Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([Cl:6])[CH2:4][OH:5].[CH2:7]([O:9][C:10](=[O:16])[CH2:11][C:12]([CH2:14]Br)=[O:13])[CH3:8].Cl>O1CCCC1>[CH2:7]([O:9][C:10](=[O:16])[CH2:11][C:12]([CH2:14][O:5][CH2:4][CH2:3][Cl:6])=[O:13])[CH3:8]
Reactant: OCCCl
Reactant: CCOC(=O)CC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCCCl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67 %

Procedure:
10.38 g (0.25 mole) of 57.8% sodium hydride are added to 110 ml of tetrahydrofurane. The mixture is cooled to a temperature between -10° C. and -20° C. whereupon at this temperature 10.08 g (0.125 mole) of ethylene chlorohydrine (III) are added under nitrogen dropwise. The mixture is stirred for 20 minutes, whereupon at the same temperature a solution of 26.18 g (0.125 mole) of ethyl-4-bromoacetoacetate (II) and 35 ml of tetrahydrofurane is added. The reaction mixture is stirred for 20 minutes, allowed to warm to room temperature, kept at this temperature for 6 hours, poured into 270 ml of 1 N hydrochloric acid under cooling and extracted with dichloro methane. The organic layer is dried and evaporated. The residual oil is made free of paraffine by treatment with a 1:1 mixture of acetonitrile and benzene. The product is distilled off in vacuo. Thus 17.47 g of the desired compound are obtained, yield 67%, bp.: 110° C./2 Hgmm.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([NH:14][C:15]([CH2:21][CH3:22])([CH2:19][CH3:20])[C:16]([OH:18])=O)=[O:13])[CH:9]=[CH:8][C:7]=2[C:23]([F:26])([F:25])[F:24])[CH2:3][CH2:2]1.Cl.[CH3:28][NH2:29]>>[CH2:21]([C:15]([NH:14][C:12]([C:10]1[CH:9]=[CH:8][C:7]([C:23]([F:24])([F:26])[F:25])=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:13])([C:16](=[O:18])[NH:29][CH3:28])[CH2:19][CH3:20])[CH3:22]
Reactant: CN
Reactant: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)O
Agent: Cl
Product: CCC(CC)(NC(=O)c1ccc(C(F)(F)F)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(6-(cyclopropylmethoxy)-5-(trifluoromethyl)picolinamido)-2-ethylbutanoic acid and methanamine hydrochloride as starting materials. MS (EI): m/e=388.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:8][C:6]1[N:5]=[C:4]([NH2:9])[C:3]([C:12]#[C:11][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[C:2]([Cl:1])[N:7]=1
Reactant: C#Cc1cccc(O)c1
Reactant: Nc1nc(N)c(I)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1nc(N)c(C#Cc2cccc(O)c2)c(Cl)n1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 500 mg (1.8 mmol) 6-chloro-5-iodo-pyrimidine-2,4-diamine, 827 mg (7.0 mmol) 3-ethynyl-phenol, 35 mg (0.19 mmol) CuI, 129 mg (0.19 mmol) PdCl2(PPh3)2 and 4.1 mL triethylamine in 4 mL dry DMF. Yield after purification by RP-HPLC: 511 mg (100%).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([NH:25][C:26]([C:28]1[C:29]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=3)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH:19]=[CH:18]2)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[NH2:1][CH2:4][C@@H:5]([NH:12][C:13]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[C:20]([NH:25][C:26]([C:28]1[C:29]([C:34]3[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:39]=3)=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:27])[CH:19]=[CH:18]2)=[O:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [N-]=[N+]=NC[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: NC[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
(S)-2-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (2-azido-1-phenyl-ethyl) amide (M, 0.722 mg, 1.22 mM) was dissolved in dioxane (10 mL). Triphenyl phosphine (0.35 g, 1.34 mM) was added and the mixture was stirred at 50° C. for 4 h. The mixture was removed from the heat and treated with an aqueous solution of NaOH (1N, 5 mL). The resulting mixture was stirred at room temperature for 2 h. The mixture was treated with 1 N HCl (10 mL) and stirred for 12 h. The precipitate was collected by filtration and washed with ether. The solid was dried under high vacuum to provide (S)-2-[(4′-trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (2-amino-1-phenyl-ethyl)-amide. ESMS (m+1), 555; calc. Mw, 554
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([O:10]C)=O)=[C:6]([OH:12])[C:5]2[S:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[C:4]=2[S:3]1(=[O:22])=[O:21].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>>[CH3:1][N:2]1[C:7]([C:8]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[O:10])=[C:6]([OH:12])[C:5]2[S:13][C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=3[C:4]=2[S:3]1(=[O:22])=[O:21]
Reactant: COC(=O)C1=C(O)c2sc3cc(C)ccc3c2S(=O)(=O)N1C
Reactant: Nc1ccccn1
Product: Cc1ccc2c3c(sc2c1)C(O)=C(C(=O)Nc1ccccn1)N(C)S3(=O)=O
Yield: 53 %

Procedure:
Prepared analogous to Example 1 from methyl 2,7-dimethyl-4-hydroxy-2H-[1] benzothieno [2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 2-amino-pyridine with a yield of 53% of theory.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[I:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Br>>[I:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: BrCc1cccc(I)c1
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cccc(I)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-iodobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16](I)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1.[CH2:21]=[CH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C.Cl>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[C:16]([CH:21]=[CH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]=1[O:18][CH3:19])[CH2:6][C:7]1[C:8]([NH2:14])=[N:9][C:10]([NH2:13])=[N:11][CH:12]=1
Reactant: C=Cc1ccccc1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(I)c1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COc1cc(Cc2cnc(N)nc2N)cc(C=Cc2ccccc2)c1OC
Temperature: 0 °C
Yield: 53.7 %

Procedure:
A mixture of 500 mg of 5-(3,4-dimethoxy-5-iodo-benzyl)pyrimidine-2,4-diamine, 1.53 g of styrene, 1.46 g of triethylamine and 31 mg of palladium-(II) acetate in 25 ml of dioxan is held at reflux under argon for 14 hrs. The mixture is poured on to ice-water, adjusted to pH 5 to 7 with 3N aqueous hydrochloric acid and extracted with methylene chloride. The organic phase is dried over magnesium sulphate, concentrated and the residue is chromatographed on silica gel with methylene chloride/methanol 97:3. 252 mg (53%) of 5-(3,4-dimethoxy-5-styryl-benzyl)pyrimidine-2,4-diamine are isolated as an orange solid. M.p.226°.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH2:12])=[CH:10][C:5]=2[N:4]=[N:3]1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]=O>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH:17]1[N:12]([CH2:11][C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[N:3]=[N:4][C:5]=3[CH:10]=2)[C:15](=[O:14])[CH2:16][CH2:19][CH2:20]1
Reactant: Cn1nnc2cc(CN)ccc21
Reactant: COc1cccc(OC)c1C=O
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2c(c1)nnn2C

Procedure:
Prepared according to the described general procedure 6 (GP6) with commercially available (1-methyl-1H-benzo[d][1,2,3]triazol-5-yl)methanamine and commercially available 2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.65 min.; [M+H]+: 381.09 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[CH:9]=2)=[CH:4][CH:3]=1.C.O.NN>C(O)(C)C.[Fe](Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cccc([N+](=O)[O-])c2)cc1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: CC(C)O
Solvent: O
Product: Cc1ccc(-c2cccc(N)c2)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
4′-Methyl-3-nitro-biphenyl (1.9 g) dissolved in isopropyl alcohol (30 mL) and iron (III) chloride (0.19 g) added followed by charcoal (0.19 g). Mixture heated to 65° C. before adding hydrazine hydrate (7.6 mL) slowly for 45 minutes under nitrogen. Mixture stirred for a further 2 hours at 70° C. Mixture filtered and washed with ethyl acetate. Organics combined and washed with water (50 mL) and brine (50 mL) before drying over sodium sulfate, filtering and evaporating to dryness to leave a yellow solid (1.55 g, 95%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20](OCC)=[O:21].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[CH2:30][NH2:31]>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:9][N:10]=2)[NH:5][C:4](=[O:19])[C:3]=1[C:20]([NH:31][CH2:30][C:26]1[S:25][CH:29]=[CH:28][CH:27]=1)=[O:21]
Reactant: NCc1cccs1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O
Product: O=C(NCc1cccs1)c1c(O)c2ncc(Cc3ccccc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 4-hydroxy-2-oxo-7-(phenylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and thiophene-2-methylamine employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 12.25 (1H, br), 11.10 (1H, br), 10.2 (1H, br), 8.28 (1H, br s), 7.38 (1H, br s), 7.34-7.22 (6H, m), 7.04 (1H, s), 6.97 (1H, d, J=4.3 Hz), 4.68 (2H, br), 4.04 (2H, br s); HRMS calcd for C21H17N3O3S+H+: 392.1069. Found: 392.1070.
Reaction SMILES: C([C:5]1[C:10]2[CH2:11][C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:13][C:9]=2[CH:8]=[C:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]=1[OH:28])(C)(C)C.O>ClCCl.CS(O)(=O)=O>[C:24]([C:7]1[C:6]([OH:28])=[CH:5][C:10]2[CH2:11][C:12]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[O:13][C:9]=2[CH:8]=1)([CH3:25])([CH3:27])[CH3:26]
Reactant: CCCCCC1(CCCCC)Cc2c(cc(C(C)(C)C)c(O)c2C(C)(C)C)O1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: ClCCl
Product: CCCCCC1(CCCCC)Cc2cc(O)c(C(C)(C)C)cc2O1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
To 1.03 g of 4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran synthesized according to JP No. 6-206842A/94 dissolved in 15 ml of dichloromethane was added 7 drops of methanesulfonic acid and the mixture was stirred at room temperature for a whole day and night. Then, the reaction mixture was combined with water and extracted with dichloromethane. The extracted layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 10% ethyl acetate) to give 0.19 g of 6-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran as a colorless oil (yield 22%).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([CH2:25]Cl)[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C-:27]#[N:28].[Na+].[I-].[K+]>CO>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([CH2:25][C:27]#[N:28])[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(CCl)cs4)ccc3o2)n1
Reactant: [C-]#N
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(CC#N)cs4)ccc3o2)n1
Temperature: 0 °C
Yield: 42.3 %

Procedure:
A mixture of 4-tert-butyl-2-{5-{[4-(chloromethyl)thiazol-2-yl]methyl}benzofuran-2-yl}thiazole (0.46 g) , sodium cyanide (0.22 g) and potassium iodide (0.19 g) in methanol (10 ml) was stirred under reflux for 21 hours. After being cooled, the mixture poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of ethyl acetate and toluene (1:20). The fractions containing object compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-{5-{[4-(cyanomethy)thiazol-2-yl]methyl}benzofuran-2-yl}thiazole (0.19 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:48]=[CH:47][C:41]([O:42][CH2:43][C:44](O)=[O:45])=[CH:40][CH:39]=2)[S:32]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:30]=[C:31]1[NH:35][C:34](=[O:36])[CH:33]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:42][CH2:43][C:44]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)=[CH:13][CH:14]=4)=[CH:4][C:3]=3[N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:45])=[CH:47][CH:48]=2)[S:32]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccccc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Yield: 89.2 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-phenylphenoxy)phenyl]-N-methylcarbamate (1.60 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (1.26 g), diethyl cyanophosphonate (0.73 g), triethylamine (0.45 g) and anhydrous tetrahydrofuran (20 ml) and the reaction mixture was purified to give the desired product (2.39 g).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].[ClH:18]>C(Cl)(Cl)Cl>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][Cl:18])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: Cl
Reactant: NC(=O)c1cc2cccc(OCC3CO3)c2o1
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc2cccc(OCC(O)CCl)c2o1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
There was suspended 2.3 g of 2-carbamoyl-7-(2,3-epoxypropoxy)benzofuran obtained in Reference Example 1 in 70 ml of chloroform, and thereto 15 ml of concentrated hydrochloric acid was added. Thereafter, the mixture was vigorously stirred at room temperature for 15 minutes. After the chloroform layer was washed with water and dried with magnesium sulfate, the solvent was distilled away from the reaction mixture under reduced pressure. The resultant residue was purified by silica-gel chromatography (eluent: 2 % ethanol-chloroform) to give the desired compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].Cl[C:40]([O:42][C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1)=[O:41]>C1COCC1.O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:40]([O:42][C:43]2[CH:44]=[CH:45][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:51][CH:52]=2)=[O:41])[CH2:10]1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OC(=O)N2CCC(c3ccccc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.9 %

Procedure:
To a solution of 238 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate in 3 mL of THF was added 200 mg of sodium hydrogen carbonate while suspending it in 2 mL of water. The reaction mixture was added 170 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka). After stirring at room temperature overnight, the mixed solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-(methoxycarbonyl)phenyl 3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidine-1-carboxylate (353 mg, colorless foamy substance) as a crude product. ESI+: 623
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=O.CN(C)C=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH2:40])=[CH:37][CH:36]=1>O>[Cl:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][NH:40][C:14]([C:3]2[CH:4]=[N:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH3:13])=[O:16])=[CH:37][CH:36]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1cccc2c(O)c(C(=O)O)cnc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 37 °C
Reaction time: 20 h

Procedure:
To a mixture of 0.50 g of 4-hydroxy-8-methoxy-3-quinolinecarboxylic acid (J. Amer. Chem. Soc., 68, 1268 (1946)) and 10 mL of dimethylformamide is added 0.41 g of carbonyldiimidazole. The mixture is stirred 20 h at 37° C. and then it is cooled to ° C. The mixture is treated with 0.25 mL of distilled water and stirred for 5 min. To the resulting solution is added 0.31 mL of 4-chlorobenzylamine. After stirring for 18 hours the mixture is warmed to 40° C. and stirred an additional 24 h. The solution is then cooled to 25° C. and it is diluted with 10 mL of distilled water. After minutes the precipitate is collected by filtration and it is washed with two successive 5 mL portions of 10% aqueous acetic acid. It is dried for 18 h in a stream of air at 25° C. This procedure yields the title compound as 485 mg of a tan solid.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]([CH3:18])[CH2:12]2)([OH:8])[C:4]([F:7])([F:6])[F:5].C1CCN2C(=NCCC2)CC1.[Si:32](Cl)([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34]>CN(C=O)C>[CH3:18][CH:13]1[CH2:12][C:11]2[C:15](=[CH:16][CH:17]=[C:9]([C:3]([O:8][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])([C:2]([F:1])([F:19])[F:20])[C:4]([F:7])([F:6])[F:5])[CH:10]=2)[NH:14]1
Reactant: CC[Si](Cl)(CC)CC
Reactant: CC1Cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2N1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC[Si](CC)(CC)OC(c1ccc2c(c1)CC(C)N2)(C(F)(F)F)C(F)(F)F
Reaction time: 10 h
Yield: 99.4 %

Procedure:
To a solution of 5.9 g (19.7 mmol) of 1,1,1,3,3,3-hexafluoro-2-(2-methyl-2,3-dihydro-1H-indol-5-yl)-propan-2-ol in DMF were added 2.94 mL (19.7 mmol) of DBU and after 30 min 3.3 mL (19.7 mmol) of TESCl. After 10 hrs, additional 0.44 mL (3.0 mmol) of DBU and 1.65 mL (9.85 mmol) of TESCl were added and stirring was continued for 2 hrs. The solvent and excess TESCl were evaporated i.v. and the residue was distributed between Et2O and a saturated aqueous solution of NH4Cl. The combined organic phases were dried over Na2SO4 and evaporated to yield 8.1 g (99%) of 2-methyl-5-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-2,3-dihydro-1H-indole, red liquid, MS: 414 (MH+).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)=O>>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)=[CH:19][CH:20]=1)(=[O:25])=[O:26]
Reactant: N#Cc1ccnc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-c2ccnn2-c2cc(C#N)ccn2)cc1
Yield: 100 %

Procedure:
The title compound was prepared in 100% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-[4-(methylsulfonyl)phenyl]prop-2-en-1-one according to the procedure for the preparation of Example 12, part B. 1H NMR (400 MHz, CDCl3): δ 3.10 (3H, s), 6.58 (1H, d, J=1.6 Hz), 7.39 (1H, dd, J=5.2, 1.2 Hz), 7.51 (2H, d, J=8.4 Hz), 7.81 (1H, d, J=1.6 Hz), 7.93 (2H, d, J=8.4 Hz), 8.20 (1H, s), 8.29 (1H, d, J=5.2 Hz).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[N:8]=[C:7]([N:9]2[CH2:13][C@@H:12]3[C@@H:14]([NH2:17])[CH2:15][CH2:16][C@@H:11]3[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>ClCCl>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:17][C@@H:14]2[C@@H:12]3[C@@H:11]([CH2:10][N:9]([C:7]4[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:18])[F:19])[N:8]=4)[CH2:13]3)[CH2:16][CH2:15]2)(=[O:36])=[O:35])=[CH:30][CH:29]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine from Example 264 Step A (0.050 g, 0.184 mmol) in dichloromethane (0.3 mL) was added triethylamine (0.051 mL, 0.369 mmol) followed by 4-chlorobenzene-1-sulfonyl chloride (0.047 g, 0.221 mmol). The reaction was stirred at ambient temperature overnight. The crude material was purified using a 12 g silica gel cartridge eluting with 5-50% ethyl acetate/hexanes over 25 minutes to give the title compound: 1H NMR (400 MHz, pyridine-d5) δ ppm 8.58 (s, 1H), 8.01-7.95 (m, 2H), 7.47-7.41 (m, 3H), 6.93 (d, J=7.3, 1H), 6.45 (d, J=8.5, 1H), 3.79-3.68 (m, 1H), 3.52-3.43 (m, 3H), 3.25 (dd, J=11.0, 4.1, 1H), 2.83-2.66 (m, 2H), 2.07-1.90 (m, 2H), 1.69 (dq, J=12.7, 7.9, 1H), 1.39-1.27 (m, 1H); MS (ESI+) m/z 446 (M+H)+.