Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:18]([C:21]([CH3:23])=[CH2:22])([O-:20])=[O:19]>C1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[CH2:22][CH:21]([N+:18]([O-:20])=[O:19])[CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)[N+](=O)[O-]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Solvent: c1ccccc1
Product: CC(Cc1c[nH]c2ccc(OCc3ccccc3)cc12)[N+](=O)[O-]

Procedure:
To a stirred 0.5 M benzene solution of 5-benzyloxy-1H-indole (6 mL) was added 2-nitro-propene (5.2 mL of the 10% benzene solution). The reaction was heated at reflux under a nitrogen atmosphere overnight. The volatiles were removed and residue was purified by silica gel chromatography (20% EtOAc/hexanes) to afford 5-benzyloxy-3-(2-nitro-propyl)-1H-indole (550 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH2:17]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)[CH2:18][CH2:19][CH3:20]>>[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH2:17][CH2:18][CH2:19][CH3:20])=[CH:22][CH:23]=1)(=[O:29])=[O:28])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Product: CCCCc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 115 mg of (2-amino-5-chloro-phenyl)-phenyl-methanone and 116 mg of 4-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 0.90 (t, 3H, J=6.8 Hz), 1.29 (m, 2H), 1.46 (m, 2H), 2.49 (t, 2H, J=7.6 Hz), 7.05 (d, 2H, J=8.4 Hz), 7.32 (d, 1H, J=2.4 Hz), 7.40 (m. 4H), 7.47 (dd, 1H, J=8.8 Hz, 2.8 Hz), 7.56 (m, 3H), 7.76 (d, 1H, J=8.8 Hz), 9.78 (s, 1H). MS: m/z 428.9 (M++1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O>[CH:7]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][OH:18])[CH2:12][CH2:11]1)([CH3:9])[CH3:8]
Reactant: CCOC(=O)CC1CCN(C(C)C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.6 %

Procedure:
Under argon gas atmosphere, lithium aluminum hydride (1.19 g) is suspended in tetrahydrofuran (50 mL) and thereto is added dropwise a solution of ethyl (1-isopropylpiperidin-4-yl)acetate (compound obtained in Reference Example 93(1), 6.43 g) in tetrahydrofuran (50 mL) over a period of 15 minutes under ice-cooling. The mixture is stirred at room temperature for 1.5 hours. To the reaction mixture is added successively water (1.2 mL), 2N sodium hydroxide solution (2.4 mL), and water (2.4 mL) under ice-cooling. The mixture is stirred at room temperature for 2 hours. After addition of magnesium sulfate, the reaction mixture is stirred for 10 minutes and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on NH-silica gel (Solvent; n-hexane:ethyl acetate=1:1) to give 2-(1-isopropylpiperidin-4-yl)ethanol (5.09 g, yield; 99%) as a colorless oil. MS (APCI) m/z: 172 [M+H]+
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][NH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([Cl:28])[CH:27]=1)[CH2:24][N:23]([CH3:29])[CH2:22][CH:21]2[C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>N1C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([Cl:28])[CH:27]=1)[CH2:24][N:23]([CH3:29])[CH2:22][CH:21]2[C:30]1[CH:31]=[C:32]([S:36]([N:10]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: CCOC(=O)CNCP(=O)(OCC)OCC
Solvent: c1ccncc1
Product: CCOC(=O)CN(CP(=O)(OCC)OCC)S(=O)(=O)c1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.1 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of ethyl 2-((diethoxyphosphoryl)methylamino)acetate (320 mg, 1.26 mmol, 1.00 equiv) in pyridine (10 mL). 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (500 mg, 1.28 mmol, 1.01 equiv) was added and the resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product (400 mg) was purified by preparative HPLC to give 200 mg (24%) of the title compound as a TFA salt.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C([O-])([O-])=O.[K+].[K+].[CH3:44][C:45]([CH3:47])=O>>[CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][O:36][CH2:44][CH2:45][CH3:47])=[CH:32][CH:33]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(C)=O
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCOc2ccc(CCO)cc2)C1c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOCCc1ccc(OCCCOC(=O)C2=C(C)NC(C)=C(C(=O)OC)C2c2cccc([N+](=O)[O-])c2)cc1

Procedure:
A solution of 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-hydroxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (125 g, 0.252 moles) in acetone (700 mL) is stirred at reflux for 8 hours with K2CO3 (48 g, 0.35 mol) and n-bromopropane (61.5 g, 0.5 mol). After evaporation of the solvent, the crude product is purified by flash chromatography (solvent=93:7 CH2Cl2 :acetone) to yield 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(3-[4-(2-propoxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine as an oil.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[Cl:17])=[CH:5][C:6]([O:8]CC)=O.[F:18][C:19]([F:34])([F:33])[O:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=O)[O:29]CC)=[CH:23][CH:22]=1>CN(C)C=O>[F:18][C:19]([F:33])([F:34])[O:20][C:21]1[CH:22]=[CH:23][C:24]([N:27]2[C:6](=[O:8])[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[NH:3][C:28]2=[O:29])=[CH:25][CH:26]=1
Reactant: CCOC(=O)Nc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C=C(N)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccccc2Cl)[nH]c(=O)n1-c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C
Yield: 72.6 %

Procedure:
2.0 g of sodium hydride (purity: 55%) was added to 100 ml of dimethylformamide, followed by dropwise addition of 7.9 g of ethyl 3-amino-3-(2-chlorophenyl)-2-propenoate to the solution with stirring at 0° C. The resulting solution was stirred at room temperature for 15 minutes and added with 8.7 g of ethyl 4-trifluoromethoxyphenylcarbamate. The solution was further stirred at 100° C. for 4 hours. Then the solvent was distilled away under reduced pressure and the residue was dissolved in 200 ml of water and washed twice with diethyl ether. This aqueous solution was added to a mixed solution of 100 g of ice and 50 ml of concentrated hydrochloric acid. The precipitated crystals were filtered out and dried under reduced pressure to obtain 10.7 g of a crude product. This crude product was washed with heated diisopropyl ether and dried to obtain 9.7 g of the objective compound.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].Cl.[CH2:15](O)[CH3:16]>CCOCC>[CH2:15]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)[CH3:16]
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CCO
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)c1ccc(N)c([N+](=O)[O-])c1

Procedure:
4-Amino-3-nitrobenzoic acid (5.0 g, 27.4 mmol) was dissolved in ethanol (100 mL) and treated with a 2N solution of HCl in ether (30 mL). The reaction mixture was refluxed for 16 h, then the solvent was removed in vacuo. The crude compound was dissolved in dichloromethane and washed with NaOH 0.5N. The organic phase was dried over sodium sulfate and the solvent was removed. 4-Amino-3-nitrobenzoic acid ethyl ester was thus obtained as a yellow solid, 4.6 g, (79%), MS (ISP): m/e=211.1 (M+H+.), and used crude in the following reaction.
Reaction SMILES: [N:1]1([C:7]2[CH:24]=[CH:23][C:10]3[CH2:11][N:12](C(OC(C)(C)C)=O)[CH2:13][CH2:14][O:15][C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:31]>>[ClH:31].[ClH:31].[N:1]1([C:7]2[CH:24]=[CH:23][C:10]3[CH2:11][NH:12][CH2:13][CH2:14][O:15][C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2cc(N3CCCCC3)ccc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(cc1N1CCCCC1)OCCNC2
Yield: 81.7 %

Procedure:
A solution of tert-butyl 8-(piperidin-1-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (280 mg, 0.843 mmol) in 4N hydrogen chloride-ethyl acetate (6 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (210 mg, 81.7%) as a solid.
Reaction SMILES: [C:1]1([C:7](=O)[CH:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:40].S>C(O)C>[C:1]1([C:7]2[S:40][C:10]([C:12]3[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=3)=[CH:9][C:8]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(C(=O)CC(C(=O)c2ccccc2)c2ccccc2)cc(OC)c1OC
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Solvent: Cc1ccccc1C
Solvent: CCO
Product: COc1cc(-c2cc(-c3ccccc3)c(-c3ccccc3)s2)cc(OC)c1OC
Temperature: 10 °C
Reaction time: 3 h
Yield: 193 %

Procedure:
In a 1-liter stirred stainless steel autoclave were placed 40.4 g 1,2-diphenyl-4-(3,4,5-trimethoxyphenyl)butane-1,4-dione, 100 ml of xylene, 22.2 g of phosphorus pentasulfide and 128 g of hydrogen sulfide. The reaction mixture was heated with stirring for 3 hours at 160°-168° C. (1210-1250 psig. pressure). The reactor was cooled to 10° C. and the hydrogen sulfide was released. The residue was stirred with 150 ml of ethanol to decompose unreacted phosphorus pentasulfide. Filtration and evaporation gave 38.8 g (96.4%) of 2,3-diphenyl-5-(3,4,5-trimethoxyphenyl)thiophene.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6](=[O:25])[N:5]([CH2:26][C:27]3[N:28]=[N:29][N:30]([CH2:32][CH3:33])[N:31]=3)[C:4]=2[CH:3]=1.[F:34][C:35]1[CH:36]=[CH:37][C:38]([O:44][CH3:45])=[C:39](B(O)O)[CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl>[CH2:32]([N:30]1[N:29]=[N:28][C:27]([CH2:26][N:5]2[C:4]3[CH:3]=[C:2]([C:37]4[CH:36]=[C:35]([F:34])[CH:40]=[CH:39][C:38]=4[O:44][CH3:45])[S:10][C:9]=3[C:8](=[O:11])[N:7]([CH:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:16][CH2:17]3)[C:6]2=[O:25])=[N:31]1)[CH3:33]
Reactant: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(Br)cc32)n1
Reactant: COc1ccc(F)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCn1nnc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4cc(F)ccc4OC)cc32)n1

Procedure:
Tert-butyl 4-{6-bromo-1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (811 mg, compound B101), (5-fluoro-2-methoxyphenyl)boronic acid (280 mg), dichlorobis(tricyclohexylphosphine)palladium (110 mg) and aqueous cesium carbonate solution (1.125 ml, 2.0 M) in DME (10 ml) are reacted according to the procedure described in example B55 to afford the title compound after purification by flash column chromatography [silica gel, elution gradient: cyclohexane/EtOAc, 100/0 to 50/50 to 30/70 (v/v)] as a solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])=[N:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH:13]([C:14]2[CH:15]=[N:16][C:17]([C:20]3[CH2:21][CH2:22][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:12][C:11]([C:26]([C:28]([F:31])([F:29])[F:30])([C:32]([F:33])([F:35])[F:34])[OH:27])=[N:10]1
Reactant: OC(C1=NN(c2ccccc2Cl)C(c2ccc(C3=CCNCC3)nc2)C1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)C1CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(C1CC1)N1CC=C(c2ccc(C3CC(C(O)(C(F)(F)F)C(F)(F)F)=NN3c3ccccc3Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.4 %

Procedure:
1-(2-chloro-phenyl)-5-[6-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-3-yl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 356, cyclopropanesulfonyl chloride (8.0 uL, 0.08 mmol), and triethylamine (38.0 uL, 0.28 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 10.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:51][C:46]2[CH:47]=[CH:48][CH:49]=[N:50][C:45]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NC1C=NC=CC=1>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:51][C:46]1[CH:45]=[N:50][CH:49]=[CH:48][CH:47]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Cl)c(C(=O)N2CCOCC2)cc1OCc1ccccc1
Reaction time: 72 h

Procedure:
To a solution of 5-chloro-4-(4-morpholinylcarbonyl)-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 67; 90 mg, 0.24 mmol) in N,N-dimethylformamide (3 ml) was added diisopropylethylamine (0.08 ml, 0.48 mmol), HATU (164 mg, 0.43 mmol) and 3-aminopyridine (27.0 mg, 0.29 mmol). The solution was stirred for 72 hours. The solvent removed in vacuo and purified by MDAP to give the title compound as a white solid. 55 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([O:25]C)=O)=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21.C([NH2:29])=O.C[O-].[Na+]>CN(C)C=O.[Cl-].[NH4+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]([NH2:29])=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: NC=O
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 120 °C
Reaction time: 19 h
Yield: 89.7 %

Procedure:
A mixture of methyl 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (2.00 g, 4.87 mmol), formamide (1.94 mL, 48.7 mmol) and sodium methoxide (28% solution in methanol, 4.8 mL) in N,N-dimethylformamide (12 mL) was stirred at 120° C. for 19 hr. The mixture was diluted with aqueous saturated ammonium chloride. The resultant precipitate was collected by filtration, washed with water and diisopropyl ether to give the title compound (1.73 g, 4.37 mmol, 90%) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[Mg].[CH2:17](Br)[CH:18]=[CH2:19]>C1COCC1>[CH2:19]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][C:11]([CH3:15])([CH3:14])[CH2:10][O:9]2)=[CH:4][CH:3]=1)[CH:18]=[CH2:17]
Reactant: C=CCBr
Reactant: CC1(C)COC(c2ccc(Br)cc2)OC1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCc1ccc(C2OCC(C)(C)CO2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 58.9 %

Procedure:
In a dry apparatus a solution of 12 (2.05 g, 7.60 mmol) in THF (15 mL) was added dropwise to magnesium powder (0.22 g, 9.1 mmol) under argon. After the addition was completed the mixture was refluxed for 45 min. Then the mixture was cooled to rt and allyl bromide (720 μL, 8.30 mmol) dissolved in THF (10 mL) was added slowly. The mixture was stirred for 4.5 h, then quenched with satd aq NH4Cl (25 mL) and extracted with ether. The combined organic phases were washed with aq NaHCO3 (5%) and brine and dried (Na2SO4). The solvents were removed under reduced pressure and the residue was crystallized from hexanes and filtered. The filtrate was purified by column chromatography (silica, ether/hexanes, 1:4), affording a light yellow oil (1.04 g, 59%). IR (neat): {tilde over (v)} 3077, 2955, 2904, 2846, 1639, 1619, 1517; 1H NMR δ 0.79 (s, 3H), 1.29 (s, 3H), 3.38 (d, 3J=6.6 Hz, 2H), 3.64 (d, 2J=11.0 Hz, 2H), 3.76 (d, 2J=11.0 Hz, 2H), 5.00–5.10 (m, 2H), 5.37 (s, 1H), 5.86–6.01 (m, 1H), 7.19, 7.43 (AA′BB′, 2×2H); 13C NMR (APT) δ 21.7 (−), 22.9 (−), 30.0 (+), 39.8 (+), 77.5 (+), 101.5 (−), 115.6 (+), 126.1 (−), 128.4 (−), 136.3 (+), 137.2 (−), 140.5 (+); GC-MS (EI) obsd 232, 231, 191, 163, 145, 115, 105, 91, 69, 56, 41; Anal. Calcd for C15H20O2: C, 77.55; H, 8.68; Found: C, 77.52; H, 8.77.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[O:35][C:36]([CH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=O>C1COCC1>[F:22][C:18]([F:23])([O:17][C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:9][CH2:10][N:5]([S:2]([CH2:1][C:36]([CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[O:35])(=[O:3])=[O:4])[CH2:6][CH2:7]2)=[CH:16][CH:15]=1)[CH:19]([F:21])[F:20]
Reactant: COC(=O)C1CCOCC1
Reactant: CS(=O)(=O)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CS(=O)(=O)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1)C1CCOCC1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
The 1-(methylsulfonyl)-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine (2.85 g, 0.008 mol) was dissolved in anhydrous THF (200 ml) and cooled to −10° C. under an argon atmosphere. 1.0M solution of lithium bis(trimethylsilyl)amide in THF (17.6 ml, 0.0176 mol) was added with cooling to −30° C. and the mixture added a solution of methyl-tetrahydro-2H-pyran-4-carboxylate (CAS Number 110238-91-0) in THF (2 ml). This was allowed to reach room temperature and stirred for 2 hours. The reaction was quenched with saturated NH4Cl solution and diluted with H2O and ethyl acetate. The organic phase was collected, dried over MgSO4, filtered and evaporated to dryness to yield crude 2-({4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazin-1-yl}sulfonyl)-1-(tetrahydro-2H-pyran-4-yl)ethanone. (3.64 g, 97%)
Reaction SMILES: [Cl-].C([Li])CCC.[CH2:7]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10].[Cl-].[Na+].[CH2:21]([O:23][CH2:24]C)C>>[CH2:7]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[CH:21][O:23][CH3:24])=[CH:13][CH:12]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCOCC
Reactant: CCCCc1ccc(C=O)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Product: CCCCc1ccc(C=COC)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
21.1 g of methoxymethyltriphnylphosphonium chloride is introduced into 280 ml of diethyl ether under nitrogen. At 0° C., 29.6 ml of n-butyllithium solution (1.6 M in hexane) is added in drops, and it is stirred for one hour at room temperature. 10 g of 4-butylbenzaldehyde in 40 ml of diethyl ether is now added, and it is stirred for one more hour. Sodium chloride solution is added to the reaction mixture, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. After chromatography on silica gel with ethyl acetate, 6.7 g of 2-(4-butylphenyl)-1-methoxyethene 48 (E,Z-mixture) is obtained as a colorless oil, which is dissolved in 200 ml of acetone and is stirred under nitrogen with 10 ml of 2N hydrochloric acid overnight. Sodium chloride solution is added, extracted with ethyl acetate, dried on sodium sulfate and concentrated by evaporation. Chromatographic purification on silica gel with ethyl acetate/hexane yields 3.9 g of title compound 49 as a colorless oil.
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]([C:17]([C:19]2[CH2:20][N:21]([CH3:26])[C:22](=[O:25])[C:23]=2[OH:24])=[O:18])[O:15][CH3:16])=[CH:9][CH:8]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:24][C:23]1[C:22](=[O:25])[N:21]([CH3:26])[CH2:20][C:19]=1[C:17]([N:14]([CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]([OH:27])=[O:5])=[CH:12][CH:11]=1)[O:15][CH3:16])=[O:18]
Reactant: CON(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CON(Cc1ccc(C(=O)O)cc1)C(=O)C1=C(O)C(=O)N(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 4-{[(4-hydroxy-1-methyl-5-oxo-2,5-dihydro-1H-pyrrole-3-carbonyl)-methoxyamino]-methyl}-benzoic acid tert-butyl ester (0.062 g, 0.16 mmol) in dichloromethane (3 ml) was treated with trifluoroacetic acid (0.6 ml) and stirred at 25° C. for 2 h. The solvent was then evaporated in vacuo and the residue was triturated with acetonitrile to give 0.041 g (80% yield) of the title material as a white solid; mp 196–197° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.97 (3H, s, NCH3), 3.73 (3H, s, OCH3), 4.19 (2H, s, NCH2), 4.96 (2H, s, NCH2), 7.42 (2H, d, J=8.3 Hz, aromatics), 7.91 (2H, d, J=8.3 Hz, aromatics), 11.4 (1H, broad s, OH), 12.9 (1H, broad s, OH). Anal. calcd for C15H16N2O6.H2O: C, 53.25; H, 5.36; N, 8.28. Found: C, 53.59; H, 4.79; N, 8.19.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=1>[O-2].[O-2].[Mn+4].C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=1
Reactant: OCc1ccc(COc2ccccn2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1ccc(COc2ccccn2)cc1
Reaction time: 8 h
Yield: 42 %

Procedure:
To a mixture of (4-(pyridin-2-yloxymethyl)-phenyl)-methanol (1.9 g, 8.6 mmol) described in Manufacturing Example 1-1-1 and methylene chloride (30 mL) was added manganese dioxide (15 g, 17 mmol) at room temperature, which was stirred overnight at this temperature. The reaction mixture was filtered through a Celite pad, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:4), to obtain the title compound (770 mg, 42%).