Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1N.S(=O)(=O)(O)O.N([O-])=O.[Na+].[I-:22].[Na+]>O.C(O)(=O)C>[F:1][C:2]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[I:22])([F:12])[F:11]
Reactant: Nc1ccccc1SC(F)(F)F
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)Sc1ccccc1I
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
2-(trifluoromethylthio)benzenamine (1 g, 5.18 mmol) prepared in accordance with a method described in J. Fluorin. Chem. 1994, 69, 207 to 212, 5 ml of glacial acetic acid, and 3 ml of 50% sulfuric acid were added into a 50-ml eggplant flask equipped with a stirrer, and were dissolved. Then the mixture was cooled to 0° C. on an ice bath. To the mixture, 1 ml of an aqueous solution of sodium nitrite (0.43 g, 6.22 mmol) was added and the mixture was stirred for 1.5 hours. 1 ml of an aqueous solution of sodium iodide (0.95 g, 6.3 mmol) was added dropwise at 0° C. and the mixture was stirred for 30 minutes. After completion of the reaction, the reaction solution was gradually heated to room temperature and added to water, and the solution was extracted three times with ether. The obtained organic layer was washed three times with water, two times with a saturated sodium bisulfite aqueous solution, and three times with water, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography (Hexane 100) to give target (trifluoromethyl)-(2-iodophenyl)sulfide (1.5 g, 95%) as a yellow oil.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=C[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17]OC(C)(C)C.O.[C:24]([Cl:28])(Cl)(Cl)Cl>>[C:1]([O:9][C:10]1[CH:15]=[C:14]([Cl:17])[C:13]([OH:16])=[C:24]([Cl:28])[CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OCl
Reactant: O=C(Oc1ccc(O)cc1)c1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Solvent: O
Product: O=C(Oc1cc(Cl)c(O)c(Cl)c1)c1ccccc1
Reaction time: 24 h
Yield: 91 %

Procedure:
A reaction vessel was charged with 24.5 g of 4-hydroxyphenyl benzoate and 500 ml of carbon tetrachloride, to which a solution of 24.8 g of t-butyl hypochlorite dissolved in 20 ml of carbon tetrachloride was slowly added dropwise, while stirring under ice cooling. After 24 hours, the reaction mixture was poured into water, followed by phase separation. The organic layer (i.e., carbon tetrachloride layer) was washed with water, dried with anhydrous magnesium sulfate, and concentrated to obtain a crude product. The crude product was subjected to silica gel chromatography, which afforded 29.5 g of 3,5-dichloro-4-hydroxyphenyl benzoate (91% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>CCO>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[NH:35][C:33](=[O:34])[NH:32]2)[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH3:18]
Reactant: NC(N)=O
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: O=C(Cc1ccccc1)c1ccc(F)cc1
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccc(F)cc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 34.2 %

Procedure:
A mixture of 1-(4-fluorophenyl)-2-phenylethanone (200 mg, 0.93 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (164 mg, 0.78 mmol), urea (140 mg, 2.3 mmol), and concentrated HCl solution (0.08 mL, 0.93 mmol) in EtOH (5 mL) was refluxed overnight. The mixture was evaporated in vacuo, and the residue was purified by preparative HPLC to give Compound 35 (120 mg, yield 29%). 1H NMR (DMSO-d6 300 MHz): δ 10.28 (s, 1H), 8.76 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 7.25-7.21 (m, 2H), 7.16 (s, 1H), 7.11-6.97 (m, 5H), 6.81 (d, J=7.5 Hz, 2H), 5.19 (s, 1H), 4.08-3.99 (m, 2H), 1.32 (t, J=6.6 Hz, 3H); MS (ESI): m/z 450.0 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH2:10][CH2:9]S[CH:7]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:6]=12.OO[S:20]([O-:22])=[O:21].[K+]>CO.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH2:10][CH2:9][S:20](=[O:22])(=[O:21])[CH:7]2[S:11][C:12]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:13][C:6]=12
Reactant: NS(=O)(=O)C1=CC2=C(OCCO)CCSC2S1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: NS(=O)(=O)C1=CC2=C(OCCO)CCS(=O)(=O)C2S1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 5,6-dihydro-4-(2-hydroxyethoxy)thieno[2,3-b]thiopyran-2-sulfonamide (1.0 g, 0.0034 mole) in CH3OH (20 ml) was added dropwise a solution of OXONE® (3.15 g, 0.005 mole) in water (20 ml). The mixture was stirred at ambient temperature overnight and then filtered, washing the filter cake thoroughly with CH3OH. Methanol was stripped from the filtrate in vacuo and the residue was extracted repeatedly with ethyl acetate. Evaporation of the dried extract left the crude product as a yellow gum that was purified by column chromatography on silica gel (75 g, 230-400 mesh). The product was eluted with 90 CHCl3 :10CH3OH:1H2O. Evaporation of the eluate left a colorless glass (0.8 g) that was triturated with ether, collected, dried in vacuo, and recrystallized from water. The yield of white crystalline product, m.p. 159°-164° C., was 430 mg (39%).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][C:10](=[O:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[Cl:26].ClC1C=CC(C2(O)CN(C(C3C=CC=CC=3)C3C=CC=CC=3)C2)=CC=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:10]2([OH:12])[CH2:11][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: Clc1ccc([Mg]Br)cc1Cl
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: OC1(c2ccc(Cl)cc2)CN(C(c2ccccc2)c2ccccc2)C1
Product: OC1(c2ccc(Cl)c(Cl)c2)CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
This compound was prepared from compound (3) and 3,4-dichlorophenylmagnesium bromide using the procedure described for compound (4).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2].[N+:20]([O-])([OH:22])=[O:21]>>[C:1]([C:4]1[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:6]([O:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)CCCOc1ccc(C(C)=O)cc1OC
Reactant: O=[N+]([O-])O
Product: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(C)=O)cc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Methyl 4-(4-acetyl-2-methoxyphenoxy)butyrate (10 g) was added to cold 70% nitric acid (140 cm3) and the resulting orange solution was stirred for 2 h and then poured into a beaker containg ice-water (1 dm3). The slurry warmed with stirring overnight to give a yellow solid which was collected and recrystallised from methanol to give methyl 4-(4-acetyl-2-methoxy-5-nitrophenoxy)butyrate as a pale yellow solid (8.5 g). 1H NMR (CDCl3) δ2.21 (2 H, m, J=6.6 Hz, CCH2C), 2.50 (3 H, s, MeCO), 2.57 (2 H, t, J=7.1 Hz, CH2CO), 3.7 (3 H, s, OMe), 3.99 (3 H, s, OMe), 4.16 (2 H, t, J=6.2 Hz, CH2O), 6.75 (1 H, s, aromatic) and 7.62 (1 H, s, aromatic).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][C:5]=1[CH3:14])#[N:2].[CH3:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19](=[O:22])[CH2:20][Br:21]>C(#N)C.C(OCC)C>[BrH:21].[C:1]([CH2:3][C:4]1[C:12]2[C:7]([N:8]([CH2:20][C:19]([C:18]3[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=3[O:16][CH3:15])=[O:22])[CH:9]=[C:10]([F:13])[CH:11]=2)=[N:6][C:5]=1[CH3:14])#[N:2]
Reactant: Cc1[nH]c2ncc(F)cc2c1CC#N
Reactant: COc1ccccc1C(=O)CBr
Solvent: CCOCC
Solvent: CC#N
Product: Br
Product: COc1ccccc1C(=O)Cn1cc(F)cc2c(CC#N)c(C)nc1-2
Yield: 78.2 %

Procedure:
A mixture of 3-(cyanomethyl)-5-fluoro-2-methylpyrrolo[2,3-b]pyridine (20 mg, 0.11 mmol) and 2-methoxyphenacyl bromide (30 mg, 0.13 mmol) in acetonitrile (0.2 ml) was refluxed under argon for 6 h, during which time the initial solution was transformed into a suspension. Then the suspension was allowed to reach room temperature, diluted with diethyl ether (2 ml), filtered, and washed with diethylether to give 36 mg (81%) of the title compound.
Reaction SMILES: [P:1](=[O:5])([OH:4])([OH:3])[OH:2].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:23][CH2:22]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15]>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[CH2:19][CH:18]([CH2:20][CH:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:25][CH2:26]3)[C:16](=[O:17])[C:11]2=[CH:12][C:13]=1[O:14][CH3:15].[P:1]([O-:5])([O-:4])([O-:3])=[O:2]
Reactant: O=P(O)(O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C

Procedure:
Phosphoric acid (0.58 ml, dissolved in 35 ml of 2-propanol) is slowly added to a solution of Donepezil (3.79 g) in ethyl acetate (70 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=1)=[O:34]>CO>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:33](=[O:34])[CH2:32][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])=[CH:36][CH:37]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccc(Cl)cc1
Yield: 88.5 %

Procedure:
Using the procedure described in example 5, treatment of L-proline-L-isoleucine benzylamide (182 mg, 0.57 mmol), with sodium carbonate (60 mg, 0.57 mmol), and 2-bromo-4'-chloroacetophenone (147 mg, 0.63 mmol, 1.0 eq), in methanol (10 mL), provided 237 mg (88%) of L-isoleucine, N-[1-(2-(4-chlorophenyl)-2-oxoethyl)-L-prolyl] benzylamide as a pale yellow oil.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([OH:26])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8].O.[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36]Br)[CH3:33]>C(#N)C>[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([O:26][CH2:36][CH:35]([O:38][CH2:39][CH3:40])[O:34][CH2:32][CH3:33])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCNC(=O)c1cc2c(-c3cc(O)c(Cl)cc3Cl)nc(N)nc2s1
Reactant: CCOC(CBr)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCNC(=O)c1cc2c(-c3cc(OCC(OCC)OCC)c(Cl)cc3Cl)nc(N)nc2s1

Procedure:
Potassium tert-butoxide was added to a suspension of 2-Amino-4-(2,4-dichloro-5-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in acetonitrile, bromoacetaldehyde diethyl acetal was added and the suspension heated under reflux for ˜8 hrs. The resulting suspension was allowed to cool and water added, the mixture was extracted with ethyl acetate and the extracts washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a red/brown gum. The crude product was purified by chromatography on silica eluting with mixtures of ethyl acetate and hexane.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:36]=[CH:35][C:34]3[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=3[CH:28]=2)O1>>[CH3:37][C:33]1([CH3:38])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]2[CH:28]=[C:27]([C:2]3[N:7]=[C:6]([N:8]4[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][OH:18])[CH2:10][CH2:9]4)[CH:5]=[CH:4][CH:3]=3)[CH:36]=[CH:35][C:34]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: OCCNC1CCCN(c2cccc(Br)n2)CC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCCC(NCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS102 starting from 79 mg (0.245 mmol) of 2-[1-(6-bromopyridin-2-yl)azepan-4-ylamino]ethanol and 96 mg (0.257 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane. The product is purified by means of preparative HPLC and converted into the hydrochloride using methanolic HCl.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:26][CH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1ccc(-c2ccccc2)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc(-c2ccccc2)c(CBr)c1
Temperature: 90 °C
Yield: 758.3 %

Procedure:
In 130 ml of carbon tetrachloride was dissolved 10 g of ethyl 2-methylbiphenyl-4-carboxylate, the whole was heated to 90° C. and then 1.0 g of NBS and 136 mg of 2,2′-azobisisobutyronitrile were added thereto. After the reaction solution was heated under reflux, 6.78 g of NBS was added thereto and the whole was heated under reflux for 1 hour and a half. After the reaction solution was cooled to room temperature, precipitate was removed by filtration, water was added to the filtrate, and the organic layer was extracted with carbon tetrachloride. After the resulting organic layer was dried over anhydrous magnesium sulfate, the solvent was removed by evaporation to obtain 13.6 g of ethyl 2-(bromomethyl)biphenyl-4-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:16]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:15][C:5]2[NH:6][C:7]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)=[N:8][C:4]=2[CH:3]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>>[CH2:18]([N:17]([CH2:20][CH3:21])[C:16]1[C:2]([NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=2)=[CH:3][C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[NH:6][C:5]=2[CH:15]=1)[CH3:19]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCN(CC)c1cc2[nH]c(C3CCCCC3)nc2cc1N
Product: CCN(CC)c1cc2[nH]c(C3CCCCC3)nc2cc1NC(=O)c1ccc(OC)cc1
Yield: 78.5 %

Procedure:
5-Amino-6-diethylamino-2-(cyclohexyl)-1H-benzo[d]-imidazole (28 mg, 0.1 mmol) was reacted with 4-methoxybenzoyl chloride (17 mg, 0.1 mmol) in the same manner as that described above to give the desired product (33 mg, 79% yield) as white powder: 1H-NMR (300 MHz, CDCl3) δ 0.97 (t, 6H, J=7.2 Hz), 1.16 (m, 3H), 1.57-1.70 (m, 5H), 1.98 (m, 2H), 2.87 (m, 1H), 3.01 (q, 4H, J=7.2 Hz), 7.05 (d, 2H, J=8.7 Hz), 7.57 (s, 1H), 7.96 (d, 2H, J=8.7 Hz), 8.94 (s, 1H); ESI MS m/z 421.0 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[S-:17].[Na+]>CN(C)P(N(C)C)(N(C)C)=O>[SH:17][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(-c2ccc(I)cc2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1ccc(-c2ccc(S)cc2)cc1
Temperature: 100 °C
Yield: 106.6 %

Procedure:
3.25 g (10.8.10-3 mol) of 4-(4-iodophenyl)benzonitrile are dissolved in 50 ml of hexamethylphosphoramide, and 3.05 g (43.4.10-3 mol) of sodium thiomethylate are then added to the solution. The reaction mixture is heated at 100° C. for 1.5 hours and then, after cooling, hydrolyzed in a 1 N hydrochloric acid/ice mixture. The expected product is extracted with ethyl acetate. The resulting organic phase is washed with water until the pH of the washings is neutral, dried over magnesium sulfate and then evaporated under reduced pressure to give 2.4 g (quantitative yield) of a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:19]=[CH:18][C:17]([N:20]([CH3:22])[CH3:21])=[CH:16][C:12]=2[C:13]([OH:15])=[O:14])=[O:10])=[CH:5][CH:4]=1.S(Cl)(Cl)=O.CO.N1C=CC=C[CH:31]=1>C(Cl)CCl>[CH3:31][O:10][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:23])[CH3:1])=[CH:8][CH:7]=2)[C:11]2[C:12](=[CH:16][C:17]([N:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=2)[C:13](=[O:15])[O:14]1
Reactant: c1ccncc1
Reactant: CN(C)c1ccc(C(=O)c2ccc(N(C)C)cc2C(=O)O)cc1
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: COC1(c2ccc(N(C)C)cc2)OC(=O)c2cc(N(C)C)ccc21

Procedure:
In a manner similar to that described in Example 1 above, 5.2 g of 2-(4-dimethylaminophenyl)carbonyl-5-dimethylaminobenzoic acid, 1.2 ml of thionyl chloride and 5.0 ml of methyl alcohol were interacted in 30.0 ml of ethylene dichloride in the presence of 1.3 ml of pyridine at ambient temperature overnight to obtain 4.5 g of 3-methoxy-3-(4-dimethylaminophenyl)-6-dimethylaminophthalide (Formula II: R0 =R=R2 =R5 =H; R1 =N(CH3)2 ; R4 =R4' =Y=CH3 ; X=O), a pale green-colored solid which melted over the range of 141° to 149° C. An infrared maximum appeared at 1770 cm-1 (C=O;s). The nuclear magnetic resonance spectrum was consistent with the assigned structure. Analysis by mass spectrum showed m/e peaks at 326 (M+) and 295 (M+ -OCH3). A toluene solution of the product spotted on an acidic clay-coated paper developed a green-colored image.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C@H:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[O:13][CH2:12][CH2:11]2)[C:3]=1[NH2:21].[C:22](Cl)(Cl)=[O:23]>C1COCC1.C1(C)C=CC=CC=1>[NH2:8][C:6]1[N:5]=[C:4]2[C:3]([NH:21][C:22](=[O:23])[N:9]2[C@H:10]2[C:19]3[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=3)[O:13][CH2:12][CH2:11]2)=[C:2]([Cl:1])[N:7]=1
Reactant: Nc1nc(Cl)c(N)c(N[C@@H]2CCOc3c(F)cccc32)n1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1nc(Cl)c2[nH]c(=O)n([C@@H]3CCOc4c(F)cccc43)c2n1
Temperature: 25 °C
Yield: 80 %

Procedure:
To a solution of (R)-6-chloro-N4-(8-fluorochroman-4-yl)pyrimidine-2,4,5-triamine (0.9 g, 2.91 mmol) in 900 mL of anhydrous THF at −78° C. under Ar was added dropwise, over 20 min, a solution of phosgene in THF (2.6 mL of a 20% solution of phosgene in toluene, 4.94 mmol, 1.7 equiv., diluted with 26 mL of anhydrous THF). The reaction mixture was left to gradually warm up to room temperature over 16 h. It was purged with air for 30 min. The solvent was then removed in vacuo, and the residue was taken in ethyl acetate/saturated aqueous NaHCO3. The layers were separated, and the aqueous layer extracted with ethyl acetate three times. The combined organic extracts were put together, dried (anhydrous Na2SO4) and the solvent removed in vacuo. The residue was purified by flash chromatography (silica gel, gradual elution with 6/1 to 4/1 methylene chloride/ethyl acetate) to give 0.78 g (80% yield) of the desired product as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ, ppm: 7.13-7.06 (m, 1H), 6.90-6.82 (m, 1H), 6.75-6.72 (m, 1H), 5.92-5.82 (m, 1H), 4.80-4.73 (m, 1H), 4.50-4.42 (m, 1H), 3.20-3.05 (m, 1H), 2.42-2.30 (m, 1H); MS (EI) m/z 336.3 (MH)+.
Reaction SMILES: N1C2C(=CC=C(C(O)=O)C=2)C=CC=1.NC1C=CC(C#N)=C(C(F)(F)F)C=1.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2[CH:47]=[C:46]3[C:41]([CH:42]=[CH:43][CH:44]=[N:45]3)=[CH:40][CH:39]=2)=[O:37])=[CH:31][C:30]=1[C:48]([F:51])([F:50])[F:49])#[N:28].C(C1C=CC(NC(C2C=C3C(CCCN3)=CC=2)=O)=CC=1C(F)(F)F)#N.[Cl:77][C:78]1[CH:79]=[C:80]([S:84](Cl)(=[O:86])=[O:85])[CH:81]=[CH:82][CH:83]=1>>[C:27]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([C:38]2[CH:47]=[C:46]3[C:41]([CH2:42][CH2:43][CH2:44][N:45]3[S:84]([C:80]3[CH:81]=[CH:82][CH:83]=[C:78]([Cl:77])[CH:79]=3)(=[O:86])=[O:85])=[CH:40][CH:39]=2)=[O:37])=[CH:31][C:30]=1[C:48]([F:51])([F:49])[F:50])#[N:28]
Reactant: N#Cc1ccc(NC(=O)c2ccc3cccnc3c2)cc1C(F)(F)F
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: N#Cc1ccc(N)cc1C(F)(F)F
Agent: N#Cc1ccc(NC(=O)c2ccc3c(c2)NCCC3)cc1C(F)(F)F
Agent: O=C(O)c1ccc2cccnc2c1
Product: N#Cc1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CCC3)cc1C(F)(F)F

Procedure:
In analogy to example 40, quinoline-7-carboxylic acid was reacted with 4-amino-2-trifluoromethyl-benzonitrile in step 2, and the resulting quinoline-7-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide was reduced to 1,2,3,4-tetrahydro-quinoline-7-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide in step 3. This was coupled with 3-chloro-benzenesulfonyl chloride in step 4, yielding 1-(3-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[O:9]=[CH:10][C@@H:11]([C@H:13]([C@@H:15]([C@@H:17]([CH2:19][OH:20])[OH:18])[OH:16])[OH:14])O>O>[CH2:1]([NH:8][CH:19]1[O:20][C@H:11]([CH2:10][OH:9])[C@@H:13]([OH:14])[C@H:15]([OH:16])[C@H:17]1[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCCCCN
Solvent: O
Product: CCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of heptylamine (11.5 g in 50 ml of ethanol) was added to a solution containing 9 g of glucose and 35 ml of water. The reaction mixture was stirred for about 24 hours at ambient temperature. The precipitate formed was filtered and recrystallized from ethanol, then lyophilized.
Reaction SMILES: [O:1]=[C:2](C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][C:4]([O-])=O.[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]([CH:43]([CH3:45])[CH3:44])[C:35]=2C=O)=[CH:30][CH:29]=1.CCCCCC.[CH2:54]([O:56][C:57](=[O:59])[CH3:58])[CH3:55]>C(#N)C>[CH2:54]([O:56][C:57](=[O:59])[CH2:58][C:2](=[O:1])/[CH:3]=[CH:4]/[C:35]1[N:36]([CH:43]([CH3:44])[CH3:45])[C:37]2[C:42]([C:34]=1[C:31]1[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH3:55]
Reactant: O=C([O-])CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)n1c(C=O)c(-c2ccc(F)cc2)c2ccccc21
Reactant: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC#N
Product: CCOC(=O)CC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Temperature: 25 °C

Procedure:
The ylide 3-oxo-4-(triphenylphosphoranylidene)butanoate (5.0 g, 12.8 mmol) is solved under argon atmosphere in 100 ml acetonitrile. Under vigorous stirring 3-(4-Fluoro-phenyl)-1-isopropyl-1H-indole-2-carbaldehyde (4.2 g, 10.7 mmol) is added in 5 portions and then heated to reflux. After 50 h the reaction is cooled to room temperature. The slight brown solvent is evaporated and the residue is dried under vacuum to obtain a brown waxy oil. Chromatography over silica gel with hexane:ethylacetate (4:1/v:v) give a yellow oil of (E)-5-[3-(4-Fluoro-phenyl)-1-isopropyl-1H-indol-2-yl]-3-oxo-pent-4-enoic acid ethyl ester. MS: 393.46