Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][C:9]=1I.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.O>O1CCOCC1>[Cl:7][C:8]1[C:9]([C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([F:16])[CH:22]=2)=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: Oc1ccc(Cl)c(I)c1
Reactant: OB(O)c1cccc(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(Cl)c(-c2cccc(F)c2)c1
Temperature: 70 °C
Reaction time: 5 h
Yield: 93.3 %

Procedure:
Caesium carbonate (1.15 g, 3.53 mmol) was added to a solution of 4-chloro-3-iodophenol (300 mg, 2.14 mmol) and 3-fluorophenylboronic acid (330 mg, 1.30 mmol) in dioxane:water (22.5 mL:4.5 mL). The reaction mixture was degassed and tetrakistriphenylphosphine palladium (0) (69 mg, 0.06 mmol) was added. The reaction mixture was stirred at 70° C. for 5 hours. The cooled reaction mixture was concentrated in vacuo and the aqueous residue was extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified on the biotage eluting with heptane:ethyl acetate (from 98:2 to 80:20) to give the title compound (270 mg, 100%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]([CH3:45])[CH2:3][CH2:4][C:5]([O:7][CH:8]([C:26](=[O:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:6].[BH4-].[Na+]>CO>[CH3:45][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([O:7][CH:8]([CH:26]([OH:44])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:6]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)C(CCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCN(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCC/C=C\C/C=C\CCCCCCCC(O)C(CCCCCCC/C=C\C/C=C\CCCCC)OC(=O)CCN(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a solution of (6Z,9Z,27Z,30Z)-19-oxohexatriaconta-6,9,27,30-tetraen-18-yl 3-(dimethylamino)propanoate (450 mg, 0.72 mmol) in anhydrous methanol (20 mL) was slowly added sodium borohydride (222 mg, 5.9 mmol). The solution was stirred for 16 hours at room temperature then quenched with water (20 mL). The solution was washed with dichloromethane (3×50 mL) and the combined extracts were dried on magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography (100% ethyl acetate) to afford the title compound as a colorless oil (416 mg, 91%). 1H NMR (400 MHz, CDCl3): δ 5.45-5.28 (m, 8H), 5.02-4.82 (m, 1H), 3.69-3.43 (m, 1H), 2.84-2.45 (m, 8H), 2.30 (s, 6H), 2.09-2.02 (m, 8H), 1.67-1.20 (m, 36H), 0.93-0.86 (m, 6H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=O)[C:22](F)(F)F)[CH2:17][CH2:16]3)=[C:11]([CH3:27])[C:9]=2[CH:10]=1)=[O:5])[CH3:2].C(N(CC)CC)C.[Cl:35][C:36]1[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])C=1CBr.C(OCC)(=O)C.CCCCCC>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][C:22]4[C:36]([Cl:35])=[CH:43][CH:42]=[CH:41][C:40]=4[Cl:44])[CH2:17][CH2:16]3)=[C:11]([CH3:27])[C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C)c(N3CCN(C(=O)C(F)(F)F)CC3)ccc2o1
Reactant: Clc1cccc(Cl)c1CBr
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C)c(N3CCN(Cc4c(Cl)cccc4Cl)CC3)ccc2o1
Temperature: 0 °C
Yield: 96.9 %

Procedure:
To a stirred solution of 4-Methyl-5-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzofuran-2-carboxylic acid ethyl ester (0.15 g, 0.0003 mol) in dry THF was added triethyl amine (0.15 ml, 0.001 mol) and cooled to 0° C. and stirred under nitrogen. 2,6 dichloro benzyl bromide (0.107 g, 0.00045 mol) was added and stirred for 2 hours at room temperature. The completion of the reaction was confirmed by TLC. Solvent was concentrated under reduced pressure added water. The solid separated was filtered, washed with water (10 ml). After drying under vacuum, the crude product was isolated as brown solid. Column chromatography using 10/90 ethyl acetate/hexane yielded 5-[4-(2,6-Dichloro benzyl)-piperazine-1-yl]-4-methyl-benzofuran-2-carboxylic acid ethyl ester (0.13 g, 78%).
Reaction SMILES: [IH:1].[C:2]1([NH:8][C:9](SC)=[NH:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][NH2:14]>C(O)C>[IH:1].[C:2]1([N:8]=[C:9]([NH:13][NH2:14])[NH2:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CSC(=N)Nc1ccccc1
Reactant: NN
Agent: I
Solvent: CCO
Product: NNC(N)=Nc1ccccc1

Procedure:
To a stirred room temperature suspension of phenyl-carbamimidothioic acid, methyl ester, monohydroiodide (91.5 g, 0.311 mol) in absolute ethanol (280 mL) was added in one portion anhydrous hydrazine (9.8 mL, 0.31 mol), and the mixture was heated to reflux. The mixture was refluxed for 3 hours and allowed to cool. The resulting solution was purged with nitrogen to remove methanethiol and rotary evaporated to an oil. The oil was dried in vacuo briefly then dissolved in water (130 mL). The solution was rotoevaporated to an oil. The oil was dried in vacuo (50° C.), yield 87.08 g (100%). 1H NMR (DMSO-d6): δ 9.5 (br s, 0.5H), 9.0 (br s, 1.5H), 7.7 (br s, 2H), 7.4 (t, 2H), 7.2 (m, 3H), 4.8 (br s, 2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C(N(CC)CC)C.Br[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>C(OCC)(=O)C>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:2]
Reactant: CCNc1ccccc1
Reactant: CCOC(=O)CCCBr
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN(CC)c1ccccc1
Temperature: 25 °C
Yield: 79.7 %

Procedure:
N-ethylaniline 5 (2.0 gm, 0.016 moles), triethylamine (5.0 ml, 0.036 moles), and ethyl 4-bromobutyrate (3.45 gm, 0.018 moles) were heated at 110° C. for 14 hours under argon. The mixture was cooled to room temperature, diluted with 50 ml ethyl acetate, washed with 50 ml water and 50 ml saturated NaCl, dried over MgSO4, filtered, and evaporated under reduced pressure to give crude ethyl 4-(ethylphenylamino)butanoate 6 (3.0 gm, 77% yield). 1H NMR (CDCl3) δ 7.2, 2H, m; 6.6; 3H, m; 4.15, 2H, q; 3.3, 4H, m; 2.38, 2H, t; 1.9, 2H, m; 1.25, 3H, t; 1.10, 3H, t.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:21][CH3:22])=[C:17]([CH:20]=1)[CH:18]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:18]/[C:17]2[CH:20]=[C:13]([Cl:12])[CH:14]=[CH:15][C:16]=2[O:21][CH3:22])/[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1F
Reactant: COc1ccc(Cl)cc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(Cl)cc1/C=C(\C#N)c1ccc(Cl)cc1F
Yield: 37.4 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenylacetonitrile (2.8 g, 16.6 mmol) was reacted with 5-chloro-2-methoxybenzaldehyde (Matrix) (3.4 g, 19.9 mmol), methanolic solution (25 wt %) of sodium methoxide (4.17 mL, 18 mmol) in methanol (100 mL) at 50° C. for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(5-chloro-2-methoxy-phenyl)-acrylonitrile as a white solid (2.0 g, 37%).
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]([CH:7]=[CH2:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:3]1.CCCCCCC.CCO>CO>[OH:1][C@@H:2]1[C@@H:6]([CH:7]=[CH2:8])[CH2:5][N:4]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:3]1
Reactant: C=C[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Solvent: CCO
Solvent: CCCCCCC
Solvent: CO
Product: C=C[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Yield: 47.9 %

Procedure:
The racemic mixture of trans-(±)-benzyl 3-hydroxy-4-vinylpyrrolidine-1-carboxylate (14 g) was resolved by using chiral HPLC (Chiralpak AD-H Heptane:EtOH:MeOH, 8:1:1). The desired enantiomerically enriched (3S,4R)-benzyl 3-hydroxy-4-vinylpyrrolidine-1-carboxylate (6.7 min; 6.3 g, >99.5% ee) and undesired (3R,4S)-benzyl 3-hydroxy-4-vinylpyrrolidine-1-carboxylate (9.3 min; 6.7 g, 99.5% ee) were obtained with 92% recovery.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][CH2:7][C:8](Br)=[O:9].C(N(CC)CC)C>ClCCl>[Br:6][CH2:7][C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: O=C(Br)CBr
Reactant: C1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CBr)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A mixture of pyrrolidine (1.7 g, 24 mmol), bromoacetyl bromide (4.6 g, 24 mmol) and triethylamine (2.02 g, 20 mmol) in dichloromethane (40 mL) was stirred at room temperature for 4 hours. The precipitate was filtered off and the residue was concentrated to give 3.1 g of 2-bromo-1-pyrrolidin-1-yl-ethanone as a light brown solid.
Reaction SMILES: ClS(O)(=O)=O.[F:6][C:7]([F:19])([F:18])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.II.[Cl:22]Cl>>[Cl:22][C:12]1[CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=[C:8]([C:7]([F:18])([F:19])[F:6])[CH:13]=1
Reactant: ClCl
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Agent: II
Agent: O=S(=O)(O)Cl
Product: FC(F)(F)c1cc(Cl)cc(C(F)(F)F)c1

Procedure:
130 parts of chlorosulfonic acid are introduced, at room temperature, into a reaction vessel, and 42.8 parts of 1,3-bis-(trifluoromethyl)-benzene and 2 parts of iodine are added. The suspension is cooled to 0° and 30 parts of chlorine are introduced in the course of 5 hours at 0° to 5°. The suspension is then poured out onto ice and the organic phase is separated from the aqueous phase. The organic phase is washed neutral with ice-cold water and is dried over calcined sodium sulfate. 38 parts of 5-chloro-1,3-bis-(trifluoromethyl)-benzene, of boiling point 111° to 112°, are obtained.
Reaction SMILES: C(OC([N:8]([CH:19]([CH3:21])[CH3:20])[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:22].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:22].[CH:19]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11][CH2:10]1)([CH3:21])[CH3:20]
Reactant: COC(=O)[C@H]1CC[C@H](N(C(=O)OC(C)(C)C)C(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CC[C@H](NC(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1.8 g of methyl trans-4-[(tert-butoxycarbonyl)(isopropyl)amino]cyclohexane carboxylate and 20 mL of ethyl acetate were added 20 mL of a 4.0 M hydrogen chloride/ethyl acetate solution, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain 1.18 g of methyl trans-4-(isopropylamino)cyclohexane carboxylate hydrochloride as a colorless solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:12]([O:14]CC1C=CC=CC=1)=[O:13])#[N:2]>CO>[C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:12]([OH:14])=[O:13])#[N:2]
Reactant: N#CCCCCCCCCC(C(=O)OCc1ccccc1)C1CCCC1
Solvent: CO
Product: N#CCCCCCCCCC(C(=O)O)C1CCCC1
Reaction time: 2 h

Procedure:
A mixture of the cyanoester from step 3 (2.89 g, 8 mmol) and 10%, Pd--C (0.6 g, DeGussa, H2O content 50%) in anhyd MeOH (35 mL) was hydrogenated for 2 h (42-26 psi). The reaction mixture was filtered through a Celite® pad and concentrated to a colorless oil (2.02 g). 1H NMR (300 MHz, CDCl3) δ 2.35(t, 8 Hz, 2H), 2.20 (m, 1H), 2.00 (m, 1H), 1.3-1.9(m, 22H).
Reaction SMILES: CI.[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[C:17](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:17][O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of methyl iodide (0.200 mL, 3.2 mmol), 93A (328 mg, 1.66 mmol), and potassium carbonate (250 mg, 1.80 mmol) in DMF (2 mL) was stirred overnight at rt. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient of 0 to 50% ethyl acetate in hexanes) to give 93B (0.22 g, 63%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.95 (s, 3H) 3.98 (s, 3H) 7.87-7.90 (m, 1H) 7.90-7.93 (m, 1H) 8.44-8.48 (m, 1H); LC/MS 212 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([CH3:25])=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[CH:7]=1.C([O:28][CH:29]=[CH:30][CH3:31])C.C(N(CC)CC)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:25][C:3]1[C:2]([C:29](=[O:28])[CH2:30][CH3:31])=[CH:7][N:6]2[N:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=[C:5]2[C:4]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1
Reactant: CC=COCC
Reactant: CC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(Br)cn2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)c1cn2nc(NC(C)=O)nc2c(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 130 °C
Reaction time: 120 h
Yield: 11 %

Procedure:
A mixture of N-[6-bromo-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-acetamide (Int. 18, 0.5 g, 1.21 mmol) was combined with ethyl-1-propenyl ether (125 mg, 1.45 mmol), triethylamine (202 μL, 1.45 mmol), palladium (II) acetate (3 mg, 0.012 mmol), tri-O-tolylphosphine (15 mg, 0.048 mmol) in DMF (7 mL) was degassed and then heated at 130° C. for 5 hrs. Further amounts of palladium (II) acetate (3 mg) and ethyl-1-propenyl ether (125 mg) were added and heating was continued for 5 days. 1 M HCl (5 mL) was added and the mixture was stirred vigorously for 40 mins. The mixture was partitioned between EtOAc (100 mL) and water (100 mL) and the organic layer was washed with saturated brine, then dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by chromatography, eluting with a gradient of 0-10% MeOH in DCM followed by trituration with DCM and ether. The resultant precipitate was collected by filtration and dried to afford the title compound as a white solid (11%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.Cl[CH:11]([O:13]C)Cl>ClCCl.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH3:9])=[CH:4][C:3]=1[CH:11]=[O:13]
Reactant: Cc1ccc(F)cc1O
Reactant: COC(Cl)Cl
Agent: [Ti+4]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C=O)c(F)cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 5-fluoro-2-methylphenol (630 mg, 5 mmol) in dichloromethane (5 ml) was added titanium chloride (1890 mg, 10 mmol) dropwise at 0° C. and then (dichloromethyl)-methyl ether (689 mg, 6 mmol) was added dropwise. The mixture was stirred at 0° C. for 1 hour, quenched with ice (50 g) and extracted with ethyl acetate. The organic layer was separated, dried over Na2SO4, concentrated and applied to a silica gel column, eluting with hexane/ethyl acetate (10:1), to furnish the title compound (545 mg, 71% yield) as a white solid. 1H NMR (270 MHz, CDCl3) δ 2.25 (3H, s), 6.04 (1H, brs), 6.60 (1H, d, J=11.2 Hz), 7.66 (1H, d, J=7.9 Hz), 10.18 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:12][C:13]([F:20])([F:19])[C:14]([NH:16][CH2:17]O)=[O:15]>OS(O)(=O)=O>[F:12][C:13]([F:20])([F:19])[C:14]([NH:16][CH2:17][C:8]1[C:9]([F:11])=[CH:10][C:2]([Cl:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(NCO)C(F)(F)F
Reactant: O=C(O)c1ccc(F)cc1Cl
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc(CNC(=O)C(F)(F)F)c(F)cc1Cl
Yield: 667543 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-26 by using 2-chloro-4-fluorobenzoic acid (5.0 g, 0.002 mmol), 2,2,2-trifluoro-N-(hydroxymethyl)acetamide (4.0 g, 0.002 mmol) and conc. H2SO4 (50 mL) to afford 4.0 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 4.44 (d, J=12.0 Hz, 2H), 7.59 (m, 1H), 7.92 (m, 1H), 10.0 (br s, 1H), 13.5 (br s, 1H).
Reaction SMILES: C1(=N[NH:10][C:11](N)=[O:12])CCCCCCC1.[CH:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.N>O1CCOCC1>[CH:14]1([NH:19][C:11](=[O:12])[NH2:10])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC(=O)NN=C1CCCCCCC1
Reactant: NC1CCCC1
Agent: N
Solvent: C1COCCO1
Product: NC(=O)NC1CCCC1

Procedure:
1.8 g of 4-[4-(β-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl]-cyclooctanone-semicarbazone, 50 ml of dioxane and 0.29 g of cyclopentyl-amine were refluxed for 1 hour. The clear solution was concentrated in vacuo and the residue obtained was treated with about 0.5 %-aqueous ammonia. After filtration the filtrate was acidified. A crystalline precipitate of N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-cyclopentyl-urea was obtained, separated by suction-filtration, dried and recrystallized from methanol. The melting point of the substance was 182° - 184°C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([NH2:14])[CH:13]=2)[CH2:4][CH2:3]1>[Pd].C(OCC)(=O)C>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1CCN(c2ccc(N)c(N)c2)CC1
Reaction time: 17 h
Yield: 116.6 %

Procedure:
A suspension of 5-(4-Methyl-piperazin-1-yl)-2-nitro-phenylamine (513.0 mg, 2.17 mmol) [See Kim, Jung Sun; et al.; J. Med. Chem.; 39; 992 (1996) for the synthesis of this compound] and 10% palladium on carbon (200.8 mg) in ethyl acetate (50 mL) was shaken under 40 psi H2 for 17 hours. The catalyst was removed by filtration through a Celite pad, and the mixture concentrated to afford crude 4-(4-Methyl-piperazin-1-yl)-benzene-1,2-diamine (522 mg) as a yellow foam. This crude diamine was added to a solution of aldehyde 19f (853.7 mg, 2.17 mmol) and elemental sulfur (83 mg, 2.60 mmol) in anhydrous dimethylformamide (40 mL), and the solution heated in an 80° C. oilbath for 6 hours. After cooling to room temperature, the solution was diluted with ethyl acetate (150 mL) and washed with water (50 mL) and saturated aqueous sodium chloride solution (50 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified by silica gel chromatography (1:20:400 concentrated aqueous NH4OH:EtOH:CH2Cl2), affording 20a (623 mg, 50%) as an orange-brown foam: Rf=0.20 (10% ethanol in dichloromethane); 1H NMR (DMSO-d6) [Some peaks are doubled due to tautomeric isomerization] δ 2.23 (s, 3H), 2.49 (m, 4H), 3.10 (m, 4H), 3.71 (s, 3H), 5.80 (s, 2H), 6.91 (m, 4H), 7.36 and 7.47 (2 d, 3H together, J=8.3, 8.7 Hz), 7.64 (d, 1H, J=8.9 Hz), 7.77 (m, 3H), 7.99 (m, 1H), 8.25 (d, 1H, J=7.2 Hz), 8.53 (s, 1H), 8.62 and 8.64 (2 s, 1H together), 9.39 (s, 1H), 12.78 and 12.83 (2 s, 1H together). Anal. (C36H33N7O.0.9 H2O) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C@:31]([CH:33]=[O:34])([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1>C(OCC)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:24]3[CH:25]=[C:26]4[C:31]([C@@H:33]([OH:34])[C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=5)([CH2:32][C:23]=3[CH:22]=[N:21]2)[CH2:30][N:29]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:28][CH2:27]4)=[CH:16][CH:15]=1
Reactant: Brc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C=O)C1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)CC2([C@@H](O)c2ccccn2)C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A solution of 2-bromopyridine (182 μL, 1.82 mmol) in dry diethyl ether (10 mL) was cooled to −78° C. and butyl lithium (2.5 M in hexanes, 730 μL, 1.82 mmol) added dropwise. The mixture was stirred for 1 hour at −78° C. A solution of (R)-tert-butyl 1-(4-fluorophenyl)-4a-formyl-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate (800 mg, 2 mmol) in dry diethyl ether (10 mL) was added dropwise and the reaction mixture was stirred for 1 hour at −78° C. The reaction mixture was stirred and warmed to 0° C. over 1 hour following which the reaction was quenched by the addition of water (10 mL). The resultant mixture was stirred for 30 minutes then extracted with dichloromethane (×2) and the combined organic phases were dried over sodium sulfate. The solids were removed by filtration, the filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (gradient: 30-50% ethyl acetate in cyclohexane) to afford the diastereoisomeric mixture (R)-tert-butyl 1-(4-fluorophenyl)-4a-(R/S)-(hydroxy(pyridin-2-yl)methyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate as a straw-coloured foam (410 mg). LCMS (Method C, ESI): RT 2.64/2.81 min, m+H=477.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][NH:12][CH3:13]>C(O)C.C(Cl)Cl>[CH3:11][N:12]([CH3:13])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCO
Product: CN(C)c1ccc([N+](=O)[O-])cn1
Temperature: 75 °C
Yield: 100.1 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (5.0 g, 31.5 mmol) and 40% solution of Dimethylamine (10.66 g, 95 mmol) in ethanol (40 mL) was heated to 75° C. for 1 hour. The mixture was cooled to ambient temperature, diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 (3×100 mL) and brine. The organic was dried (MgSO4), filtered and concentrated to afford 5.27 g (100%) of the title compound. MS (ESI) m/z 168 (M+H)+.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:19]([CH3:21])[CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:22]([O-])=[O:23].[Na+]>Cl>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH:19]([CH3:21])[CH3:20])[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: CC(C)N(C(=O)NCCCl)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)N(C(=O)N(CCCl)N=O)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Yield: 30.6 %

Procedure:
6.0 g of 1-(2-chloroethyl)-3-isopropyl-3-D-glucopyranosylurea are dissolved in 50 ml of 10% hydrochloric acid, and 6 g of sodium nitrite are added gradually thereto at 0° to 5° C. under stirring. The mixture is further stirred at the same temperature for 10 minutes. The reaction mixture is extracted with ethyl acetate. The extract is washed with an aqueous sodium bicarbonate solution, dried and evaporated to remove solvent. Then, the residue thus obtained is purified by silica gel chromatography (Solvent: chloroform-methanol(5:1)). 2.0 g of 1-(2-chloroethyl)-1-nitroso-3-isopropyl-3-D-glucopyranosylurea are thereby obtained as pale yellow caramel.