Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([PH:3][CH2:4][CH3:5])[CH3:2].[Li]CCCC.Cl[CH2:12][CH2:13][N:14]([CH2:19][CH2:20]Cl)[Si](C)(C)C.[Li][P:23]([CH2:26][CH3:27])[CH2:24][CH3:25]>C1COCC1.O>[CH2:1]([P:3]([CH2:4][CH3:5])[CH2:12][CH2:13][NH:14][CH2:19][CH2:20][P:23]([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:2]
Reactant: C[Si](C)(C)N(CCCl)CCCl
Reactant: CCPCC
Reactant: [Li]P(CC)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCP(CC)CCNCCP(CC)CC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a stirred solution of diethylphosphine (6.72 g, 74,6 mmol) in THF (150 ml) at −35° C., was added 47 ml of n-BuLi (1.6 M). Next, bis(2-chloroethyl)trimethylsilylamine (8.18 g, 38.4 mmol) in 40 ml tetrahydrofuran was then added dropwise to the LiP(Et)2 in tetrahydrofuran at −50° C. The mixture was allowed to warm to room temperature and stirred for 30 minutes. It was then heated to 60° C. and stirred overnight after which 100 ml of water was added to hydrolyse the silyl groups and the reaction mixture heated to 60° C. for 1 hour to ensure complete removal of the silyl groups. The reaction mixture was dried by passing it through a small bed of MgSO4, which was subsequently washed through with 60 ml diethyl ether. The solvent was removed to give 6.96 g bis(2-diethylphosphino-ethyl)-amine (Yield: 73%). 1H-NMR (C6D6) δ 1.12 (12H, d of t, CH2CH3, J=7.2 and 14.1 Hz), 1.38 (8H, q, CH2CH3, J=7.2), 1.60 (4H, t, (CH2)P, J=7.2) and 2.84 (4H, q, (CH2)N, J=7.8). 31P-NMR (C6D6) δ −26.02.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.OC1C=CC([C:28]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([NH2:32])=[O:31])=CC=1.[OH-:39].[Na+]>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][CH2:16][O:39][C:7]2[CH:12]=[CH:11][C:10]([NH:32][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[CH:28]=3)=[CH:9][CH:8]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: COc1cccc(C(N)=O)c1-c1ccc(O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: [OH-]
Agent: [Na+]
Product: COc1cccc(C(=O)Nc2ccc(OCCCOc3ccc(C[C@H](OC)C(=O)O)cc3)cc2)c1

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with N-(4-Hydroxy-phenyl-3-methoxy-benzamide from Step A under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C NaOH) to give the title compound. MS(ES) for C27H29NO7 [M+H]+: 480.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:24][C:25](=[O:27])[CH3:26])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1>CO.C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH:24][C:25](=[O:27])[CH3:26])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1)=[O:1]
Reactant: CC(=O)Nc1nc(-c2ccc(CO)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(-c2ccc(C=O)cc2)c(-c2ccc(S(C)(=O)=O)cc2)s1
Reaction time: 19 h

Procedure:
To a solution of N-{4-[4-(hydroxymethyl)phenyl]-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide (867.4 mg) in methanol (0.6 ml) and chloroform (10 ml) was added manganese(IV) oxide (6.65 g) at 20° C. under N2 atmosphere, and the mixture was stirred for 19 hrs. The reaction mixture was filtered through a celite pad. The filtrate was evaporeted to give N-{4-(4-formylphenyl)-5-[4-(methylsulfonyl)phenyl]-1,3-thiazol-2-yl}acetamide as a yellow solid, that was used as crude in the next reaction.
Reaction SMILES: [NH2:1][C:2]1[N+:7]([O-:8])=[C:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[N:3]=1.Cl[S:20]([OH:23])(=[O:22])=[O:21].C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[OH-:8].[NH2:1][C:2]1[N:3]=[C:4]([NH:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH:5]=[C:6]([CH3:9])[N+:7]=1[O:8][S:20]([OH:23])(=[O:22])=[O:21]
Reactant: O=S(=O)(O)Cl
Reactant: Cc1cc(NC2CCCCCCC2)nc(N)[n+]1[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1cc(NC2CCCCCCC2)nc(N)[n+]1OS(=O)(=O)O
Product: [OH-]
Reaction time: 8 h

Procedure:
A mixture of 1.00 grams of 2-amino-4-methyl-6-(cyclooctylamino)pyrimidine-3-oxide, 1.00 grams of chlorosulfonic acid, and 2.5 g of di-isopropylethylamine in 25 ml of chloroform is stirred overnight. The mixture is concentrated in vacuo. The residue is stirred with aqueous sodium bicarbonate, filtered and washed with ether to give the crude product. This is recrystallized from DMF and ethyl acetate to yield the purified 2-amino-6-methyl-4-(cyclooctylamino)-1-(sulfooxy)pyrimidinium hydroxide, inner salt.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)=[CH:7][CH:6]=1.[H][H].C1(P(C2C=CC=CC=2)(O[NH2:27])=O)C=CC=CC=1.[Cl-].[Na+]>O1CCCC1>[NH2:27][N:15]1[CH:14]=[CH:13][N:12]=[C:11]1[C:8]1[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=1
Reactant: [H][H]
Reactant: COc1ccc(-c2ncc[nH]2)cc1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nccn2N)cc1
Reaction time: 0.08 h

Procedure:
9.0 g of sodium hydride (55 percent dispersion in oil) are suspended in 600 ml of absolute tetrahydrofuran. 8.5 g of 2-(p-methoxyphenyl)imidazole are added thereto within 5 minutes. The mixture is stirred until hydrogen is no longer liberated (1 hour). Then, 34.5 g of O-diphenylphosphinylhydroxylamine are added portionwise thereto at 10° and the mixture is stirred at 10° for an additional 40 minutes and then at room temperature for 18 hours. Saturated sodium chloride solution is added thereto at 5° and the mixture is subsequently extracted with methylene chloride/methanol (99.5:0.5). The extract is dried over sodium sulfate and evaporated. There is obtained 1-amino-2-(p-methoxyphenyl)imidazole as a brown oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[CH:11]=[CH:10][CH:9]=[N:8]1.[Li]CCCC.N#N.[CH3:21][N:22]([CH2:42][CH:43]=[O:44])[C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1.CCOCC>[CH3:21][N:22]([C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:42][CH:43]([C:11]1[N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:13])([CH3:12])[CH3:1])[N:8]=[CH:9][CH:10]=1)[OH:44]
Reactant: C[Si](C)(C)CCOCn1cccn1
Reactant: CN(CC=O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(CC(O)c1ccnn1COCC[Si](C)(C)C)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -79 °C
Reaction time: 1 h
Yield: 33.8 %

Procedure:
A solution of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole (Heterocycles (1992), 34(2), 303-14)(0.80 g, 4.03 mmol) in 50 mL of THF/ether (3/2) was cooled to −78° C. and treated with 2.5M solution of n-BuLi (1.8 mL, 4.43 mmol) dropwise under N2 atmosphere. The resulting mixture was stirred for 30 min. [Methyl(trityl)amino]acetaldehyde (1.27 g, 4.04 mmol) in 5 mL of the THF/ether solution was added to reaction mixture and stirred for 1 h at −79° C. and warmed up to room temperature. The reaction was quenched by adding NH4Cl (sat. aq.) and water dropwise and the resulting suspension was extrcted into EtOAc (2×100 mL). The organic phase was washed with water (100 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with 20% EtOAc in n-heptane, and those fractions with Rf=0.3 by TLC(EtOAc/hexane, 3/7) were combined and concentrated in vacuo to give 0.7 g of the product as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][C:6]=1[C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.O.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1.[H-].[Na+]>CC(N(C)C)=O>[F:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[C:6]([C:21]2[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=2)[CH:7]=1)=[O:20]
Reactant: Nc1nnn[nH]1
Reactant: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCNc1nnn[nH]1
Reaction time: 2 h
Yield: 20.3 %

Procedure:
To a solution of N-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobenzamide (61.0 mg, 0.146 mmol) and 5-amino-1H-tetrazole monohydrate (42.5 mg, 0.500 mmol) in DMA (4 mL) was added NaH (30 mg, 60% dispersion in mineral oil) and the reaction was stirred for two hours. The resulting material was purified by HPLC. The product was dried under reduced pressure to afford the title compound as a white solid (12.5 mg, 20%). LCMS m/z (%)=423 (M+H, 100).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrCc1ccccn1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), potassium carbonate (0.77 g), 2-(bromomethyl)pyridine hydrobromide (1.06 g) and N,N-dimethylformamide (10 mL) was stirred at 50° C. for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.87 g, 69%).
Reaction SMILES: [CH:1]1([C:7]2[CH:31]=[CH:30][C:10]([C:11]([N:13]3[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17][N:16]4[C:24]([C:27](Cl)=[O:28])=[CH:25][CH:26]=[C:15]4[CH2:14]3)=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[CH3:41][O:42][C:43]1[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=1>ClCCl>[CH3:41][O:42][C:43]1[CH:49]=[CH:48][C:46]([NH:47][C:27]([C:24]2[N:16]3[C:15]([CH2:14][N:13]([C:11](=[O:12])[C:10]4[CH:9]=[CH:8][C:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:31][CH:30]=4)[C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH2:17]3)=[CH:26][CH:25]=2)=[O:28])=[CH:45][CH:44]=1
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)c1ccc(C3CCCCC3)cc1)C2
Reactant: COc1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(C4CCCCC4)cc2)C3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude 10-(4-cyclohexyl-benzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carbonyl chloride prepared in the manner of Example 23 (1.0 g) was added to a stirred mixture of N,N-diisopropylethyl amine (0.31 g) and 4-methoxy aniline (0.35 g) in dichloromethane (25 mL). After stirring overnight at room temperature the reaction mixture was washed with water and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solution was filtered through a short column of Magnesol® and the eluate evaporated to dryness to provide the desired title compound (1.0 g) as an off-white amorphous solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[OH:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:33](Cl)(=[O:35])[CH3:34].C(N(CC)CC)C>ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:31][CH3:32])=[CH:20][C:21]([CH:23]([O:24][C:33](=[O:35])[CH3:34])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:22][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(O)c3ccccc3)cc(OC)c21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(OC(C)=O)c3ccccc3)cc(OC)c21
Yield: 98.7 %

Procedure:
A solution of 136 mg (0.30 mmol) [2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-phenyl-methanol, 46 μl (0.66 mmol) acetyl chloride and 125 μl (0.90 mmol) triethylamine in 3 ml dichloromethane is stirred at room temperature for 1 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:1) to afford 140 mg of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:21][C:22]1[CH2:23][C:24](=[C:36]=O)[C:25]2[O:32][C:29]3([CH2:31][CH2:30]3)[CH2:28][C:27]([CH3:34])([CH3:33])[C:26]=2[CH:35]=1.C(OCC)(=O)C>CCCCCC>[Br:21][C:22]1[CH:23]=[C:24]([CH:36]=[CH2:1])[C:25]2[O:32][C:29]3([CH2:31][CH2:30]3)[CH2:28][C:27]([CH3:34])([CH3:33])[C:26]=2[CH:35]=1
Reactant: CC1(C)CC2(CC2)OC2=C1C=C(Br)CC2=C=O
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C=Cc1cc(Br)cc2c1OC1(CC1)CC2(C)C

Procedure:
Following general procedure N and using A solution of methylidene triphenyl phosphorane [generated from methyl triphenylphosphonium bromide (7 g, 20 mmol) and 1.6M solution of n-butyl lithium in hexanes (11.8 mL, 19 mmol)], 6-bromo-8-carbonyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane](Intermediate 40, 2.06 g, 7 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 1-2% ethyl acetate in hexane as the eluent, the title compound was obtained as a clear oil (1.36 g, 66%).
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:23][C:24]1[C:39]([OH:40])=[CH:38][CH:37]=[CH:36][C:25]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27].[CH3:41][N:42]1[CH:47]=[CH:46][C:45](=[O:48])[C:44]([C:49]2[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=2)=[CH:43]1>O.CN(C)C=O.C(N(CC)CC)C>[ClH:35].[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26](=[O:27])[C:25]2[CH:36]=[CH:37][CH:38]=[C:39]([OH:40])[C:24]=2[NH:23][C:53](=[O:54])[C:52]2[CH:51]=[CH:50][C:49]([C:44]3[C:45](=[O:48])[CH:46]=[CH:47][N:42]([CH3:41])[CH:43]=3)=[CH:57][CH:56]=2)=[N:30][CH:31]=1
Reactant: Cn1ccc(=O)c(-c2ccc(C(=O)O)cc2)c1
Reactant: Nc1c(O)cccc1C(=O)Nc1ccc(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1ccc(=O)c(-c2ccc(C(=O)Nc3c(O)cccc3C(=O)Nc3ccc(Cl)cn3)cc2)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 104.8 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (72 mg), 1-hydroxybenzotriazole (62 mg), triethylamine (64 μl) and 2-amino-N-(5-chloro-2-pyridinyl)-3-hydroxybenzamide (121 mg) were added to an N,N-dimethylformamide solution (3 ml) of 4-(1-methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoic acid (88 mg), followed by stirring at room temperature for 14 hours. After this, water (30 ml) was added to the reaction solution, and the precipitated insoluble solid was collected by filtration. The resulting solid was dried at 60° C. under reduced pressure, then tetrahydrofuran (5 ml), N,N-dimethylformamide (1 ml) and acetic acid (104 μl) were added to the solid, followed by stirring under heating at 60° C. for 2 days. After this, the reaction solution was concentrated under reduced pressure, an aqueous saturated sodium hydrogencarbonate solution (30 ml) was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous saturated sodium hydrogencarbonate solution and saturated brine, dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by NH-silica gel column chromatography (chloroform:methanol=97:3). The purified product was suspended in ethanol, 1 M hydrochloric acid (324 μl) was added, followed by concentration under reduced pressure. The residue was recrystallized from ethanol to obtain N-(5-chloropyridin-2-yl)-3-hydroxy-2-{[4-(1-methyl-4-oxo-1,4-dihydropyridin-3-yl)benzoyl]amino}benzamide hydrochloride (123 mg).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH2:33][CH2:32][C:31]4[C:26](=[CH:27][C:28]([C:34]5[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=5)=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[I:42].[C:43](OCC)(=O)C>CN(C=O)C>[I-:42].[CH2:1]([CH:8]1[CH2:13][CH2:12][N+:11]([CH3:43])([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[CH2:33][CH2:32][C:31]4[C:26](=[CH:27][C:28]([C:34]5[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=5)=[CH:29][CH:30]=4)[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN4CCC(Cc5ccccc5)CC4)cc2)CC3)cc1
Reactant: CI
Reactant: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C[N+]4(C)CCC(Cc5ccccc5)CC4)cc2)CC3)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 23 h

Procedure:
In DMF (3 ml) was dissolved N-[4—(4-benzyl-piperidino-methyl)phenyl]-7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamide (150 mg), and to the mixture was added methyliodide (53 μl). The mixture was stirred at room temperature for 23 hours. To the reaction mixture was added ethyl acetate(100 ml), and the resulting precipitate was filtered to give 4-benzyl-1-methyl-1-[4-[7—(4-methylphenyl)-3,4-dihydronaphthalene-2-carboxamido]benzyl]-piperidinium iodide (Compound 36) (141 mg, ratio of isomers=19:81) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].N1CCCC1.[C:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:28]1[CH2:29][CH2:30][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:26][CH:27]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Solvent: CCO
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Yield: 99.2 %

Procedure:
A solution of 5-nitroindole (38) (2.0 g, 12.334 mmol) in dry ethanol (20 mL) was treated with pyrrolidine (3.08 mL, 37.002 mmol) followed by N-Boc-4-piperidone (4.91 g, 24.668 mmol) at room temperature and the resulting solution was refluxed for 3 days. The reaction was brought to room temperature, the solvent was evaporated and the crude product was purified by column chromatography (ethyl acetate:hexanes, 1:3) to obtain compound 85 (4.2 g, quantitative) as a solid. mp 210-212° C.; 1H NMR (DMSO-d6) δ 1.36-1.43 (m, 11H), 3.57 (t, 2H, J=5.7 Hz), 4.08 (s, 2H), 6.20 (s, 1H), 7.56 (d, 1H, J=9.0 Hz), 7.71 (s, 1H), 8.02 (dd, 1H, J=2.1, 9.0 Hz), 8.71 (d, 1H, J=2.1, Hz), 11.93 (s, 1H); ESI-MS m/z (%): 366 (M.Na+, 100), 288 (52).
Reaction SMILES: [CH:1]1([CH:4]([O:24][CH3:25])[CH:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([C:16]([O:18]C(C)(C)C)=[O:17])=[C:8]2[CH3:23])[CH3:6])[CH2:3][CH2:2]1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[CH:1]1([CH:4]([O:24][CH3:25])[CH:5]([N:7]2[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]([C:16]([OH:18])=[O:17])=[C:8]2[CH3:23])[CH3:6])[CH2:3][CH2:2]1
Reactant: COC(C1CC1)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(C1CC1)C(C)n1c(C)c(C(=O)O)c2cccnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 1-(1-cyclopropyl-1-methoxypropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (100 mg, 0.29 mmol) in CH2Cl2 (2 mL) were added CF3CO2H (2 mL). The solution was stirred at 25° C. for 2 h. After the reaction completed, the solution was concentrated under reduced pressure to obtain 1-(1-cyclopropyl-1-methoxypropan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid as red oil. (87 mg, yield 99%).
Reaction SMILES: [Br:1][C:2]1([CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH2:5]1)CBr.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[OH:19].[C:20](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[O:19][CH2:20][C:5]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Br:1]
Reactant: O=C([O-])[O-]
Reactant: Oc1cc(F)ccc1Br
Reactant: FC1=CC=CC(Br)(CBr)C1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Br)c(OCc2c(F)cccc2Br)c1
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of 1-bromo-3-fluorobenzyl bromide (1.75 kg, 6.52 mol) and 2-bromo-5-fluorophenol (730 mL, 16.56 mol, 1.01 eq) in N,N-dimethylformamide (14 L) at 0° C. add potassium carbonate (1.36 kg, 9.80 mol) in one portion and stir the resulting slurry cold for one hour and then at room temperature overnight. Transfer the reaction mixture to a 50 liter flask, add water (14 L) drop wise over 30 min and ice periodically to control the exotherm of the crystallization. Stir at room temperature for one hour, collect off-white solids by filtration, wash with water, and dry overnight at 50° C. to obtain the title compound (2.22 kg, 90%). 1H NMR (CDCl3) δ 7.51 (m, 2H), 7.30 (m, 1H), 7.14 (t, 1H), 6.89 (dd, 1H), 6.67 (m, 1H), 5.26 (d, 2H).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O.O.[Cl:29][Sn]Cl.C(O)C.Cl>O>[ClH:29].[CH:1]1([N:6]2[C:10]3=[N:11][C:12]([C:16]4[CH:17]=[CH:18][C:19]([NH2:22])=[CH:20][CH:21]=4)=[N:13][C:14](=[O:15])[C:9]3=[C:8]([CH2:25][CH3:26])[NH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc([N+](=O)[O-])cc3)nc(=O)c1-2
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(N)cc3)nc(=O)c1-2
Yield: 60.6 %

Procedure:
To a mixture of 1-cyclopentyl-3-ethyl-6-(4-nitrophenyl)pyrazolo[3,4-d]pyrimidin-4-one (1.38 g, 3.9 mmol), SnCl2.2H2O (2.64 g, 11.72 mmol), ethanol (24 ml) and water (10 ml) was added concentrated HCl (14.5 ml). The reaction mixture was refluxed for 2 hours, cooled, and the product was collected by filtration and dried in vacuo to afford 0.85 g (67%) of 1-cyclopentyl-3-ethyl-6-(4-aminophenyl)pyrazolo[3,4-d]pyrimidin-4-one hydrochloride 1/3 hydrate, m.p. 279° C. (dec.).
Reaction SMILES: [NH4+:1].[Cl-:2].[C:3](=[NH:13])(OCC)[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1>C(O)C>[ClH:2].[C:3]([NH2:13])(=[NH:1])[C:4]1[CH:5]=[CH:6][N:7]=[CH:8][CH:9]=1
Reactant: CCOC(=N)c1ccncc1
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CCO
Product: Cl
Product: N=C(N)c1ccncc1
Reaction time: 8 h
Yield: 59.3 %

Procedure:
An aqueous solution of NH4Cl (26.9 g) is added to a solution of ethyl isonicotinimidate (75.5 g) in ethanol (325 ml). The reaction mixture is heated to reflux for four hours and stirred overnight. A white precipitate is filtered, washed with the mother liquor, dried at 90° C. under house vacuum for 8 hours, yielding 47 g of a white crystalline solid mp. 233°-237° C. The precipitate is dried overnight yielding 44.2 g of the desired hydrochloride, m.p. 237°-240° C.