen atmosphere at 80° C., and the reaction mixture was stirred for 39 hours. After cooled, the reaction mixture was diluted with 30 mL of ethyl acetate, washed successively with diluted aqueous ammonia, water and saturated brine, then dried over sodium sulfate, and concentrated. Ethyl ether was added to the resulting residue, and the insoluble solid thus formed was taken out through filtration. This was washed with ethyl ether and dried under reduced pressure to obtain the intended compound as a pale yellow-brown solid. 1H-NMR (300 MHz, CDCl3) δ: 8.20 (1H, d, J=2.0 Hz), 7.71 (1H, d, J=8.2 Hz), 7.74 (1H, dd, J=8.6, 2.0 Hz), 7.42 (1H, t, J=8.2 Hz), 7.19 (1H, s), 7.13 (1H, d, J=8.6 Hz), 7.08 (1H, d, J=8.2 Hz), 4.63-4.54 (1H, m), 4.26-4.17 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.64-3.52 (1H, m), 3.42-3.29 (1H, m), 2.88 (1H, d, J=16.8 Hz), 2.81 (1H, d, J=16.8 Hz), 2.23-2.13 (1H, m), 2.09-1.85 (3H, m). MS [M+H]+=458.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16][CH:17]([CH3:21])[C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:16][CH:17]([CH3:21])[C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[CH2:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1)=[O:19]
Reactant: CC1CC(=O)NN=C1c1ccc(N)cc1
Reactant: CC(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: CC(Cl)C(=O)Nc1ccc(C2=NNC(=O)CC2C)cc1
Yield: 90.9 %

Procedure:
6.0 g (29.6 millimoles) of 6-(p-aminophenyl)-5-methyl-4,5-dihydropyridaz-3-one and 4.1 g (32.3 millimoles) of 2-chloropropionyl chloride in 100 ml of absolute toluene are kept at 80° C. for 4 hours. The product is filtered off at 10° C., washed with water and dried under reduced pressure at 50° C. 7.9 g (91% of theory) of 6-[p-(2-chloropropionylamino)-phenyl]-5-methyl-4,5-dihydropyridaz-3-one are isolated as beige crystals which, after recrystallization from methanol, melt at 215°-217° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl.[NH2:19][OH:20].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[Cl:1][C:2]1[C:11]([CH:12]=[N:19][OH:20])=[C:10]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NO
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1C=NO
Temperature: 25 °C
Reaction time: 12 h

Procedure:
15.00 g (54 mmol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate and 4.20 g (60 mmol) of hydroxylamine hydrochloride were taken up in 300 ml of methanol, and a solution of 3.18 g (30 mmol) of sodium carbonate in 80 ml of water was added dropwise. After the mixture had been stirred for 12 hours at room temperature, the methanol was distilled off, the residue was diluted with water and the mixture was extracted with diethyl ether. After the organic phase had been dried, the solvent was removed. This gave 14.40 g (91% of theory) of methyl 2-chloro-3-hydroxyiminomethyl-4-methylsulfonylbenzoate.
Reaction SMILES: [CH3:1][O:2][S:3]([CH3:6])(=[O:5])=[O:4].[Li]CCCC.[CH2:12]([O:14][P:15](Cl)(=[O:19])[O:16][CH2:17][CH3:18])[CH3:13].[NH4+].[Cl-]>C1COCC1.CCCCCC.O>[CH3:1][O:2][S:3]([CH2:6][P:15]([O:16][CH2:17][CH3:18])([O:14][CH2:12][CH3:13])=[O:19])(=[O:5])=[O:4]
Reactant: COS(C)(=O)=O
Reactant: CCOP(=O)(Cl)OCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)OC)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 50.8 %

Procedure:
Methanesulfonic acid methyl ester (0.43 mL, 5.0 mmol) is dissolved in THF (10 mL) and it is cooled down to −78° C. 1.6 M n-BuLi (3.4 mL, 5.5 mmol) in hexane is added into it dropwise and the mixture is stirred for 30 min at −78° C. Then Phosphorochloridic acid diethyl ester (0.41 mL, 2.8 mmol) is added dropwise into the mixture and it is then gradually warmed up to −50° C. in 2 hrs. 5 mL of sat. NH4Cl and 20 mL of water are added and it is further warmed up to room temperature. The mixture is extracted with EtOAc (3×40 mL) and the organic layers are combined, dried (Na2SO4) and concentrated to give crude product. Purification by flash column chromatography affords 350 mg (53%) of (Diethoxy-phosphoryl)-methanesulfonic acid methyl ester.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH2:10]([N:17]1[C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[C:27]([NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][CH2:40][CH2:41][NH2:42])[CH:34]=[CH:33]2)=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(OP(C#N)(=O)OCC)C>CN(C)C=O.O>[CH2:10]([N:17]1[C:21]2[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[C:27]([NH:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][CH2:40][CH2:41][NH:42][C:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)=[O:9])[CH:34]=[CH:33]2)=[O:28])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)c1cccnc1
Reactant: NCCCn1ccc2cc(NC(=O)c3nc4ccc(Cl)cc4n3Cc3ccccc3)ccc21
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NCCCn1ccc2cc(NC(=O)c3nc4ccc(Cl)cc4n3Cc3ccccc3)ccc21)c1cccnc1
Temperature: 0 °C
Yield: 75.4 %

Procedure:
To 0.29 g of nicotinic acid was added 50 ml of dimethylformamide, further 1.2 g of 1-benzyl-6-chloro-2-[1-(3-aminopropyl)indol-5-ylaminocarbonyl]-benzimidazole and 0.7 ml of triethylamine were added, the mixture was stirred under cooling at 0° C. Next, 0.49 g of diethylcyanophosphonate was dissolved in 20 ml of dimethylformamide and added thereto and the reaction mixture was stirred at room temperature for 1 day. After the reaction was finished, water was added then the whole mixture was extracted with ethyl acetate, the extract thus obtained was washed with water and an aqueous solution saturated with sodium chloride. The washed extract was dried with anhydrous magnesium sulfate, then the solvent was removed by distillation under reduced pressure. The resulting residue was subjected to a silica gel column chromatography (eluent: 2% methanol/dichloromethane), recrystallized from chloroform, there was obtained 1 g of 1-benzyl-6-chloro-2-{1-[3-(pyridin-3-ylcarbonylamino)propyl]indol-5-ylaminocarbonyl}benzimidazole as in the form of yellow needle crystals.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([N+:13]([O-:15])=[O:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1ccc(F)c(F)c1F
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 48 h
Yield: 97.5 %

Procedure:
2,3,4-Trifluorobenzoic acid (2.5 g) was dissolved in concentrated sulfuric acid (15 ml). Potassium nitrate (1.62 g) was added to the solution under ice cooling. The temperature of the reaction mixture was (given back to room temperature to conduct stirring for 2 days. The reaction mixture was poured into ice water (300 ml) and extracted with ether (200 ml). An organic layer was dried and concentrated. Hexane was added to the residue to conduct filtration, thereby obtaining the title compound (3.06 g) as a pale yellow powder.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][C:10]1=[O:14])([O:3][CH2:4][CH3:5])=[O:2].[C:15](OC(=O)C)(=[O:17])[CH3:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:15]([O:14][C:10]1[CH2:11][CH2:12][CH2:13][C:9]=1[CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)CCCC1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CCCC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 10, treatment of 2-(3-carbethoxypropyl)cyclopentan-1-one (Example 6) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 98°-103° C. (0.35 mm).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([OH:1])[CH:7]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: O=C(CBr)OCc1ccccc1
Product: CC(=O)c1ccc(OCC(=O)OCc2ccccc2)cc1O

Procedure:
1-(2,4-Dihydroxy-phenyl)-ethanone was treated with 1 equivalent of benzyl 2-bromoacetate and processed as described in the synthesis of example 20a to obtain the title compound. The crude was purified using flash chromatography (silica gel, 3% CH3CN in chloroform) and crystallization was effected using ether-PE 60-80° C. Yield, 75%, white solid; mp, 66-67° C.; MS (EI): 300 (M+), 285, 165, 91 (100%); analysis: C17H16O5 requires C, 67.99; H, 5.37. found: C, 67.99; H, 5.53%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].FC(F)(F)C([N:12]([C:27]1[CH:42]=[CH:41][C:30]([C:31](ON2C(=O)CCC2=O)=[O:32])=[CH:29][CH:28]=1)[CH2:13][CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=O.[OH-].[Na+].Cl>O.C(O)C.C(N(CC)CC)C>[CH2:13]([NH:12][C:27]1[CH:28]=[CH:29][C:30]([C:31]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:32])=[CH:41][CH:42]=1)[CH2:14][CH2:15][CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NCCS(=O)(=O)O
Reactant: CCCCCCCCCC=CCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCCC=CCCCNc1ccc(C(=O)NCCS(=O)(=O)O)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of 2.50 g. of taurine and 5.6 ml. of triethylamine in 22.5 ml. of water is added 5.55 g. of N-{p-[2,2,2-trifluoro-N-(4-tetradecenyl)acetamido]benzoyloxy}succinimide as a solution in 45 ml. of ethanol. After 24 hour, the mixture is treated with 20 ml. of 2.0M sodium hydroxide and 25 ml. of water. After stirring for 10 minutes, the mixture is acidified with dilute hydrochloric acid, and the crude product is collected by filtration. Recrystallization affords the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:29]=[CH:28][C:16]3[N:17](COCC[Si](C)(C)C)[CH:18]=[N:19][C:15]=3[CH:14]=2)[C:9]1=[O:30].CO>Cl.O1CCOCC1.C(Cl)(Cl)Cl>[NH:17]1[C:16]2[CH:28]=[CH:29][C:13]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:30])=[CH:14][C:15]=2[N:19]=[CH:18]1
Reactant: Cc1ccncc1N1CCN(c2ccc3c(c2)ncn3COCC[Si](C)(C)C)C1=O
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2ccc3[nH]cnc3c2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 14.4 %

Procedure:
1-(4-Methyl-pyridin-3-yl)-3-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-5-yl]-imidazolidin-2-one (260 mg, 0.6138 mmol) in 1,4-dioxane hydrochloride (15 mL) was taken in a reaction flask and the flask was stirred at room temperature for 12 hours. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was concentrated under reduced pressure and the concentrate was washed with diethyl ether and hexane to afford 26 mg of the product (46.8% yield).
Reaction SMILES: [H][H].[Br-].[I-].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[N:6]1)(=[O:16])[CH3:15]
Reactant: [H][H]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2[nH]ncc2c1
Agent: [Br-]
Agent: [I-]
Product: CC(=O)n1ncc2ccccc21

Procedure:
To prepare 1-substituted 1H-indazole of formula 1 wherein R1 is formyl, alkanoyl, cycloalkylalkanoyl ##STR45## wherein R2', R5, X", p" and q' are as above, a 1-unsubstituted 1H-indazole 8 wherein R is as above, with the proviso that R is not hydrogen, and X, m, n and p are as before, is treated, respectively, with a formyl, alkanoyl or cycloalkylalkanoyl chloride, bromide or iodide, a compound of the formula ##STR46## R2'OCOHal or R5COHal wherein R2', R5, X", p" and q' are as above and Hal is iodo, bromo or chloro, or the corresponding acid anhydrides thereof, at an elevated temperature of about the reflux temperature of the reaction medium. For example, treatment of a 1H-indazole 8 wherein R is methyl with acetic anhydride at the reflux temperature of the reaction mixture affords a 1-acetyl-1H-indazole 14 wherein R2 is methyl, and treatment of a 1H-indazole 8 wherein R is methyl with benzoyl chloride at a reaction temperature of about 100° C. yields a 1-benzoyl-1H-indazole 14 wherein R2 is phenyl.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][O:25]4)=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(OC(=O)[O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)C.C(N(CC)CC)C.O>C(Cl)Cl>[OH:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)=[CH:19][CH:18]=2)(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: CCOC(=O)Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1cc(OC2CCCCO2)ccc1CNc1ccc(OCCN2CCCC2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(O)cc1)N(Cc1ccc(OC2CCCCO2)cc1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 60 h

Procedure:
A solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (264 mg, 0.666 mmol) in methylene chloride (10 mL) was treated with carbonic acid 4-chlorosulfonyl-phenyl ester ethyl ester (278 mg, 1.05 mmol) and triethylamine (0.3 mL). The reaction mixture was stirred for 60 hr. and water was added. The aqueous solution was washed with methylene chloride (2×). The combined organic layers were dried (sodium sulfate), filtered, and concentrated in vacuo. The crude product was purified via radial chromatography using a solvent gradient (methylene chloride to 5% methanol/methylene chloride) to obtain the title compound of Step A.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl.[NH2:16][CH2:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[CH2:22][CH2:21]1)=[O:19].O[Li].O>CN(C=O)C>[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]([CH2:2][NH:16][CH2:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])[CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:5]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: Cl
Agent: [Li]O
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CNCc1ccc(-c2ccccc2)cc1)N1CCC(Oc2ccccc2Cl)CC1
Reaction time: 8 h
Yield: 11.5 %

Procedure:
A mixture of biphenyl-4-yl-methanol (250 mg, 1.35 mmol) and aqueous HBr (48%) (3 mL) was stirred at 10° C. for 3 hrs. After completion of the reaction, the mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer collected was concentrated under reduced pressure to afford 330 mg (98.5% Yield) 4-bromomethyl-biphenyl. 4-Bromomethyl-biphenyl (120 mg, 0.485 mmol) was added to a stirred mixture of 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (134 mg, 0.44 mmol) (prepared according to Step 1 and 5 of the General Scheme), LiOH.H2O (40 mg, 0.97 mmol) and 4 Å molecular sieves (350 mg) in DMF (4 mL) and stirring was continued overnight. The reaction mixture was filtered and filtrate was diluted with cold water, extracted with ethyl acetate and organic layer was dried over sodium sulfate. The organic layer was concentrated under reduced pressure. Purification by column chromatography (using neutral alumina and 5% MeOH in DCM as eluent) to afford 22 mg (11.4% Yield) of 2-[(biphenyl-4-ylmethyl)-amino]-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone. LC/MS [M+H]+: 435, 90.56%. 1H NMR (CDCl3): δ7.64-7.52 (m, 4H), 7.5-7.3 (m, 6H), 7.24-7.15 (dt, 1H), 7.0-6.86 (m, 2H), 4.6 (q, 1H), 4.0-3.8 (m, 3H), 3.7-3.6 (m, 3H), 3.5 (s, 2H), 3.4-3.3 (m, 1H), 2.0-1.8 (m, 4H).
Reaction SMILES: [Li+].[Cl-].[CH3:3][O:4][C:5]([CH2:7]P(OC)(OC)=O)=[O:6].C1CCN2C(=NCCC2)CC1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47][CH:48]=O)([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1>CC#N>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][C:32]1[CH:33]=[C:34]([C:38]23[CH2:45][CH2:44][C:41]([CH2:46][CH2:47]/[CH:48]=[CH:7]/[C:5]([O:4][CH3:3])=[O:6])([CH2:42][CH2:43]2)[CH2:40][O:39]3)[CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=CCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C/CCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a 0° C. suspension of LiCl (55.4 mg, 1.306 mmol) in MeCN (2 mL) under N2 was added trimethyl phosphonoacetate (0.188 mL, 1.306 mmol) and DBU (0.197 mL, 1.31 mmol). The reaction was stirred at 0° C. for 30 minutes, and then 3-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)propanal (300 mg, 0.871 mmol) was added. The reaction was stirred at rt for 2 h and concentrated in vacuo. The residue was diluted with Et2O, washed with 1 N aq. HCl, satd aq. NaHCO3, brine, dried (MgSO4), filtered, and concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford the title compound (300 mg, 86% yield) as a white solid. LCMS, [M+NH4]+=418.2. 1H NMR (500 MHz, CDCl3) δ 7.23 (t, J=8.0 Hz, 1H), 7.14-7.11 (m, 1H), 7.03-6.93 (m, 3H), 5.86 (dt, J=15.7, 1.5 Hz, 1H), 5.45 (t, J=3.2 Hz, 1H), 3.94 (ddd, J=11.3, 9.9, 3.0 Hz, 1H), 3.84 (s, 2H), 3.75 (s, 3H), 3.65-3.59 (m, 1H), 2.23-2.15 (m, 2H), 2.09-1.98 (m, 5H), 1.89-1.84 (m, 2H), 1.75-1.58 (m, 8H), 1.37-1.31 (m, 2H).