Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[O:32]=[C:31]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:33])[N:23]1[C:11]1[S:12][CH:13]=[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[C:10]=1[C:8]([OH:9])=[O:7]
Reactant: CCOC(=O)c1c(-c2cccc(OC)c2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cccc(-c2csc(N3C(=O)c4ccccc4C3=O)c2C(=O)O)c1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-(3-methoxyphenyl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 18 & 19, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [S:1]1[C:5]([C:6](=[O:8])[CH3:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[S:1]1[C:5]([C:6](=[O:8])/[CH:7]=[CH:15]/[N:16]([CH3:18])[CH3:17])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cc2ccccc2s1
Product: CN(C)/C=C/C(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 84 %

Procedure:
A solution of 1-(benzo[b]thiophen-2-yl)ethanone (1 g) in dimethoxy-N,N-dimethyl-methanamine (10 mL) was refluxed for 6 h and then cooled to rt. The precipitate was filtered and washed with diethyl ether to afford the title compound (1.1 g, 84%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]=[C:9]2[CH3:33])=[CH:4][CH:3]=1.Br[C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][C:35]([CH3:41])([CH3:40])[C:36]([O:38][CH3:39])=[O:37])=[CH:7][CH:6]=3)[C:9]([CH3:33])=[N:10][C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: COC(=O)C(C)(C)Br
Reactant: CCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a solution of 4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and methyl 2-bromo-2-methylpropanoate (1.25 g) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), and the mixture was stirred at 80° C. for 5 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.97 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:19])([CH3:18])[C:10](=[O:17])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:19])([CH3:18])[C:10](=[O:17])[C:11]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:22][N:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: CC(C)(Cc1ccc(Cl)cc1)C(=O)Cn1cncn1
Product: CN(C)C=C(C(=O)C(C)(C)Cc1ccc(Cl)cc1)n1cncn1
Yield: 123 %

Procedure:
50 g (0.18 mol) of 1-(4-chlorophenyl)-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-3-butanone are heated under reflux with 23.6 g (0.138 mol) of dimethylformamide dimethylacetal for 8 hours. To isolate the end product, the reaction mixture is concentrated in vacuo. 56.5 g (94.4% of theory) of 1-(4-chlorophenyl)-2,2-dimethyl-5-dimethylamino-4-(1,2,4-triazol-1-yl)-4-penten-3-one of refractive index n20 1.5797 are obtained. ##STR17##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15]2[NH:16][N:17]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[CH:19]=2)[N:3]=1.C(OC([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([NH2:39])[CH:37]=2)[C:32](=[O:40])[NH:31]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(O)CCC.ClCCl>[CH:20]1([C:18]2[CH:19]=[C:15]([NH:14][C:4]3[N:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:7]=[C:2]([NH:39][C:36]4[CH:37]=[C:38]5[C:33]([C:32](=[O:40])[NH:31][NH:30]5)=[CH:34][CH:35]=4)[N:3]=3)[NH:16][N:17]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)n1[nH]c(=O)c2ccc(N)cc21
Reactant: Clc1nc(Nc2cc(C3CC3)n[nH]2)nc(-c2ccccc2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: O=c1[nH][nH]c2cc(Nc3nc(Nc4cc(C5CC5)n[nH]4)nc(-c4ccccc4)n3)ccc12
Temperature: 85 °C
Yield: 49.9 %

Procedure:
To a sealed tube was added (4-Chloro-6-phenyl-[1,3,5]triazin-2-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (50 mg, 0.16 mmol) and 6-amino-3-oxo-2,3-dihydro-indazole-1-carboxylic acid tert-butyl ester (80 mg, 0.32 mmol) in 1 ml of n-butanol. The contents were heated to 85° C. for 3 hours. The reaction was concentrated in vacuo to give a white solid that was dissolved in 3 ml of dichloromethane and 1 ml of trifluoro acetic acid and stirred for 5 hours at room temperature. The reaction concentrated and the crude residue purified by prep HPLC to afford 34 mg of the desired product as a light yellow solid (39.4% yield). H-NMR (DMSO-d6, 500 mHz) δ 10.95 (m, 1H), 10.30 (m, 1H), 9.91 (s, 1H), 8.32 (m, 2H), 8.04 (m, 1H), 7.49 (m, 4H), 7.25 (m, 1H), 6.14 (s br, 1H), 1.85 (s, 1H), 0.87 (s, 2H), 0.67 (s, 2H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][OH:15])[CH:9]=[C:8]([NH2:16])[N:7]=1>O.C(O)(=O)C>[NH2:5][C:6]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][OH:15])[C:9]([N:1]=[O:3])=[C:8]([NH2:16])[N:7]=1
Reactant: Nc1cc(OCCO)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c(N=O)c(OCCO)n1
Reaction time: 2 h
Yield: 67.4 %

Procedure:
A solution of 4.55 g (0.066 mol) of sodium nitrite in 20 ml of water was added in drops to a solution of 8.50 g (0.050 mol) of 2-[(2,6-diaminopyrimidin-4-yl)oxy]ethan-1-ol in 100 ml of acetic acid (10% in water) over 1 h at 3-5° C. while stirring was performed. Then stirring was performed further for 2 h at room temperature. The resulting precipitate was sucked off, post-washed with water, and dried, whereby 2-[(2,6-diamino-5-nitrosopyrimidin-4-yl)oxy]ethan-1-ol (6.71 g, 67%) was obtained as a purple solid.
Reaction SMILES: [S:1]([O:5][C@H:6]1[C@@H:42]([OH:43])[C@@H:41]([CH2:44][OH:45])[O:40][C@@H:8]([O:9][CH2:10][CH:11]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@@H:7]1[OH:46])([O-:4])(=[O:3])=[O:2].[Na+:47].[S:48](=[O:51])([OH:50])[OH:49].C[NH+](C)C>>[S:1]([O:5][C@H:6]1[C@@H:42]([O:43][S:48]([O-:50])(=[O:49])=[O:51])[C@@H:41]([CH2:44][O:45][S:1]([O-:4])(=[O:3])=[O:2])[O:40][C@@H:8]([O:9][CH2:10][CH:11]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C@@H:7]1[OH:46])([O-:4])(=[O:3])=[O:2].[Na+:47].[Na+:47].[Na+:47].[S:48]([O:46][C@@H:7]1[C@@H:6]([O:5][S:1]([O-:4])(=[O:3])=[O:2])[C@@H:42]([O:43][S:48]([O-:50])(=[O:49])=[O:51])[C@@H:41]([CH2:44][O:45][S:1]([O-:4])(=[O:3])=[O:2])[O:40][C@H:8]1[O:9][CH2:10][CH:11]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])([O-:50])(=[O:49])=[O:51].[Na+:47].[Na+:47].[Na+:47].[Na+:47]
Reactant: O=S(O)O
Reactant: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)CO[C@@H]1O[C@H](CO)[C@H](O)[C@H](OS(=O)(=O)[O-])[C@H]1O
Agent: C[NH+](C)C
Agent: [Na+]
Product: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)CO[C@@H]1O[C@H](COS(=O)(=O)[O-])[C@H](OS(=O)(=O)[O-])[C@H](OS(=O)(=O)[O-])[C@H]1O
Product: CCCCCCCCCCCCCCC(CCCCCCCCCCCCCC)CO[C@@H]1O[C@H](COS(=O)(=O)[O-])[C@H](OS(=O)(=O)[O-])[C@H](OS(=O)(=O)[O-])[C@H]1OS(=O)(=O)[O-]

Procedure:
By treating as described in Example 2 excepting that sodium 2-tetradecylhexadecyl β-D-galactopyranoside 3-sulfate (100 mg) obtained by Example 31 and a complex of sulfurous acid and trimethyl ammonium (105 mg) were selected, the titled compound of trisodium 2-tetradecylhexadecyl β-D-galactopyranoside 3,4,6-trisulfate (57 mg) and tetrasodium 2-tetradecylhexadecyl β-D-galactopyranoside 2,3,4,6-tetrasulfate (41 mg) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9].C([Li])CCC.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[NH4+]>O1CCCC1.C(OCC)(=O)C.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:9])=[O:10]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1Cl
Reactant: Ic1ccccc1
Agent: [Li]CCCC
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)NS(=O)(=O)c1c(Cl)cccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
A solution of 21.5 g (0.087 mol) 2-chloro-N-t-butylbenzenesulfonamide in anhydrous tetrahydrofuran was cooled to -30° under a nitrogen atmosphere while 121 ml of 1.6M n-butyllithium in hexanes was added over ten minutes. The mixture was then stirred for one hour at room temperature then recooled to below 0° and 16.6 g (0.087 mol) cuprous iodide (Alfa ultrapure grade) was added. After ten minutes at 0°, 10 ml (0.089 mol) iodobenzene was added and the mixture heated to reflux for 18 hours. The suspension was subsequently cooled to below 15° and 20 ml of acetic acid was added followed by 400 ml each of ethyl acetate and concentrated ammonium hydroxide. After stirring vigorously in air for 15 minutes the mixture was filtered, rinsed with water and ethyl acetate and the filtrate separated. The blue aqueous phase was extracted with 200 ml ethyl acetate and the combined organic phase washed successively with 200 ml concentrated ammonium hydroxide, water and brine, then dried and evaporated in vacuo. The solid residue was triturated with ether and collected by filtration to afford 23.5 g (84%) of the title compound, m.p. 168°-170°. An NMR spectrum (90 MHz) in CDCl3 had resonances at 1.10 (s, 9H), 5.08 (s, br, NH), 7.35-7.65 (m, ArH, 8H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([OH:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:27][O:28][CH2:29]Cl.O>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([O:17][CH2:27][O:28][CH3:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cc(OCc2ccccc2)ccc1C=O
Yield: 78.7 %

Procedure:
To a solution of 4-benzyloxy-2-hydoxy-benzaldehyde (44.9 g, 197 mmol) synthesized in step (a) of Example 197 in dichloromethane (200 ml) were added diisopropylethylamine (52.0 ml, 300 mmol) and methoxymethyl chloride (20.5 ml, 270 mmol) at 0° C. with stirring, and the resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. After stirring, water (200 ml) was added, and the resulting mixture was extracted with dichloromethane (200 ml×2). The organic layer was washed successively with water (300 ml×1) and saturated aqueous sodium chloride solution (300 ml×1), dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo to afford the crude product. The crude product was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (5:1-1:1) as the eluent to afford the title compound (42.2 g, yield: 79%) as a colorless oil.
Reaction SMILES: [N+]([CH2:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])=[O:6])([O-])=O.[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][C:17]([CH3:19])=O.[H][H]>[Pt].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[C:5]([NH:7][C:8]1[CH:9]=[C:10]([NH:11][CH:17]([CH3:19])[CH2:16][C:15]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:13][CH:14]=1)(=[O:6])[CH3:4]
Reactant: [H][H]
Reactant: Nc1cccc(NC(=O)C[N+](=O)[O-])c1
Reactant: CCOC(=O)CC(C)=O
Agent: [Pt]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)CC(C)Nc1cccc(NC(C)=O)c1
Yield: 73.9 %

Procedure:
A mixture of 18.0 g (0.1 mole) of m-nitroacetamido aniline, 26.0 g (0.2 mole) ethyl acetoacetate, 100 ml ethanol, 3.0 g of 5% Pt/C and 0.5 g of p-toluenesulfonic acid is treated in an autoclave at 165° C. and 1,000 psi of hydrogen until the uptake of hydrogen ceases. The solvent and catalyst are removed to yield 19.53 g of ethyl 3-(3'-acetamidophenylamino)butyrate.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15]([CH3:16])=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=[O:5].I[C:19]1[N:20]=[CH:21][N:22]([C:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=1.CC1N=CN(C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=1C(C1C=CC=C2C=1N=CC=C2)O.N1C2C(=CC=CC=2C=O)C=CC=1>>[CH3:16][C:15]1[C:6]([C:4]([C:19]2[N:20]=[CH:21][N:22]([C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:23]=2)=[O:5])=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CON(C)C(=O)c1ccc2cccnc2c1C
Agent: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C(O)c1cccc2cccnc12
Agent: O=Cc1cccc2cccnc12
Product: Cc1c(C(=O)c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)ccc2cccnc12

Procedure:
(8-Methylquinolin-7-yl)(1-trityl-1H-imidazol-4-yl)methanone (21) was synthesized from (20) and 4-iodo-1-trityl-1H-imidazole via the procedure used in the preparation of (4) from (3) above.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.NC1CCN(CC2C3C(=CC=CC=3)C=CC=2)CC1>C(N(CC)CC)C>[CH:11]1([N:8]2[CH:7]=[N:6][C:5]3[C:9]2=[N:10][CH:2]=[N:3][CH:4]=3)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Agent: NC1CCN(Cc2cccc3ccccc23)CC1
Solvent: CCN(CC)CC
Product: c1ncc2ncn(C3CCCC3)c2n1

Procedure:
2-Chloro-6-[4-1-(1-naphthyl)methyl]piperidinylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 4-amino-1-(1-naphthyl)methylpiperidine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][C:5]([CH2:15][NH2:16])([C:8]2[CH:9]=[N:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>CN(C=O)C.O>[Cl:18][C:19]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:16][CH2:15][C:5]1([C:8]2[CH:9]=[N:10][C:11]([F:14])=[CH:12][CH:13]=2)[CH2:4][CH2:3][C:2]([F:1])([F:17])[CH2:7][CH2:6]1)=[O:22]
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1Cl
Yield: 38.2 %

Procedure:
A solution of C-[4,4-difluoro-1-(6-fluoro-pyridin-3-yl)-cyclohexyl]-methylamine (38 mg, 0.157 mmol), 2,3-dichlorobenzoic acid (30 mg, 0.157 mmol), HOBt (25 mg, 0.185 mmol), EDCI.HCl (36 mg, 0.185 mmol) and DIPEA (48 mg, 0.345 mmol) in DMF (2 mL) was stirred at room temperature overnight. Water was added to the solution followed by extraction with EtOAc (3×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by Prep. HPLC to give the title compound (25 mg, yield: 38%). 1H NMR (CDCl3 300 MHz): δ ppm 8.18 (d, J=2.8 Hz, 1H), 7.89-7.80 (m, 1H), 7.50 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.33 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.28-7.18 (m, 1H), 6.98 (dd, J=8.8 Hz, 3.2 Hz, 1H), 5.85 (t, J=6.8 Hz, 1H), 3.64 (d, J=6.8 Hz, 2H), 2.36-2.00 (m, 6H), 1.87-1.65 (m, 2H). LCMS (MH+): m/z=417.1, tR (minutes, Method C)=1.11
Reaction SMILES: CC(C[AlH]CC(C)C)C.[C:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)#N.CCCCC.S(=O)(=O)(O)[OH:41]>CCCCCC.O>[CH:10]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)[CH2:14][CH2:13]1)=[O:41]
Reactant: O=S(=O)(O)O
Reactant: CCCCCc1ccc(-c2ccc([C@H]3CC[C@H](C#N)CC3)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CCCCCC
Solvent: CCCCC
Solvent: O
Product: CCCCCc1ccc(-c2ccc([C@H]3CC[C@H](C=O)CC3)cc2)cc1
Reaction time: 18 h

Procedure:
112 ml of a 20% solution of DIBALH in hexane are added dropwise to a solution of 33.2 g of 4-(trans-4-cyanocyclohexyl)-4'-pentylbiphenyl in 11 of pentane, and the mixture is stirred for 18 hours. Water is then added dropwise until the evolution of gas subsides and then 200 ml of 25% sulfuric acid are added dropwise. The organic phase is separated off, dried over Na2SO4 and evaporated. Colorless deliquescent crystals are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)[C:20]1C=CC=C[CH:21]=1.[Na]>C(O)C>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][CH2:20][CH3:21])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(O)ccc12
Reactant: CN(C)c1ccccc1
Agent: [Na]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: CCOc1ncnc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-hydroxyquinazolin-4-one (105 mg, 648 μmol), phosphorous oxychloride (2 ml), and dimethylaniline (85 μl, 671 μmol) was heated at reflux for 15 minutes in an argon atmosphere. The cooled mixture was concentrated under vacuum, and kept in an argon atmosphere to avoid hydrolysis. This residue was dissolved in ethanol (anhydrous, 3 mL), and a solution of sodium (283 mg, 12.34 mmol) in ethanol (3 ml) was added dropwise. The resulting yellow mixture was stirred at room temperature under argon for 2 hours, acidified to pH 6 using NaH2PO4 and extracted with ethyl acetate (3×50 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The white solid (156 mg) was used without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([NH:6][S:7]([C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1Br)(=[O:9])=[O:8])(=[O:5])=[O:4].[Na].[OH-:21].[NH4+:22].[Na][Na]>C(O)CC.[Cu].CN(C=O)C>[F:1][C:2]([F:19])([F:18])[S:3]([NH:6][S:7]([C:10]1[C:11]([C:11]2[C:10]([S:7]([NH:22][S:3]([C:2]([F:1])([F:18])[F:19])(=[O:5])=[O:4])(=[O:8])=[O:21])=[CH:15][C:14]([Br:16])=[CH:13][CH:12]=2)=[CH:12][CH:13]=[C:14]([Br:16])[CH:15]=1)(=[O:9])=[O:8])(=[O:5])=[O:4]
Reactant: [OH-]
Reactant: [NH4+]
Reactant: O=S(=O)(NS(=O)(=O)C(F)(F)F)c1cc(Br)ccc1Br
Agent: [Cu]
Agent: [Na]
Agent: [Na][Na]
Solvent: CN(C)C=O
Solvent: CCCO
Product: O=S(=O)(NS(=O)(=O)C(F)(F)F)c1cc(Br)ccc1-c1ccc(Br)cc1S(=O)(=O)NS(=O)(=O)C(F)(F)F
Temperature: 120 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
Inside a glove box, a 200 mL round-bottom flask equipped with a stirring bar, reflux condenser, and a septum was charged with N-trifluoromethanesulfonyl-2,5-dibromo-benzene-sulfonamide, sodium salt (11.24 g, 24 mmoles), activated copper powder (23.5 g), and DMF (50 mL). The flask was heated to 120° C. under nitrogen and stirred overnight. The solution was cooled to room temperature, filtered, and the solids washed with DMF. The solvent was evaporated by distilling under high vacuum and the resulting solids were dried under vacuum. The solids were dissolved in water by adding hydrochloric acid to give a pH of 2-3. Residual dark solids were filtered off then the solution was heated to a reflux, treated with sodium chloride (30 g), and concentrated to 125 mL to induce precipitation. The mixture was cooled to room temperature to give colored solids. Ammonium hydroxide was added to give a dark blue solution, which removed most of the color from the solids. The solids were collected by vacuum filtration, washed with ether, and dried under vacuum to give 9.02 g (97% crude yield). The solids were dissolved in n-propanol at a reflux, treated with decolorizing carbon, filtered, evaporated, and dried under vacuum. The solids were recrystallized twice from dioxane, dried in a vacuum oven at 150° C. under nitrogen purge, and transferred to a glove box for storage and handling to give 4.195 g (45% yield) of N,N′-bis(trifluoromethanesulfonyl)-4,4′-dibromo-biphenyl-2,2′-disulfonamide, disodium salt. 1H NMR (DMSO-d6): 7.26 (d, J=8.2 Hz, 2H), 7.62 (dd, J=8.2 and 2.2 Hz, 2H), 8.03 (d, J=2.2 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.Cl.[NH:16]1[CH2:19][CH:18]([OH:20])[CH2:17]1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:16]3[CH2:19][CH:18]([OH:20])[CH2:17]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: OC1CNC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: OC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Yield: 81.8 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (5.56 g, 25 mmol), azetidin-3-ol hydrochloride (3.01 g, 27.50 mmol) and DIPEA (10.89 mL, 62.50 mmol) in DMF (50 mL) was heated at 70° C. for 1 hour. The solution was slowly diluted with water and the product crystallised. The precipitate was collected by filtration, washed with water, drained well and washed with ether. It was dried under vacuum to afford 1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]azetidin-3-ol (5.30 g, 82%) as a white crystalline solid.
Reaction SMILES: C1N2CN3CN(C2)CN1C3.[N:11]1[N:12]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[N:13]=[N:14][CH:15]=1.S(=O)(=O)(O)O.FC(F)(F)[C:30](O)=[O:31]>>[OH:22][C:19]1[CH:18]=[CH:17][C:16]([N:12]2[N:13]=[N:14][CH:15]=[N:11]2)=[CH:21][C:20]=1[CH:30]=[O:31]
Reactant: Oc1ccc(-n2ncnn2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Product: O=Cc1cc(-n2ncnn2)ccc1O

Procedure:
Hexamethylenetetramine (5.6 g) was added to 4-tetrazol-2-yl-phenol (1.6 g) in trifluoroacetic acid (40 ml) and the mixture heated at 60° for 24 h. On cooling, the solution was poured into sulphuric acid (2N, 100 ml), extracted with ether (3×100 ml), dried (Na2SO4) and evaporated. The residue was purified by FCC (dichloromethane) to give the title compound as a yellow solid (930 mg). T.l.c. (Dichloromethane), Rf 0.56.