Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1]C1C=C(O)C=CC=1CC(O)=O.[CH2:13]1[CH2:18][CH2:17][CH:16]([N:19]=[C:20]=[N:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:15][CH2:14]1>C(OCC)(=O)C.CCCCCC>[CH:22]1([NH:21][C:20](=[O:1])[NH:19][CH:16]2[CH2:15][CH2:14][CH2:13][CH2:18][CH2:17]2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cc1ccc(O)cc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 1 h

Procedure:
1.5 g of 2,4-dihydroxyphenylacetic acid (1.8 mole) was dissolved in 20 mL of 50:50 v/v ethyl acetate and hexane. Then 1.5 mL of DCC (˜1.4 mmole) was added and the reaction continued for 1 hr at room temperature under argon that was bubbled into the solution. A white precipitate of dicyclohexyl urea formed during the reaction. After 3 hr. the urea precipitate was removed and 1.8 mL (5.6 mmol) of oleylamine (C18-content 80-90%; Fisher), was initially dissolved in 10 mL of hexane in the presence of 4-dimethylaminopyridine (0.5 g) and added to the reaction product of the 2,4-dihydroxyphenylacetic acid and DCC. The reaction continued at room temperature for 1 hr and then stored at −20° C. for one week.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:23]3[CH:24]=[C:25]4[O:30][CH2:29][O:28][C:26]4=[CH:27][C:22]=3[CH2:21][C:20]([CH3:31])=[N:19][N:18]=2)=[CH:13][CH:12]=1>CN(C)C=O.C(OCC)C>[C:1]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:23]4[CH:24]=[C:25]5[O:30][CH2:29][O:28][C:26]5=[CH:27][C:22]=4[CH2:21][C:20]([CH3:31])=[N:19][N:18]=3)=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1=NN=C(c2ccc(NC(=O)Nc3ccccc3)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
0.22 ml (2.04 mmol) of phenyl isocyanate was added to a solution of 0.50 g (1.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in 4 ml of dimethylformamide and the reaction mixture was stirred at 25° C. for one hour. Then it was diluted with 20 ml of diethyl ether and filtered at 5° C. The crystals were washed with 2×5 ml of diethyl ether and dried at 60°-100° C. The resulting 0.70 g of raw product, m.p. 239°-240° C. (sintering at 180° C.) was refluxed in 15 ml of ethanol, filtered after cooling, washed wtih 3×1 ml of ethanol and dried at 100° C. to yield 0.55 g (78.6%) of the aimed product, m.p. 240°-241° C. (decomp.).
Reaction SMILES: [B-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)([C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[OH:21])[CH:18]=3)[N:13]3[N:35]=[N:36][N:37]=[C:12]3[N:11]=2)[CH:7]=[CH:8][CH:9]=1.C(Cl)Cl>CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)([C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[OH:21])[CH:18]=3)[N:13]3[N:35]=[N:36][N:37]=[C:12]3[NH:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)nc1nnnn12
Agent: [B-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1cncc1C(O)(c1ccc(F)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)Nc1nnnn1-2
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
Sodium hydroborate (0.001 mol) was added portionwise at room temperature to a mixture of intermediate 8 (0.001 mol) in methanol (5 ml). The mixture was stirred at room temperature for 2 hours and poured out into ice water. DCM was added. The organic layer was washed with water, separated, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from 2-propanone. The precipitate was filtered off and dried in a vacuo. The residue (0.35 g, 70%) was crystallized from ethanol. The precipitate was filtered off and dried in a vacuo, yielding 0.105 g (21%) of 5-(3-chlorophenyl)-α-(4-fluorophenyl)-4,5-dihydro-α-(1-methyl-1H-imidazol-5-yl)- tetrazolo[1,5-α]quinazoline-7-methanol (intermediate 9), mp. 230° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20](F)[N:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2].[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH2:1]([C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[N:19]=4)[C:11]=3[CH:10]=2)[CH:6]=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(F)n2)c1
Reactant: C1CNCCN1
Product: CCc1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCNCC3)n2)c1
Yield: 18 %

Procedure:
Following the procedures as described in EXAMPLE 8 and starting with 6-(5-ethylpyridin-3-yl)-1-(6-fluoropyridin-2-yl)-1H-pyrazolo[4,3-c]pyridine and piperazine, 104 was obtained as an off-white solid (22.3 mg, 18%) over 2 steps. 1H NMR (400 MHz, DMSO) δ 9.35-9.27 (s, 1H), 9.16-9.08 (d, J=2.0 Hz, 1H), 9.08-9.01 (s, 1H), 8.67-8.59 (s, 1H), 8.57-8.50 (d, J=1.9 Hz, 1H), 8.30-8.21 (s, 1H), 7.85-7.73 (m, 2H), 7.66-7.44 (m, 2H), 7.28-7.23 (d, J=7.7 Hz, 1H), 6.85-6.78 (d, J=8.4 Hz, 1H), 3.65-3.57 (m, 4H), 2.98-2.81 (m, 4H), 2.79-2.70 (q, J=7.6 Hz, 2H), 1.75-1.52 (m, 3H), 1.32-1.24 (t, J=7.6 Hz, 3H).; MS (ESI) m/z: 386.2 [M+H]+
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH2:6]([O:8][C:9]([C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N+:18]2[O-])=[CH:13][CH:12]=1)=[O:10])[CH3:7].O.[OH-].[K+]>ClCCl>[Cl:3][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])=[CH:12][CH:13]=2)[N:18]=1
Reactant: CCOC(=O)c1ccc2ccc[n+]([O-])c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1ccc2ccc(Cl)nc2c1
Temperature: 50 °C
Yield: 52.1 %

Procedure:
Phosphorus oxychloride (1.94 mL, 20.7 mmol) was added to a solution of 7-(ethoxycarbonyl)quinoline 1-oxide (450 mg, 2.07 mmol) in dichloromethane (15 mL). The reaction was heated to 50° C. for 3 hours. The reaction was then cooled to room temperature and was slowly poured into 200 mL of water, with stirring. The mixture was allowed to stir for 1 hour and was then neutralized with 1 N aqueous potassium hydroxide. The mixture was extracted with dichloromethane (3×). The extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated. Purification by column chromatography (0-20% ethyl acetate/heptanes) gave the title compound (254 mg, 52%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 8.70-8.79 (m, 1H), 8.13-8.18 (m, 2H), 7.87 (d, J=8.39 Hz, 1H), 7.47 (d, J=8.58 Hz, 1H), 4.44 (q, J=7.02 Hz, 2H), 1.43 (t, J=7.12 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[I:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH2:22][NH2:23])[CH:19]=[N:18]2)=[CH:13][CH:12]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:23][CH2:22][C:20]2[CH:19]=[N:18][N:17]([C:14]3[CH:15]=[CH:16][C:11]([I:10])=[CH:12][CH:13]=3)[CH:21]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1cnn(-c2ccc(I)cc2)c1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NCc1cnn(-c2ccc(I)cc2)c1)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.9 %

Procedure:
To a solution of 5-chloro-thiophene-2-carboxylic acid (237 mg, 1.46 mmol), (1-(4-iodophenyl)-1H-pyrazol-4-yl)methanamine (396 mg, 1.32 mmol) and TEA (0.500 mL, 3.59 mmol) in DMF (10 mL), BOP (828 mg, 1.87 mmol) were added. The mixture was stirred at room temperature overnight. H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 5-chloro-N-((1-(4-iodophenyl)-1H-pyrazol-4-yl)methyl)thiophene-2-carboxamide (462 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13](=[S:21])OC1C=CC=CC=1.[CH3:22][C:23]1[CH:24]=[C:25]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:26]=[C:27]([CH3:29])[CH:28]=1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[CH:5][C:4]=1[NH:12][C:13]([N:33]1[CH2:34][CH2:35][N:30]([C:25]2[CH:26]=[C:27]([CH3:29])[CH:28]=[C:23]([CH3:22])[CH:24]=2)[CH2:31][CH2:32]1)=[S:21]
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: COc1nc2c(cc1NC(=S)Oc1ccccc1)CCC2
Product: COc1nc2c(cc1NC(=S)N1CCN(c3cc(C)cc(C)c3)CC1)CCC2
Yield: 53 %

Procedure:
Phenyl N-(2-methoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)thiocarbamate and 1-(3,5-dimethylphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][N:13]3[C:14](=[O:21])[C:15]([C:18](Cl)=[O:19])=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[C:25]([NH2:28])(=[NH:27])[CH3:26].N1C=CC=CC=1>O1CCOCC1.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:23]=[CH:22][N:13]3[C:14](=[O:21])[C:15]([C:18]4[O:19][N:28]=[C:25]([CH3:26])[N:27]=4)=[CH:16][N:17]=[C:12]3[CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=N)N
Reactant: O=C(Cl)c1cnc2cc(C#Cc3cccc(F)c3)ccn2c1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1noc(-c2cnc3cc(C#Cc4cccc(F)c4)ccn3c2=O)n1
Temperature: 70 °C

Procedure:
8-((3-fluorophenyl)ethynyl)-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carbonyl chloride was dissolved in 1,4-dioxane (3 mL). To the solution was added acetamidine hydrochloride (18 mg, 0.162 mmol, 1 equiv) and pyridine (2 mL). The reaction mixture was then heated at 70° C. overnight. After it was cooled to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by preparative TLC to give 2.2 mg of the desired product. MS (ESI): 347 (MH+).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([CH:23]=[C:24]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[CH:25]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:21][OH:22])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH3:40][O-].[Na+].CO>C(Cl)Cl>[C:1]([C:5]1[C:6]([O:34][CH3:35])=[C:7]([CH:23]=[C:24]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[NH:28][C:27]2=[O:33])[CH:25]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])=[CH:12][C:11]=1[CH2:21][O:22][CH3:40])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CO)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-n2ccc(=O)[nH]c2=O)cc(C(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To a solution of the product from Example 127 (32 mg, 0.064 mmol) in anhydrous CH2Cl2 (1 ml) was added thionyl chloride (23 μL, 0.32 mmol), and the resulting mixture was stirred at room temperature for 30 min. The mixture was partitioned between saturated aq. NaHCO3 (5 ml) and CH2Cl2 (5 ml) and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in MeOH (1 ml), and a solution of 25% NaOMe in MeOH (58 μL, 0.254 mmol) was added. The resulting mixture was stirred at 50° C. for 2 h. The mixture was partitioned between 1 N aq. HCl (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 3% MeOH in CH2Cl2 as the eluent to give the title compound (15 mg, 46%). 1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H) 9.86 (s, 1H) 7.62-7.87 (m, 3H) 7.12-7.39 (m, 5H) 5.66 (d, J=7.72 Hz, 1H) 4.58 (s, 2H) 3.78 (s, 3H) 3.35 (s, 3H) 3.00 (s, 3H) 1.38 (s, 9H).
Reaction SMILES: [CH:1]1([C:5]2[S:9][C:8]([NH2:10])=[N:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[N:18]1[C:27]2[C:22](=[CH:23][C:24]([CH2:28][C:29](O)=[O:30])=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(Cl)(Cl)Cl>[CH:1]1([C:5]2[S:9][C:8]([NH:10][C:29](=[O:30])[CH2:28][C:24]3[CH:23]=[C:22]4[C:27](=[CH:26][CH:25]=3)[N:18]=[CH:19][CH:20]=[CH:21]4)=[N:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ncc(C2CCC2)s1
Reactant: O=C(O)Cc1ccc2ncccc2c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccc2ncccc2c1)Nc1ncc(C2CCC2)s1
Reaction time: 2 h
Yield: 87.2 %

Procedure:
A solution of 5-cyclobutyl-thiazol-2-ylamine (Preparation 2; 30 mg, 0.195 mmol) was treated with triethylamine (81 μl, 0.585 mmol), 6-quinolylaceticacid (40 mg, 0.214 mmol) and propylphosphonic acid cyclic anhydride (T3P, 126 mL, 0.214 mmol). After 2 hours, an additional 0.2 equiv. of T3P (22 μl) was added and the reaction was complete by TLC after 15 minutes. The reaction mixture was diluted with CHCl3, was washed with saturated aqu. NaHCO3, and was dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (40:1 CHCl3—MeOH) to afford 55 mg of N-(5-cyclobutyl-thiazol-2-yl)-2-quinolin-6-yl-acetamide, the title compound, as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[C:8]([CH3:15])[C:3]=1[O:4][CH2:5][CH2:6][OH:7].C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:2]([CH3:1])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:8]=2[CH3:15])(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OCCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCCOc2c(C)cc([N+](=O)[O-])cc2C)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 56.8 %

Procedure:
2-(2,6-Dimethyl-4-nitrophenoxy)ethanol (22 g) was dissolved into chloroform (200 ml) and triethylamine (20 ml) was added into this solution. Further, p-toluenesulfonylchloride (24.5 g) solution in chloroform (100 ml) was added into this solution in an ice bath. After being stirred for 6 hours at room temperature, the reaction mixture was washed with water (150 ml), 1N HCl (150 ml) and then 1N sodium hydroxide (150 ml). After being dehydrated with anhydrous magnesium sulfate (20 g), the solution was concentrated under vacuum to remove chloroform and residue was dissolved into ethyl acetate (50 ml). Hexane (200 ml) was added into ethyl acetate solution and separated solids were collected by filtration. Solids were dried under vacuum to obtain 2-(2,6-dimethyl-4-nitrophenoxy)ethyl p-toluenesulfonate (21.6 g) as yellowish solid.
Reaction SMILES: O.NN.[CH2:4]([N:11]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1C(=O)C2=CC=CC=C2C1=O)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl>C(O)C.CCOCC>[CH2:4]([N:11]([CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH3:37])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COc1ccccc1OCCN(CCCCN1C(=O)c2ccccc2C1=O)Cc1ccccc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1OCCN(CCCCN)Cc1ccccc1
Temperature: 25 °C

Procedure:
A solution of hydrazine hydrate solution (0.83 ml, 0.017 mole) in ethanol (20 ml) is added to a solution of N-[4-{benzyl[2-(2-methoxyphenoxy)ethyl]amino}butyl]phthalimide (7.2 g, 0.016 mole) in ethanol (70 ml), the solution is stirred and heated to reflux for 3 hours. After cooling to ambient temperature, the solvent is evaporated at reduced pressure and the residual oil is treated with 1 N hydrochloric acid (40 ml). The precipitate formed is removed by filtration, washed in water, and the filtrate and the washing liquids are made basic with potassium carbonate (16 g). The separated oil is extracted with dichloromethane (3×80 ml) and the extracts dried over magnesium sulfate. Filtration and evaporation of the solvent at reduced pressure yields 4.4 g (86%) of the theoretical yield in the form of an oil. The treatment of an etherized solution of the free base with a saturated solution of hydrogen chloride gas in ether makes it possible to obtain N-benzyl-N-[2-(2-methoxyphenoxy)ethyl]-1,4-butanediamine as a dihydrochlorated salt; mp 200-202 degrees C. after recrystallization from ethanol.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:7]1=[O:19].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:27]=[CH:26][C:25]([C@:28]23[CH2:33][C@H:32]2[CH2:31][NH:30][CH2:29]3)=[CH:24][CH:23]=1>CN(C=O)C>[ClH:1].[ClH:1].[CH3:18][C:15]1[N:14]=[CH:13][C:12]([C:8]2[C:7](=[O:19])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:30]3[CH2:31][C@H:32]4[C@:28]([C:25]5[CH:24]=[CH:23][C:22]([C:21]([F:20])([F:35])[F:34])=[CH:27][CH:26]=5)([CH2:33]4)[CH2:29]3)[CH:11]=[CH:10][CH:9]=2)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-c2cccn(CCCCCl)c2=O)cn1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cccn(CCCCN3C[C@@H]4C[C@]4(c4ccc(C(F)(F)F)cc4)C3)c2=O)cn1
Product: Cl
Temperature: 90 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
TEA (0.056 ml, 0.4 mmol) was added to a solution of 1-(4-chlorobutyl)-6′-methyl-3,3′-bipyridin-2(1H)-one (55 mg, 0.2 mmol, Prep8) and (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (Prep4, 70 mg, 0.31 mmol, reference procedure for preparation also reported in WO 2005080382) in anhydrous DMF (2 ml). The reaction mixture was heated at 90° C. for 1 hour and then at 100° C. for 24 hours, quenched with water and extracted with ethyl acetate. The combined organics layers were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by SCX cartridge (eluting with methanol followed by 2N ammonia solution in methanol) and then by SPE cartridge eluting with a gradient of methanol in DCM (from 0 to 5%) to afford the free base of the title compound (19 mg, 20%).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:16].[C:17]1(B(O)O)[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:17]1([C:2]2[CH:7]=[C:6]([CH:8]3[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]3)[CH:5]=[CH:4][C:3]=2[NH2:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: Nc1ccc(C2CCS(=O)(=O)CC2)cc1Br
Reactant: OB(O)C1=CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Nc1ccc(C2CCS(=O)(=O)CC2)cc1C1=CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a mixture of 2-bromo-4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-phenylamine (as prepared in the previous step, 150 mg, 0.493 mmol), cyclohexen-1-yl boronic acid (70 mg, 0.542 mmol) and Pd(PPh3)4 (57 mg, 0.0493 mmol) in 5 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (2.0 mL, 4.0 mmol). The resulting mixture was stirred at 80° C. for 8 h under Ar, and then cooled to RT. Treated with 50 mL of EtOAc, the mixture was washed with H2O (3×15 mL), brine (20 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (2-5% EtOAc/DCM) gave 130 mg (86%) of the title compound as a brown solid. 1H-NMR (CDCl3; 400 MHz): δ 6.89 (dd, 1H, J=8.4, 2.3 Hz), 6.84 (d, 1H, J=2.3 Hz), 6.65 (d, 1H, J=8.4 Hz), 5.74 (m, 1H), 3.74 (br s, 2H), 3.08-3.17 (m, 4H), 2.66 (dddd, 1H, J=12.1, 12.1, 3.1, 3.1 Hz), 2.29-2.42 (m, 2H), 2.13-2.25 (m, 6H), 1.73-1.81 (m, 2H), 1.65-1.73 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C17H23NO2S, 306.1 (M+H). found 306.1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[C:25](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Reaction time: 0.5 h
Yield: 51.6 %

Procedure:
To a solution of 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (1.37 g, 4.1 mmol) in DMF (10 mL) at room temperature was added cesium carbonate (1.35 g, 4.1 mmol) and methyliodide (587 mg, 0.26 mL, 4.1 mmol) and the resulting mixture stirred for 30 min. The resulting mixture was then evaporated and extracted with ethyl acetate and water. The organic extract was then washed with water, brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=4:1 to 2:3) afforded the title compound (730 mg, 51%) which was obtained as a colorless oil. MS: m/e=346.1 [M+H]+.
Reaction SMILES: [CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].Cl[CH2:27][C:28]#[N:29].C(N(CC)CC)C.Cl.C(N(CC)CC)C>CC(C)=O>[CH2:1]([S:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:24])(=[O:25])[NH2:23])[C:14]=1[O:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]([O:11][CH2:27][C:28]#[N:29])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Reactant: N#CCCl
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CCCCSc1cc(C(=O)OCC#N)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
A mixture of 3-n-butylthio-4-phenoxy-5-sulfamylbenzoic acid (2.3 g), chloroacetonitrile (1.4 g), triethylamine (0.61 g), and dry acetone (20 ml) is refluxed for 20 hours. After cooling the triethylamine hydrochloride formed is removed by filtration, and the filtrate is evaporated in vacuo. To the residue, water (35 ml) and ethylacetate (75 ml) are added, and the pH of the aqueous layer is adjusted to pH 7.5 by addition of 4 N hydrochloric acid. The organic layer is then separated, washed with diluted sodium hydrogen carbonate, dried and evaporated in vacuo. The residue is crystallized from chloroform petroleum ether to yield cyanomethyl 3-n-butylthio-4-phenoxy-5-sulfamylbenzoate with a melting point of 134°-135° C.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1I.CN(C=[O:17])C.[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1B(O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>[Cl:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=1[C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=[CH:2][C:3]=1[OH:17]
Reactant: CN(C)C=O
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(O)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(O)c1-c1ccc(Cl)cc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
5.6 g of methyl 4-hydroxy-3-iodobenzoate are introduced under argon into 50 ml of anhydrous DMF and then 4.2 g of 2,4-dichlorophenylboronic acid and 5.54 ml of triethylamine and then 240 mg of tri-orthotolylphosphine are added and the mixture is left under argon for 1 hour. 180 mg of palladium acetate are added and then the mixture is heated at 100° C. for 4 hours. 2 g of 2,4-dichlorophenylboronic acid, 5.54 ml of triethylamine, 120 mg of tri-orthotolylphoshine and 180 mg of palladium acetate are added and then the mixture is heated at 100° C. for 8 hours. It is concentrated under vacuum and the residue is taken up in AcOEt and then washed with 10% NH4OH solution. Extraction is carried out with AcOEt and the extract is washed with water and then with saturated NaCl solution. The residue is dried and then chromatographed on silica, eluting with a cyclohexane/AcOEt mixture (82/18; v/v), to give 3.4 g of the expected compound.