Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[CH3:20][O:21][CH2:22][C:23]([NH:25][NH2:26])=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][O:21][CH3:20])=[N:25][N:26]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: COCC(=O)NN
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CCCCO
Product: COCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with methoxyacetic acid hydrazide to give 8-chloro-1-(methoxymethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[OH:7][CH2:8][C@@H:9]1[CH2:11][C@H:10]1[CH2:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>CC(C)=O.O.O.[Ru](=O)=O>[CH2:16]([O:15][C:13](=[O:14])[CH2:12][C@@H:10]1[CH2:11][C@H:9]1[C:8]([OH:2])=[O:7])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C(C[C@@H]1C[C@H]1CO)OCc1ccccc1
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(C[C@@H]1C[C@H]1C(=O)O)OCc1ccccc1
Reaction time: 1 h
Yield: 98 %

Procedure:
Sodium metaperiodate (107 mg, 0.50 mmol) and ruthenium(IV) oxide hydrate (3.02 mg, 0.02 mmol) were added to a solution of benzyl trans-2-(2-(hydroxymethyl)cyclopropyl)acetate (44 mg, 0.20 mmol) in acetone (1 mL) and water (1 mL) at 0° C., and the mixture was stirred at 0° C. to room temperature for 1 hr. The reaction mixture was filtered through Celite (while washing with acetone), and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was washed with brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give trans-2-(2-(benzyloxy)-2-oxoethyl)cyclopropanecarboxylic acid (46.0 mg, 0.196 mmol, 98%) as a colorless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:10]([C:19]([OH:21])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:25])=O>C(Cl)Cl.CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][S:16][CH:15]=2)[CH:10]([C:19]([Cl:25])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CN(Cc2ccccc2)CCC1c1ccsc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1CN(Cc2ccccc2)CCC1c1ccsc1

Procedure:
A solution of the product from step d) (4.68 g, 13.8 mmol) in CH2Cl2 (77 ml) was treated with DMF (3-4 drops) and oxalyl chloride (2.72 ml, 31 mmol) at 22° C. for 1 hour. Next, the solvent was evaporated providing the subtitle compound (4.38 g) that was used without further purification.
Reaction SMILES: N1C2C(=CC=CC=2)C=NC=1.[Cl:11][C:12]1[CH:13]=[C:14]([C:16]([F:20])=[CH:17][C:18]=1[Cl:19])[NH2:15].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:35])=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([NH:15][C:22]2[C:31]3[C:26](=[CH:27][C:28]([F:35])=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[C:16]([F:20])=[CH:17][C:18]=1[Cl:19]
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Reactant: Nc1cc(Cl)c(Cl)cc1F
Agent: c1ccc2ncncc2c1
Product: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1F

Procedure:
In another particular, which includes a quinazoline that is substituted by two different reactive groups at positions 6 and 7 thereof, 3,4-dichloro-6-fluoroaniline is reacted with 4-chloro-7-fluoro-6-nitroquinazoline, so as to produce 4-[(3,4-dichloro-6-fluorophenyl)amino]-7-fluoro-6-nitroquinazoline. The 4-[(3,4-dichloro-6-fluorophenyl)amino]-7-fluoro-6-nitroquinazoline is then reacted with a sodium salt of 3-(4-morpholinyl-1-propanol), so as to produce 4-[(3,4-dichloro-6-fluoro-phenyl)amino]-7-[3-(4-morpholinyl)propoxy]-6-nitroquinazoline, which is reduced, by means of an ethanolic solution of hydrazine hydrate and Raney®Nickel, so as to produce 6-amino-4-[(3,4-dichloro-6-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]quinazoline. The product is then reacted with a carbon-11 labeled acryloyl chloride so as to produce a carbon-11 labeled N-{4-[(3,4-dichloro-6-fluorophenyl)amino]-7-[3-(4-morpholinyl)propoxy]quinazoline-6-yl}acrylamide (carbon-11 labeled morpholino-substituted Compound 3).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:17]([F:20])(=[O:19])=[O:18])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:21](O)(=[O:26])[CH2:22][C:23](O)=[O:24].C(Cl)(=O)C>O>[CH:1]1([N:7]2[C:21](=[O:26])[CH2:22][C:23](=[O:24])[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[S:17]([F:20])(=[O:19])=[O:18])[C:8]2=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CC(=O)O
Reactant: O=C(Nc1ccccc1S(=O)(=O)F)NC1CCCCC1
Solvent: O
Solvent: CC(=O)Cl
Product: O=C1CC(=O)N(C2CCCCC2)C(=O)N1c1ccccc1S(=O)(=O)F
Temperature: 25 °C

Procedure:
A mixture of N-cyclohexyl-N'-(2-fluorosulphonylphenyl) urea (300 g, 1 mole), malonic acid (156 g, 1 mole) and acetylchloride (427 ml, 6 moles) was refluxed for 4 hours with stirring, cooled to room temperature, poured into water (4.25 l) and stirred for 1 hour to decompose the excess of acetylchloride. Then the 1-cyclohexyl-3-(2-fluorosulphonylphenyl)barbituric acid formed was added with portions and with stirring to 1N ammoniumhydroxide (5 l, 5 moles). After the last addition, stirring was continued for still an hour. Some insoluble material was filtered off and the filtrate was carefully acidified with 6N sulphuric acid (835 ml) whilst cooling by the addition of crushed ice. After 1 hour the precipitate was collected, digested with water (2.5 l), filtered off and dried, yielding 180-270 g of a product containing 69-81% of the desired barbituric acid (by titration of the CH2), the remaining 19-31% consisting mainly of 1-cyclohexyl-2-acetyl-3-(2-sulphamoylphenyl)barbituric acid, as determined by TLC and NMR.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11](=[O:16])[CH2:12][C:13](=O)[CH3:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:19][C:20]1[N:27]=[CH:26][C:25]([I:28])=[CH:24][C:21]=1[CH:22]=O.N1CCCCC1>CO>[C:1]([C:5]1[CH:18]=[CH:17][C:8]([CH2:9][NH:10][C:11]([C:12]2[C:13]([CH3:14])=[N:19][C:20]3[C:21]([CH:22]=2)=[CH:24][C:25]([I:28])=[CH:26][N:27]=3)=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Nc1ncc(I)cc1C=O
Reactant: CC(=O)CC(=O)NCc1ccc(C(C)(C)C)cc1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1nc2ncc(I)cc2cc1C(=O)NCc1ccc(C(C)(C)C)cc1
Temperature: 120 °C
Yield: 63 %

Procedure:
In a screw cap pressure tube were N-(4-tert-butylbenzyl)-3-oxobutanamide (104.2 mg, 0.42 mmol) and 2-amino-5-iodonicotinaldehyde (95.0 mg, 0.38 mmol) suspended in piperidine (151.0 μl, 1.53 mmol). The tube was sealed and the mixture heated to 120° C. for 2 h. The mixture was allowed to cool, diluted with MeOH, adsorbed in silica and purified by flash chromatography (CH2Cl2/MeOH 99:1→97:3) yielding 110 mg of the title compound (63%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.C(N(CC)CC)C>[C:18]1([C:17]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][N:6]=[C:5]3[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(Nc1ccc2[nH]nc(-c3ccccc3)c2c1)c1ccccc1
Yield: 7 %

Procedure:
To a mixture of 5-amino-3-phenyl-1H-indazole (190 mg, 0.909 mmol) in acetonitrile (6 mL) was added benzoyl chloride (123 mg, 0.909 mmol). The solution was allowed to reflux for three hours. Triethylamine (3 drops) was added over a period of one hour while reflux continued for an additional hour. The solution was condensed and distilled water was added. The reaction mixture was extracted with ethyl acetate. The organics were dried using sodium sulfate, and condensed to give a solid. The solid was purified using chromatography (SiO2, 30–45% ethyl acetate/hexanes) to give the title compound (20 mg, 8% yield). 1H NMR (DMSO-d6) δ 13.40 (br s, 1H), 10.32 (s, 1H), 8.56 (s, 1H), 7.96 (m, 4H), 7.75 (d, 1H), 7.55 (m, 6H), 7.39 (t, 1H); ES-MS (m/z) 314 [M+1]+.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:33])[CH:23]([NH2:32])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:18]([CH2:34][CH:35]=[CH2:36])[C:17]1=[O:37])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[CH2:34]([C@@H:18]1[N:19]([C:22](=[O:33])[C@H:23]([NH2:32])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:20][CH2:21][N:16]([C@@H:4]([CH2:5][C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[C:3]([OH:38])=[O:2])[C:17]1=[O:37])[CH:35]=[CH2:36]
Reactant: C=CCC1C(=O)N(C(Cc2ccc3ccccc3c2)C(=O)OC)CCN1C(=O)C(N)Cc1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CC[C@H]1C(=O)N([C@@H](Cc2ccc3ccccc3c2)C(=O)O)CCN1C(=O)[C@H](N)Cc1ccc(F)cc1
Reaction time: 3 h

Procedure:
To a solution of 2-{3-allyl-4-[2-amino-3-(4-fluorophenyl)propionyl]-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 10, (168 mg, 0.324 mmol) in a mixture of THF (1 mL)/CH3OH (0.5 mL)/H2O (0.5 mL) is added LiOH (43 mg, 1.78 mmol). The reaction mixture is stirred for 3 hours, acidified with 1N HCl to pH 3 and extracted with EtOAc. The extract is dried over Na2SO4, filtered, concentrated and dried under high vacuum to afford the desired product in quantitative yield.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[C:31]([F:34])([F:33])[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:78][CH:79]1[CH2:84][CH2:83][N:82]([C:85]([O:87][C:88]([CH3:91])([CH3:90])[CH3:89])=[O:86])[CH2:81][CH2:80]1>CN(C)C=O>[C:88]([O:87][C:85]([N:82]1[CH2:81][CH2:80][CH:79]([NH:78][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:14])([F:13])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)[CH2:84][CH2:83]1)=[O:86])([CH3:91])([CH3:90])[CH3:89]
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3C(F)(F)F)ncc21
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)cc3C(F)(F)F)ncc21
Reaction time: 0.17 h
Yield: 34.2 %

Procedure:
To a mixture of 0.075 g (0.155 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoic acid (I-204) and 8 mL of dimethylformamide was added 0.0313 g (0.232 mmole) of 1-hydroxybenzotriazole, 0.088 g (0.232 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.080 g (0.617 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0465 g (0.232 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0354 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-trifluoromethyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-211) as a white solid.
Reaction SMILES: Cl.O1CCCC1.C([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([C:23]1[C:24](=[O:35])[C:25]2[C:30]([C:31](=[O:34])[C:32]=1[CH3:33])=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=O)C>C(OCC)(=O)C>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([C:23]1[C:24](=[O:35])[C:25]2[C:30]([C:31](=[O:34])[C:32]=1[CH3:33])=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)OCCCCCC(C1=C(C)C(=O)c2ccccc2C1=O)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1=C(C(CCCCCO)c2ccccc2)C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 5 h
Yield: 83.7 %

Procedure:
6N Hydrochloric acid (20 ml) was added to a tetrahydrofuran solution (20 ml) containing 1-acetoxy-6-(3-methyl-1,4-naphthoquinon-2-yl)-6-phenylhexane (2.8 g, 7.2 mmole), followed by stirring for 5 hours with heating at 70° C. After cooling, ethyl acetate was added to the reaction solution, and the organic layer was separated out, washed with water, dried and evaporated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl ether-ethyl acetate (1:1), followed by recrystallization of the object compound from isopropyl ether to give 1-hydroxy-6-(3-methyl-1,4-naphthoquinon-2-yl)-6-phenylhexane (2.1 g). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 75, 79 and 81 were prepared.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([O:24][Si](C)(C)C)C#N)=[CH:17][CH:16]=1.[CH:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[Cl-].[NH4+]>COCCOC>[OH:36][CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:21]([C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:24]
Reactant: COc1ccc(C(C#N)O[Si](C)(C)C)cc1
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: COCCOC
Product: COc1ccc(C(=O)C(O)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
According to the procedure in the literature [J. Chem. Soc. Perkin Trans. I, 1992, 2409-2417], dissolve 292 ml (2.08 mol) diisopropylamine in 3.6 liter 1,2-dimethoxyethane and cool to −78° C. Add 826 ml n-butyllithium solution (2.5 M in n-hexane, 2.066 mol) at a temperature below −60° C. Stir the mixture for a further 15 min at <−60° C. and then add a solution of 442 g (1.877 mol) (4-methoxyphenyl)[(trimethylsilyl)oxy]acetonitrile in 1.41 liter 1,2-dimethoxyethane dropwise at <−60° C. After further stirring for 30 min at −60° C., add a solution of 199.3 g (1.878 mol) benzaldehyde in 1.4 liter 1,2-dimethoxyethane in the space of 20 min at −60° C. Next, heat the reaction mixture slowly to RT in 4 h. Add 7 liter saturated ammonium chloride solution and extract with ethyl acetate. Wash the organic phase with saturated ammonium chloride solution, dry, and concentrate under vacuum. Take up the residue in 7 liter dioxan and 5 liter methanol, and add 6 liter 1 N hydrochloric acid. Stir the mixture for 3 h at RT, then add 3 liter saturated sodium chloride solution and extract the mixture with 6.5 liter ethyl acetate. Wash the organic phase with 1.0 liter 1 N sodium hydroxide solution and with saturated sodium chloride solution, dry, and concentrate under vacuum. Take up the residue in 2 liter diisopropyl ether, decant from the insoluble matter and seed with crystals. Stir the resultant suspension for 2 h at RT and then filter off the crystals with suction. Wash with 300 ml diisopropyl ether and petroleum ether and dry under vacuum. 236.8 g (47.8% of theor.) of the target compound is obtained.
Reaction SMILES: ClC(Cl)(Cl)C(=N)O[CH:5]([C:7]1[C:15]2[N:14]=[CH:13][N:12]([CH2:16][CH3:17])[C:11]=2[CH:10]=[C:9]([C:18]([F:21])([F:20])[F:19])[CH:8]=1)[CH3:6].[OH:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.ClC(Cl)C.C1CCCCC1>>[CH2:16]([N:12]1[C:11]2[CH:10]=[C:9]([C:18]([F:21])([F:19])[F:20])[CH:8]=[C:7]([CH:5]([O:25][CH2:26][C:27]3([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:28]3)[CH3:6])[C:15]=2[N:14]=[CH:13]1)[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: CCn1cnc2c(C(C)OC(=N)C(Cl)(Cl)Cl)cc(C(F)(F)F)cc21
Solvent: C1CCCCC1
Solvent: CC(Cl)Cl
Product: CCn1cnc2c(C(C)OCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)cc(C(F)(F)F)cc21
Temperature: 0 °C

Procedure:
(±)-(1-(1-Ethyl-6-(trifluoromethyl)-1H-benzo[d]imidazol-4-yl)ethyl 2,2,2-trichloroacetimidate (670 mg, 1.664 mmol) and tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (727 mg, 2.496 mmol) were combined in a dichloroethane/cyclohexane mixture (4:2, 6 mL) and cooled to 0° C. The reaction mixture was treated with tetrafluoroboric acid-diethyl ether complex (91 μL, 0.67 mmol), and subsequent processing including extractive work up and purification were carried out as described in example 8 to give 274 mg (30.7%) as white foam-like solid. 1H-NMR (500 MHz, CHLOROFORM-D) δ ppm 7.97 (s, 1 H), 7.54 (s, 1 H), 7.29-7.37 (m, 5 H), 7.16-7.24 (m, 1 H), 5.11 (q, J=6.4 Hz, 1 H), 4.20-4.29 (m, 2 H), 3.64-3.80 (m, J=13.1 Hz, 2 H), 3.29-3.37 (m, 2 H), 2.93-3.10 (m, 2 H), 2.09-2.22 (m, 2 H), 1.87-2.03 (m, 2 H), 1.56 (t, 3 H), 1.39-1.48 (m, 12 H). 532.40 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([O:18][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Oc2ccccc2)ncc1[N+](=O)[O-]
Temperature: 110 °C
Reaction time: 4 h

Procedure:
A solution of 2-chloro-4-methyl-5-nitropyridine (10 g, 0.058 mol), in DMF (100 mL) was treated with phenol (6.6 g, 0.07 mol) and potassium carbonate (9.6 g, 0.07 mol) and the reaction mixture was stirred at 110° C. for 4 hr and then cooled. To the reaction mixture was then added water. The reaction mixture was extracted into EtOAc, dried and concentrated to a syrup, which was purified via column chromatography (4:2:0.5; CHCl3:hexanes:EtOAc, v/v) to yield 4-methyl-5-nitro-2-phenoxy-pyridine as a light yellow solid.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]([F:15])([F:14])[C:6]1[NH:10][N:9]=[CH:8][C:7]=1[C:11]([O-:13])=[O:12].CO.Cl>O.C1COCC1>[F:15][C:5]([F:4])([F:14])[C:6]1[NH:10][N:9]=[CH:8][C:7]=1[C:11]([OH:13])=[O:12]
Reactant: O=C([O-])c1cn[nH]c1C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cn[nH]c1C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of lithium hydroxide hydrate (1.265 g, 30.2 mmol) in water was added to a solution of ethyl 1-(((+/−)cis)-2-allylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylate as a racemate (0.996 g, 3.02 mmol) in THF and MeOH and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The resulting turbid solution was diluted with water to provide a clear solution. The pH was adjusted to 1 by adding 1 M HCl and the mixture was stirred vigorously for 30 min. The resulting precipitate was collected by vacuum filtration to provide 1-(((+/−)-cis)-2-allylcyclohexyl)-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid as a racemate (D60) as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:40])(=[O:39])[NH:26][CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][CH3:38])[N:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=1[S:25](=[O:39])(=[O:40])[N:26]([C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1)[CH2:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[N:33]([CH2:37][CH3:38])[N:32]=[CH:31]2)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: CCOC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3CC)c2)c(Cl)c1
Product: CCOC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3CC)c2)c2ncc(C(F)(F)F)cc2Cl)c(Cl)c1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and ethyl 3-chloro-4-(N-((1-ethyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-4 of Example 14).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1.[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=O.C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:16][O:17][C:18]1[C:25]([O:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH:2][CH2:3][CH:4]([OH:15])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1
Reactant: COc1cccc(C=O)c1OC
Reactant: COc1ccc(C(O)CN)cc1OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(C(O)CNCc2cccc(OC)c2OC)cc1OC
Temperature: 25 °C
Yield: 75.5 %

Procedure:
α-Aminomethyl-3,4-dimethoxybenzyl alcohol hydrochloride (5.84 g, 25 mmol) was suspended in methanol (30 ml). 2,3-Dimethoxybenzaldehyde (5 g, 30 mmol) was added to the suspension and then triethylamine (3.83 ml, 27.5 mmol) was added dropwise thereto under stirring at room temperature. The resultant solution was heated under reflux for 30 minutes and then sodium borohydride (1.4 g, 37 mmol) was slowly added thereto under stirring under cooling with ice. After the completion of foaming, the solvent was distilled off under reduced pressure. Water was added to the residue, which was made acidic with 3N hydrochloric acid and washed with ether. The cistern was made basic with aqueous ammonia and then subjected to extraction with dichloromethane. The dichloromethane layer was washed with water and then a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resultant crystals were washed with isopropyl ether to obtain 6.56 g of α-[[(2,3-dimethoxybenzyl)amino]methyl]-3,4-dimethoxybenzyl alcohol.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2.[N:23]12[CH2:30][CH2:29][CH:26]([CH2:27][CH2:28]1)[C@@H:25](O)[CH2:24]2.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:7]([O:9][C@@H:25]2[CH:26]3[CH2:29][CH2:30][N:23]([CH2:28][CH2:27]3)[CH2:24]2)=[O:8])[C:3]2[CH:19]=[CH:20][CH:21]=[CH:22][C:2]1=2
Reactant: COc1cccc(NC(C(=O)O)c2csc3ccccc23)c1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: COc1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2csc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A mixture of 2-(benzo[b]thiophen-3-yl)-2-(3-methoxyphenylamino)acetic acid (I46) (1.02 g, 3.25 mmol), (R)-quinuclidin-3-ol (496 mg, 3.90 mmol), DCC (805 mg, 3.90 mmol), and HOBT (597 mg, 3.90 mmol) in dry THF (30 ml) was stirred at r.t. overnight. THF was evaporated, and the crude product was taken up with EtOAc and washed twice with 1M K2CO3 and then with brine. The organic phase was dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH=98/2 to 95/5) to obtain (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(3-methoxyphenylamino)acetate (213 mg, 15.5% yield over two steps).