Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33](OCC)=[O:34])[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45].NN>CCO.O>[NH2:3][CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45])=[O:34])[C:15]1=[O:38]
Reactant: NCCOCCO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCn1c(=O)c(C(=O)NCCOCCO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.252 g, 0.49 mmol) in EtOH (15 mL) under nitrogen was treated with 2-[(2-aminoethyl)oxy]ethanol (0.176 mL, 2.44 mmol) for 15 min.@150° C. in a microwave vessel. Transferred the mixture to a test tube, diluted with EtOH (30 mL), and treated with hydrazine (0.4 mL, 13 mmol)@50° C. overnight. After the reaction was cooled to ambient temperature the resulting suspension was diluted with water (120 mL) and refrigerated overnight. The resulting suspension was filtered, washed with 2:1 water:EtOH and thoroughly dried under high vacuum to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.27 (s, 1 H), 2.79 (t, J=6.81 Hz, 2 H), 3.45-3.61 (m, 8 H), 4.12-4.17 (m, 2 H), 4.22 (t, J=6.74 Hz, 2 H), 4.62 (s, 1 H), 7.10-7.18 (m, 2 H), 7.33-7.42 (m, 2 H), 8.07-8.16 (m, 1 H), 8.46-8.54 (m, 1 H), 10.44 (t, J=5.19 Hz, 1 H); ES+ MS: 445 (M+H+).
Reaction SMILES: [OH-:1].[Na+].[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[O:17][CH2:18][CH:19]([OH:24])[CH2:20][N:21]([CH3:23])[CH3:22])#[N:4].Cl>C(O)C.C(Cl)Cl>[CH3:23][N:21]([CH3:22])[CH2:20][CH:19]([OH:24])[CH2:18][O:17][C:16]1[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([NH2:4])=[O:1]
Reactant: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1C#N
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CN(C)CC(O)COc1ccccc1CCCCc1ccccc1C(N)=O
Yield: 52.7 %

Procedure:
2 ml of an aqueous solution containing 1 g of sodium hydroxide were added to a solution of 430 mg of 1-{2-[4-(2-cyanophenyl)butyl]phenoxy}-3-dimethylamino-2-propanol [prepared as described in Example 9(b)] in 5 ml of ethanol, and the resulting mixture was heated under reflux for 15 hours. At the end of this time, the reaction mixture was neutralized by the addition of aqueous hydrochloric acid, after which it was concentrated by evaporation under reduced pressure. The resulting residue was mixed with ethanol, and insoluble materials were filtered off. The filtrate was concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 3:1 by volume mixture of methylene chloride and methanol as the eluent, to give a colorless oily material, which was dissolved in a small amount of methylene chloride and then allowed to stand at room temperature. The crystals which precipitated were collected by filtration and dried in vacuo, to give 238 mg (yield 62%) of the title compound as colorless crystals, melting at 149°-151° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=[C:16]([N:17]3[CH2:21][CH2:20][C@@H:19]([OH:22])[CH2:18]3)[C:11]=2[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C2N=C(C(C)(C)C)N=C(Cl)C=2N=N1)C1C=CC=CC=1.N1CCC(O)C1>>[CH2:1]([N:8]1[C:12]2[N:13]=[C:14]([C:23]([CH3:26])([CH3:25])[CH3:24])[N:15]=[C:16]([N:17]3[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]3)[C:11]=2[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1nc(N2CC[C@@H](O)C2)c2nnn(Cc3ccccc3)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3)c2n1
Agent: OC1CCNC1
Product: CC(C)(C)c1nc(N2CCC(O)C2)c2nnn(Cc3ccccc3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of (R)-1-(3-Benzyl-5-tert-butyl-3H-[1,2,3]triazolo[4,5-d]pyrimidin-7-yl)-pyrrolidin-3-ol (example 113, a) the title compound was prepared from 3-benzyl-5-tert-butyl-7-chloro-triazolo[4,5-d]pyrimidine and pyrrolidin-3-ol and isolated as light yellow oil.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[C:2]=[O:3].[NH2:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]1>ClCCl>[CH3:26][C:20]1([CH3:27])[CH2:19][CH:18]([NH:17][C:2]([NH:1][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[O:3])[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21]1
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: ClCCl
Product: CCO[Si](CCCNC(=O)NC1CC(C)(C)NC(C)(C)C1)(OCC)OCC
Reaction time: 18 h

Procedure:
59.5 g (0.228 mol) of isocyanatopropyltriethoxysilane were initially charged in 50 ml of dichloromethane (abs.) and admixed with 35.63 g (0.228 mol) of 4-amino-2,2,6,6-tetramethylpiperidine in 30 ml of dichloromethane by dropwise addition at 20-40° C. and stirring for 18 h. Removal of the solvent in vacuo left 97.62 g of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N′-[3-(triethoxysilyl)propyl]urea with residual traces of solvent as a colorless oil. The product was characterized using 1H NMR.
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:5]=1[C:6]([C:8]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[O:7].C(O)(=O)C.O>O1CCCC1>[F:3][C:4]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:5]=1[CH:6]([C:8]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[CH:16]=[CH:15][C:9]=1[NH:10][S:11]([CH3:14])(=[O:13])=[O:12])[OH:7]
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1C(O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.1 %

Procedure:
Sodium borohydride (1.49 g) was added portionwise to a stirred mixture of 2'-(2,4-difluorobenzoyl)-4'-nitromethanesulfonanilide (5.6 g) in tetrahydrofuran (50 ml). The mixture was stirred at room temperature for 4 hours, treated with acetic acid (5 ml) and water (20 ml), had concentrated to dryness. The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried and evaporated to give a powder of 2'-(2,4-difluoro-α-hydroxybenzyl)-4'-nitromethanesulfonanilide (5.3 g).
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.II.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([S:16]([NH:19]Cl)(=[O:18])=[O:17])=[CH:14][CH:15]=1>O1CCOCC1>[C:10]1([CH3:9])[CH:11]=[CH:12][C:13]([S:16]([N:19]2[CH:6]3[CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]3)(=[O:18])=[O:17])=[CH:14][CH:15]=1
Reactant: C1=CCCCC1
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: II
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N2C3CCCCC32)cc1
Temperature: 80 °C
Reaction time: 10 h

Procedure:
To a solution of 200 g cyclohexene and 30.7 g iodine in 800 ml of anhydrous dioxane was added 611.7 g of chloramine T. The mixture was stirred at 80° C. for 10 h. After cooling to room temperature the mixture was poured into ice water and extracted with ethyl acetate twice. The combined organic phases were dried over sodium sulphate and concentrated and the residue was purified by chromatography (Silica, hexane/Ethyl acetate) to afford 180 g (29%) of) 7-(Toluene-4-sulfonyl)-7-aza-bicyclo[4.1.0]heptane as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:14]([O:21][C@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@@H:23]1[N:28]=[C:29]=[O:30])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:29]([NH:28][C@H:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C@@H:22]2[O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:30])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Reactant: O=C=N[C@H]1CCCC[C@@H]1OCc1ccccc1
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1c(Cl)ccc(NC(=O)N[C@H]2CCCC[C@@H]2OCc2ccccc2)c1O
Yield: 27 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (109 mg, 0.49 mmol) and the crude (1S,2S)-(−)-2-benzyloxycyclohexyl isocynate in 2 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. Purification upon Gilson HPLC, eluting with acetonitrile/water (10/90, v/v to 90/10, v/v, over 10 min), gave the desired product (60 mg, 27% two steps). LC-MS (m/z) 454.0 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[F:30][C:31]1([F:38])[CH2:37][CH2:36][CH2:35][NH2+:34][CH2:33][CH2:32]1>>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([C:24]([N:34]4[CH2:35][CH2:36][CH2:37][C:31]([F:38])([F:30])[CH2:32][CH2:33]4)=[O:25])[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CCC[NH2+]CC1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)N4CCCC(F)(F)CC4)C3)c2CC1

Procedure:
Prepared according to example 38c starting from 300 mg (0.58 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) and 120 mg (0.70 mmol) of 4,4-Difluoro-perhydro-azepinium chloride.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11](O)=O)[CH:6]=[CH:7][CH:8]=1.FC(F)(F)S(O)(=O)=O>O>[F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][CH:8]=1)[CH2:11][CH2:10][CH2:9]2
Reactant: O=C(O)CCc1cccc(C(F)(F)F)c1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O
Product: FC(F)(F)c1ccc2c(c1)CCC2
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 3-(3-trifluoromethylphenyl)propionic acid was added trifluoromethanesulfonic acid at room temperature, followed by stirring at 60° C. for 3 hours. The reaction liquid was put into cold water, followed by extraction with a mixed solvent of ethyl acetate and THF. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=9:1 to 5:1) to obtain 5-trifluoromethylindane (2.2 g) and a compound of Reference Example 11 (0.70 g) as colorless solids, respectively.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17](=[O:33])[NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])[N:22]=[CH:21][N:20]=2)[CH2:12]1)=O)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[CH3:32][O:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:23]1[N:22]=[CH:21][N:20]=[C:19]([NH:18][C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)=[O:33])[CH:24]=1
Reactant: COc1ccccc1-c1cc(NC(=O)C2CCCN(C(=O)OCc3ccccc3)C2)ncn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1cc(NC(=O)C2CCCNC2)ncn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.8 %

Procedure:
To a solution of compound 3-[6-(2-methoxy-phenyl)-pyrimidin-4-ylcarbamoyl]-piperidine-1-carboxylic acid benzyl ester (3 g) in 20 mL of methanol was added 10% palladium hydroxide (300 mg) under an atmosphere of nitrogen and the mixture was stirred at room temperature under an atmosphere of hydrogen for 4 hours. The reaction mixture was filtered through celite and the solvent was evaporated. Diethyl ether was added to the product, the mixture was stirred, filtered and the obtained solid was rewashed with diethyl ether and dried under vacuum to yield piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #16A) as a white solid (1.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[O:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1>[C:17]([N:12]1[C:11](=[O:16])[CH:10]([C:3]2[C:4]([O:8][CH3:9])=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[O:14][C:13]1=[O:15])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc(Cl)c1C1OC(=O)NC1=O
Solvent: C1CCOC1
Product: COc1cccc(Cl)c1C1OC(=O)N(C(C)=O)C1=O
Temperature: 25 °C
Reaction time: 44 h

Procedure:
5-(2-Chloro-6-methoxyphenyl)oxazolidin-2,4-dione (1.21 g., 5 mmoles) was dissolved in 10 ml. of tetrahydrofuran. Acetic anhydride (613 mg., 0.57 ml. 6 mmoles) was added and the solution stirred at room temperature for 44 hours. The reaction mixture was concentrated to an oil, partitioned between chloroform and saturated sodium bicarbonate. The chloroform layer was washed with fresh bicarbonate and then brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to solid. Repulp of the residue in about 50 ml. of ether gave 3-acetyl-5-(2-chloro-6-methoxyphenyl)oxazolidin-2,4-dione (790 mg., 56%; m.p. 132°-135° C. m/e 285/283).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].S(=O)(=O)(O)O>>[Cl:1][C:2]1[C:6]([N+:13]([O-:15])=[O:14])=[CH:5][N:4]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:3]=1
Reactant: Clc1ccn(-c2cccnc2)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl

Procedure:
In step 2a, 3-(3-chloro-1H-pyrazol-1-yl)pyridine (5b) is nitrated with nitric acid (HNO3), preferably in the presence of sulfuric acid (H2SO4) to yield 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (2-6). The nitration may be conducted at temperatures from about −10° C. to about 30° C.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]#[N:10])[CH:4]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CS(C)=O>[C:12]1([NH:11][C:9]([C:5]2[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=2)=[NH:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1cccnc1
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N=C(Nc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.3 %

Procedure:
Sodium hydride (60% in mineral oil, 11.52 g, 288 mmol) was added portion-wise over 30 min to a stirred solution of 3-pyridinecarbonitrile (30 g, 288 mmol) and aniline (26 g, 290 mmol) in dimethylsulfoxide (150 mL) at 10° C. The reaction mixture was allowed to warm to ambient temperature with stirring for 18 h. The reaction mixture was slowly and cautiously poured into water containing crushed ice. The solid that precipitated was filtered, washed with petroleum ether, dissolved in dichloromethane and dried over anhydrous Na2SO4. The volatiles were removed under reduced pressure (high vacuum) and the residue was dried to afford 36.5 g of the title compound as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:20][O:21][CH2:22][C:23](O)=O>>[CH3:20][O:21][CH2:22][C:23]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COCC(=O)O
Reactant: Nc1cnc2ccccc2c1NCc1ccccc1
Product: COCc1nc2cnc3ccccc3c2n1Cc1ccccc1

Procedure:
Using the general method of Example 91, 3-amino-4-(phenylmethylamino)quinoline (4.0 g, 16 mmol) was reacted with methoxyacetic acid (3.7 mL) to provide 4.4 g of the desired product as a solid. The structure was confirmed by nuclear magnetic resonance spectroscopy.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pt]=O>[ClH:2].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: Clc1ccc(C2CCNCC2)cc1
Yield: 188.1 %

Procedure:
A mixture of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (2 g, 8.7 mmol) and platinum oxide (100 mg) in ethanol (100 ml) was stirred at room temperature under an atmospheric pressure of hydrogen. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting precipitates by treating the residue with diethyl ether were collected by filtration to afford 4-(4-chlorophenyl)piperidine hydrochloride (1.9 g, yield 94%) as a pale gray powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH:16](OC)[O:17]C)[O:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH3:1][O:2][C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH:16]=[O:17])[O:12]1
Reactant: COC(=O)CCCCCCCC1CCC(C(OC)OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: COC(=O)CCCCCCCC1CCC(C=O)O1
Temperature: 60 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
8-(5-Dimethoxymethyl-tetrahydro-2-furyl)-octanoic acid methyl ester (I) (1.51 g, 0.00500 mole), p-toluene-sulfonic acid (30 mg), and acetone (50 ml) were stirred and heated for about 6 hours in such a way that every 30 minutes about 30 ml of the acetone were distilled off, and a similar new portion of acetone was added to the reaction mixture. The reaction was followed by thin layer chromatography (tlc). After cooling, sodium bicarbonate (0.1 g) was added, and the suspension was stirred for 1 hour. After filtration, the solvent was removed by heating on a water bath (60° C, 10 mmHg), and the residual yellow oil (1.45 g) was purified by distillation, giving 1.00 g (78%) of II as a colourless oil, b0.05 119°-122° C, nD25 1.4603.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([S:23]([C:26]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][N:30]=[CH:31]2)(=[O:25])=[O:24])[CH2:12][CH2:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])=O)(C)(C)C.[ClH:36].CO>>[ClH:36].[CH:31]1[C:32]2[C:27](=[C:26]([S:23]([N:11]([CH2:12][CH2:13][S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10][CH2:9][NH2:8])(=[O:25])=[O:24])[CH:35]=[CH:34][CH:33]=2)[CH:28]=[CH:29][N:30]=1
Reactant: CC(C)(C)OC(=O)NCCN(CCS(=O)(=O)c1ccccc1)S(=O)(=O)c1cccc2cnccc12
Agent: Cl
Solvent: CO
Product: NCCN(CCS(=O)(=O)c1ccccc1)S(=O)(=O)c1cccc2cnccc12
Temperature: 25 °C

Procedure:
According to the method of Example 1, Step C, deprotection was performed (50° C., 2 hours) by using Intermediate 11 (260 mg) and 10% hydrogen chloride/methanol solution (5 ml). The reaction mixture was cooled to room temperature, and then the solvent was evaporated under reduced pressure. The residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (197 mg) as white powdery solid.
Reaction SMILES: O.[NH2:2]N.C[N:5]([CH:7]=[N:8][C:9]([C:11]1[O:15][N:14]=[C:13]([O:16][CH2:17][CH3:18])[C:12]=1[CH3:19])=O)C>C(O)(=O)C>[CH2:17]([O:16][C:13]1[C:12]([CH3:19])=[C:11]([C:9]2[N:8]=[CH:7][NH:5][N:2]=2)[O:15][N:14]=1)[CH3:18]
Reactant: CCOc1noc(C(=O)N=CN(C)C)c1C
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCOc1noc(-c2nc[nH]n2)c1C
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 77.2 %

Procedure:
To a solution of hydrazine hydrate (0.6 mL, 12.4 mmol) in acetic acid (15 mL) was added N-(dimethylamino)methylidene 3-ethoxy-4-methylisoxazole-5-carboxamide (1.8 g, 8.0 mmol). The reaction mixture was stirred at 90° C. for 15 min and then left at room temperature to crystallize affording pure title compound (1.2 g, 77%): mp 194-196° C. Water was added (40 mL) and the aqueous phase was extracted with EtOAc (3×30 mL). The organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo to give crude title compound (0.3 g, 20%). The two crops were combined.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10](Br)=[C:9]([Cl:12])[C:8]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH3:22])=[CH:16][CH:15]=2)=[CH:7][C:6]=1[CH:23]1[C@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@@H:27]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@H:26]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C@@H:25]([CH2:53][O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[O:24]1)[CH:2]=[CH2:3].C([SnH](CCCC)CCCC)CCC.CC(N=NC(C#N)(C)C)(C#N)C>C1(C)C=CC=CC=1>[Cl:12][C:9]1[C:10]2[CH:2]([CH3:3])[CH2:1][O:4][C:5]=2[C:6]([CH:23]2[C@H:28]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@@H:27]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@H:26]([O:45][CH2:46][C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@@H:25]([CH2:53][O:54][CH2:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[O:24]2)=[CH:7][C:8]=1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH3:22])=[CH:18][CH:19]=1
Reactant: C=CCOc1c(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccc(OCC)cc2)c(Cl)c1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)C(C)CO3)cc1
Yield: 34.4 %

Procedure:
To a solution of (3S,4R,5R,6R)-2-(2-(allyloxy)-3-bromo-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran (325 mg, 0.359 mmole) in toluene (15 mL) were added tributyltin hydride (0.29 mL, 1.08 mmole) and AIBN (5.9 mg, 0.0359 mmole) in one portion. The resulting solution was refluxed overnight. The reaction mixture was filtered on the KF pad followed by concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the title compound (102 mg, 34%) as a colorless gum.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[S:13]([NH2:16])(=[O:15])=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17](=[S:19])=[S:18].[OH-].[K+:21].C(OCC)(=O)C>CN(C)C=O>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13]([N:16]=[C:17]([S-:19])[S-:18])(=[O:14])=[O:15].[K+:21].[K+:21]
Reactant: NS(=O)(=O)c1ccccc1-c1ccccc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(N=C([S-])[S-])c1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 166.3 %

Procedure:
115.5 g of 2-phenylbenzenesulfonamide were dissolved in 500 ml of dimethylformamide, and 38 g of carbon disulfide and 28 g of potassium hydroxide were added to the resulting solution. The mixture was stirred at room temperature for 7 hours. Potassium hydroxide (28 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours. Then, 400 ml of ethyl acetate were added dropwise to precipitate pale yellow crystals. The crystals were filtered, and washed with ethyl acetate to give 160 g of potassium N-(2-biphenylylsulfonyl)carbonimidodithioate represented by the following formula: ##STR25##
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1.[F:14][C:15]1[C:16]([O:25][CH3:26])=[C:17]([C:20]([O:23][CH3:24])=[CH:21][CH:22]=1)[CH:18]=O>>[F:14][CH:15]1[CH2:22][CH:18]([C:17]2[C:20]([O:23][CH3:24])=[CH:21][CH:22]=[C:15]([F:14])[C:16]=2[O:25][CH3:26])[N:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:12])([F:13])[F:1])=[CH:9][CH:8]=2)[C:16]1=[O:25]
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: COc1ccc(F)c(OC)c1C=O
Product: COc1ccc(F)c(OC)c1C1CC(F)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedures 10A2 (GP10A2), 10B (GP10B), 10F (GP10F), and 10I (GP10I) using commercially available (4-(trifluoromethoxy)phenyl)methanamine and synthesized 3-fluoro-2,6-dimethoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.90 min.; [M+H]+: 431.90 g/mol.