Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[C:1]([O:5][C:6]([CH:8]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:17][CH:18]=1)[CH2:20][CH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: ICC1CCOCC1
Reactant: COC(=O)c1ccc(CC(=O)OC(C)(C)C)cc1
Product: COC(=O)c1ccc(C(CC2CCOCC2)C(=O)OC(C)(C)C)cc1

Procedure:
Methyl 4-tert-butoxycarbonylmethylbenzoate (1.71 g, 6.84 mmol) was alkylated with 4-iodomethyltetrahydropyran (1.86 g, 8.21 mmol), employing the method described in Preparation 41, to afford methyl 4-[1-tert-butoxycarbonyl-2-(tetrahydropyran-4-yl)ethyl]benzoate: RTA=3.86 min. A solution of this compound (1.37 g, 3.94 mmol) in CH2Cl2 (5 mL) was treated with TFA-CH2Cl2 (2:1, 15 mL) at 0° C. over 10 min. The mixture was stirred at 20° C. for 3 h, before being concentrated in vacuo. The residue was treated with PhMe and the solvents were evaporated off under reduced pressure. This process was repeated twice to provide crude methyl 4-[1-carboxy-2-(tetrahydropyran-4-yl)ethyl]benzoate. This carboxylic acid was condensed with thiazol-2-ylamine, utilizing the protocol outlined in EXAMPLE 65, to furnish methyl 4-[2-(tetrahydropyran-4-yl)-1-(thiazol-2-ylcarbamoyl)ethyl]benzoate: m/z (ES+)=375.2 [M+H]+. This ester (1.20 g, 3.21 mmol) was saponified with LiOH.H2O, using the procedure described in Preparation 22, to furnish the title compound: m/z (ES−)=359.2 [M−H]−.
Reaction SMILES: N1C(N[C:7]([C:9]2[CH:43]=[CH:42][C:12]([CH2:13][N:14]3[C:18]([C:19]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)=[O:20])=[CH:17][C:16]([C:33]4[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=4)=[N:15]3)=[CH:11][CH:10]=2)=[O:8])=NN=N1.[OH-:44].[Na+]>C1COCC1.CO>[F:31][C:29]([F:32])([F:30])[O:28][C:25]1[CH:26]=[CH:27][C:22]([NH:21][C:19]([C:18]2[N:14]([CH2:13][C:12]3[CH:42]=[CH:43][C:9]([C:7]([OH:44])=[O:8])=[CH:10][CH:11]=3)[N:15]=[C:16]([C:33]3[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=3)[CH:17]=2)=[O:20])=[CH:23][CH:24]=1
Reactant: [OH-]
Reactant: O=C(Nc1nnn[nH]1)c1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)cc2C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(Cn2nc(-c3cc(F)c(F)c(F)c3)cc2C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
To a solution of the intermediate from step A (0.1 g, 0.18 mmol) in 10 ml of THF/MeOH was added 5 N NaOH (1 mL). After stirring the reaction at room temperature for 2 hours it was concentrated in vacuo. The residue was acidified with 1N HCl (10 ml) and was extracted with ethyl acetate, dried over anhydrous Na2SO4 filtered and concentrated in vacuo. This material was used in the next step without any further purification. 1H NMR (CD3OD, 500 MHz): 7.96 (d, J=8.2 Hz, 2H), 7.73 (d, J=8.9 Hz, 2H), 7.62 (t, J=7.1 Hz, 2H), 7.4 (s, 1H), 7.35 (d, J=8.2 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 5.88 (s, 2H). LC-MS=4.0 min; (M+H)=536.0.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:35])[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[NH:23][CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.Cl[C:46]1[N:51]=[CH:50][CH:49]=[CH:48][N:47]=1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:35])[NH:10][CH:11]([C:16]([N:18]1[CH2:22][CH2:21][CH:20]2[N:23]([C:46]3[N:51]=[CH:50][CH:49]=[CH:48][N:47]=3)[CH2:24][CH:25]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([F:34])[CH:28]=3)[CH:19]12)=[O:17])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2NCC(Oc3ccc(F)c(F)c3)C21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(NC(=O)OCc1ccccc1)C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2c1ncccn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 60.4 %

Procedure:
Secondary amine 24 (200 mg, 0.41 mmol), DIPEA (110 μL, 0.62 mmol), and 2-chloro-pyrimidine (62 mg, 0.53 mmol) were dissolved in DMF (4 mL) and stirred at 80° C. After 12 h, the reaction mixture was cooled to ambient temperature, diluted with water, and extracted with EtOAc. The combined organic extracts were washed with brine and dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 hexanes/EtOAc) to afford 140 mg (60%) of 29 as a colorless oil. Mass spectrum, m/z [566.0] (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[N:14]([C:15]3[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=3)[N:13]=[CH:12][C:11]=2[CH2:23][CH2:24][OH:25])=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C(Cl)Cl>[CH3:33][S:34]([O:25][CH2:24][CH2:23][C:11]1[CH:12]=[N:13][N:14]([C:15]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[CH:17][N:16]=2)[C:10]=1[O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)(=[O:36])=[O:35]
Reactant: N#Cc1ccnc(-n2ncc(CCO)c2OCc2ccc(F)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cnn(-c2cc(C#N)ccn2)c1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a mixture of 2-[5-[(4-fluorophenyl)methoxy]-4-(2-hydroxyethyl)pyrazol-1-yl]pyridine-4-carbonitrile (40 mg, 0.12 mmol), Et3N (26 mg, 0.26 mmol) in DCM (5 mL) was added MeSO2Cl (17 mg, 0.15 mmoL) at 0° C. The reaction mixture was then stirred for 2 h at r.t. Water was added and extracted with DCM and concentrated to afford the title compound (42 mg, 87%). [M+H] Calc'd for C19H17FN4O4S, 417. Found, 417.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:34][CH2:33][C:28]3(OCC[O:29]3)[CH2:27][CH2:26]2)[CH2:21][CH2:20]1.C(O)=O.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]2)[CH:5]=[CH:4][C:3]=1[CH:19]1[CH2:24][CH2:23][CH:22]([CH:25]2[CH2:26][CH2:27][C:28](=[O:29])[CH2:33][CH2:34]2)[CH2:21][CH2:20]1
Reactant: CCCCCC1CCC(c2ccc(C3CCC(C4CCC5(CC4)OCCO5)CC3)c(F)c2)CC1
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: O
Product: CCCCCC1CCC(c2ccc(C3CCC(C4CCC(=O)CC4)CC3)c(F)c2)CC1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
The compound (5) (26.35 g), formic acid (10 ml) and toluene (100 ml) were put in a reaction vessel under a nitrogen atmosphere, heated under reflux for 8 hours, and cooled slowly to room temperature. Water (200 ml) and toluene (200 ml) were added and mixed thereto. Subsequently, the mixture was allowed to stand until it had separated into two phases, the organic and aqueous phases, and an extractive operation to an organic phase was carried out. The organic phase was fractionated, and washed sequentially with a saturated aqueous solution of sodium hydrogencarbonate and water, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using a mixed solvent of toluene and ethyl acetate (toluene:ethyl acetate=9:1 by volume) as an eluent and silica gel as a stationary phase powder, and further purified by means of recrystallization from a mixed solvent of toluene and heptane (toluene: heptane=1:1 by volume), and dried, giving 22.39 g of 4′-[2-fluoro-4-(4-pentyl-cyclohexyl)-phenyl]-bicyclohexyl-4-one (6). The yield based on the compound (5) was 93.7%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=1)=[O:10].[CH3:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:28]([C:25]2[CH:24]=[CH:23][C:22]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:27][CH:26]=2)(=[O:30])=[O:29])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[CH:12]=2)=[O:10])[CH:4]=1
Reactant: CS(=O)(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc(C(=O)c2cc(Cl)ccc2N)ccn1
Product: Cc1cc(C(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(S(C)(=O)=O)cc2)ccn1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using (2-Amino-5-chloro-phenyl)-(2-methyl-pyridin-4-yl)-methanone and 4-methanesulfonyl-benzenesulfonyl chloride and purified by HPLC. 1H NMR (CDCl3) δ 10.38 (s, 1H) 8.64 (s 1H) 7.95 (s, 4H) 7.72 (s, 1H) 7.51 (s, 1H) 7.31 (s, 1H) 7.11 (s, 1H) 6.99 (s, 1H) 3.04 (s, 3H) 2.64 (s, 3H). MS: (ES) m/z=464.9 (M++1).
Reaction SMILES: ClC(OCC)=O.[C:7]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1)(O)=[O:8].C(N(CC)CC)C>O1CCCC1>[OH:8][CH2:7][CH:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][CH2:11]1
Reactant: CCOC(=O)N1CCC(C(=O)O)CC1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(CO)CC1
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
A solution of 0.67 g of ethyl chloroformate in 2 ml of tetrahydrofuran was added to a solution of 1.01 g of ethyl 4-carboxypiperidine-1-carboxylate and 0.72 g of triethylamine in 20 ml of tetrahydrofuran at -10° to -5° C., and the mixture was stirred for 30 minutes. The resultant crystalline precipitate was filtered off, the filtrate was added to a solution of 0.57 g of sodium borohydride in 10 ml of water with ice cooling over 30 minutes, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was made acidic with 1N hydrochloric acid with ice cooling and then extracted with ether. The ether layer was washed in sequence with water, saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. Elution with a hexane-ethyl acetate (1:1 v/v) mixture gave 0.69 g of ethyl 4-hydroxymethylpiperidine-1-carboxylate
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:8][N:9]([CH3:11])[CH3:10].N[C:27]1[CH:28]=C(C=[C:35](S(=O)(=O)N)[C:36]=1CC1C=CC=CC=1)CN(C)C.Cl.Cl.C(I)CCC.C(=O)([O-])O.[Na+].CN(C)P(=O)(N(C)C)N(C)C>O>[CH2:15]([C:14]1[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:12][C:7]([CH2:8][N:9]([CH3:10])[CH3:11])=[CH:6][C:5]=1[NH:4][CH2:28][CH2:27][CH2:36][CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CN(C)Cc1cc(N)c(Cc2ccccc2)c(S(N)(=O)=O)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCCCI
Solvent: O
Product: CCCCNc1cc(CN(C)C)cc(S(N)(=O)=O)c1Cc1ccccc1
Reaction time: 24 h

Procedure:
A mixture of (3-amino-4-benzyl-5-sulfamylbenzyl)dimethylamine dihydrochloride hemihydrate (4.0 g; dried in vacuo at 78° C. for 16 hours; prepared as described in Example 209), n-butyl iodide (1.9 g), sodium hydrogen carbonate (5.0 g) and hexamethylphosphoric triamide (20 ml) is stirred at 22°-25° C. for 24 hours, and is then diluted with water (200 ml) to precipitate crude (4-benzyl-3-n-butylamino-5-sulfamylbenzyl)dimethylamine. After filtration and recrystallization from ethanol it is obtained with a melting point of 111°-113° C. The material (IR, analysis) is identical with the material prepared as in Example 172.
Reaction SMILES: C([CH2:4][C@@H:5]1[C:14]([CH3:16])([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:17])[CH:12]=2)[C:7]([CH3:19])([CH3:18])[CH2:6]1)(O)=O.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[Cl-:37].[Li+]>C1C=CC=CC=1>[Cl:37][CH2:4][C@@H:5]1[C:14]([CH3:16])([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:17])[CH:12]=2)[C:7]([CH3:19])([CH3:18])[CH2:6]1
Reactant: Cc1ccc2c(c1)C(C)(C)[C@@H](CC(=O)O)CC2(C)C
Reactant: [Cl-]
Agent: CC(=O)[O-]
Agent: [Li+]
Agent: [Pb+4]
Solvent: c1ccccc1
Product: Cc1ccc2c(c1)C(C)(C)[C@@H](CCl)CC2(C)C
Yield: 63.3 %

Procedure:
To a solution of (R)-3-carboxymethyl1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene ([α]546 -23.8° (C=1 in benzene)) (2.00 g; 7.69 mmol) in benzene (30 ml), lead tetraacetate (4.00 g; 9.02 mmol) and anhydrous lithium chloride (0.80 g; 18.9 mmol) were added, and the resultant mixture was refluxed for 6 hours. The reaction mixture was washed with water, dilute hydrochloric acid and 6% ammonia water in order. The benzene layer was dried, concentrated and purified on column chromatography to give (S)-3-chloromethyl-1,1,4,4,6-pentamethyl-1,2,3,4-tetrahydronaphthalene (1.22 g; 4.87 mmol). From the ammonia water layer, there was recovered the unreacted carboxylic acid (0.35 g; 1.34 mmol). The yield was 77% (based on the consumed carboxylic acid). [α]546 +26.1° (C=1 in n-hexane).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.O[CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:19][CH2:20][NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc2cc([C@H](C)C(=O)OCCNC(=O)OC(C)(C)C)ccc2c1
Yield: 82.4 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 7.60 g, 33.0 mmol), tert-butyl N-(2-hydroxyethyl)carbamate (5.30 g, 32.9 mmol), N,N-dimethylaminopyridine (DMAP, 0.35 g, 2.86 mmol) and 1,3-dicyclohexylcarbodiimide (6.80 g, 33.0 mmol) in CH2Cl2 (200 mL) was stirred at ambient temperature overnight. The byproduct, dicyclohexyl urea, was removed by filtration. The filtrate was concentrated, dissolved in EtOAc (50 mL) and then cooled in a dry-ice bath to precipitate the remaining dicyclohexyl urea and then filtered. The filtrate was concentrated, dissolved in CH2Cl2 (15 mL) and hexane (200 mL) and then stirred until the product precipitated. The solid was dried under vacuum to give the title compound (10.12 g, 82% yield). Mp 82–84° C. 1H NMR (300 MHz, CDCl3) δ 7.72–7.65 (m, 3H), 7.42–7.38 (m, 1H), 7.16–7.11 (m, 2H), 5.05 (br, 1H), 4.13 (t, J=5.3 Hz, 2H), 3.91 (s, 3H), 3.87 (q, J=7.1 Hz, 1H), 3.30 (br. q, 2H), 1.58 (d, J=7.1 Hz, 3H), 1.45 (s, 9H). 13C NMR (75 MHz, CDCl3) δ 174.4, 157.6, 155.6, 135.4, 133.6, 129.2, 128.8, 127.1, 126.0, 125.8, 119.0, 105.5, 79.3, 63.7, 55.2, 45.2, 39.5, 28.2, 18.3. Mass spectrum (API-TIS) m/z 374 (MH)+. Anal. calcd. for C21H27NO5: C, 67.54; H, 7.29; N, 3.75. Found: C, 67.43; H, 7.16; N, 3.66.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[CH3:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:16]2[CH2:17][CH2:18][CH:13]([CH3:12])[CH2:14][CH2:15]2)[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CC1CCNCC1
Solvent: O
Product: CC1CCN(c2cc(Br)ccc2[N+](=O)[O-])CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a round bottom flask containing 4-bromo-2-fluoro-1-nitro-benzene (640 mg, 2.92 mmol) was added 4-methyl piperidine (4 mL) and the reaction was stirred at 40° C. overnight. At this time the dark solution was poured into water (25 mL) and extracted with DCM (2×25 mL). The combined organic layers were washed with water (2×25 mL), dried (Na2SO4) and concentrated in vacuo to afford 556 mg (64%) of 1-(5-bromo-2-nitro-phenyl)-4-methyl-piperidine as an orange oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[C:7]([F:17])=[CH:6][C:5]=2Br.[OH-].[Na+].[H][H]>C(O)C.[C].[Pd]>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)[C:7]([F:17])=[CH:6][CH:5]=2
Reactant: [H][H]
Reactant: Cc1cc2c(N3CCOCC3)c(F)cc(Br)c2[nH]1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(N3CCOCC3)c(F)ccc2[nH]1
Yield: 65.7 %

Procedure:
To a solution of 24 g of 2-methyl-4-morpholino-5-fluoro-7-bromoindole in 200 ml of ethanol was added 1 of palladium-carbon and then 15 ml of a 20% aqueous sodium hydroxide solution. This mixture was subjected to catalytic reduction at room temperature and at atmospheric pressure. The reaction was stopped when a theoretical amount (about 1.7 l) of hydrogen was absorbed, and the catalyst was removed by filtration followed by concentration. The residue was purified through silica gel column chromatography (Wako gel C-200; eluent: chloroform: n-hexane=5:1) to give 11.8 g of 2-methyl-4-morpholino-5-fluoroindole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14](I)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)#[CH:20]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([F:18])[C:11]3[N:12]([C:14]([C:20]#[C:19][C:21]4[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=4)=[CH:15][N:16]=3)[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1cc(-c2ccc(Cl)cc2)cn2c(I)cnc12
Reactant: C#Cc1cnc(N)nc1
Product: Nc1ncc(C#Cc2cnc3c(F)cc(-c4ccc(Cl)cc4)cn23)cn1

Procedure:
The title compound was prepared from 6-(4-chloro-phenyl)-8-fluoro-3-iodo-imidazo[1,2-a]pyridine (example C.30 step 2) (300 mg, 0.8 mmol) and 5-ethynyl-pyrimidin-2-ylamine (example D.2) (115 mg, 0.8 mmol) according to general procedure II. Obtained as an off-white solid (101 mg, 34%). MS (ISP) 364.1 [(M+H)+], 366 [(M+2+H)+]; mp 279-280° C.
Reaction SMILES: [SH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([OH:5])=[O:4].[C:10]1(C)C=CC(S(O)(=O)=O)=C[CH:11]=1.O>C(O)C.C(Cl)(Cl)Cl>[SH:1][C@@H:2]([CH2:6][CH:7]([CH3:9])[CH3:8])[C:3]([O:5][CH2:10][CH3:11])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)C[C@H](S)C(=O)O
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H](S)CC(C)C
Reaction time: 4 h
Yield: 3077.9 %

Procedure:
A solution of 7.2 g (48.6 mmole) of (S)-2-mercapto-4 methylpentanoic acid [J. A. Yankeelov, Jr., K. F. Fok, and D. J. Carothers, J. Org Chem., 43, 1623 (1978)] and 219 mg of p-toluenesulfonic acid in 12 ml of absolute ethanol and 12 ml of CHCl3 was stirred under reflux with collection of liberated H2O in a Dean-Stark trap pre-filled with CHCl3. After 4 hours, the solution was cooled, diluted with an equal volume of CHCl3, and washed successively with H2O, saturated aqueous NaHCO3 solution, and H2O. The organic phase was dried over MgSO4, filtered, and concentrated to give 6.90 g (81%) of an oil, [α]20D -19.0° (c 2, ether), TLC in 9:1 hexane-ethyl acetate. The structure was verified by 200 MHz NMR (CDCl3).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=O)[O:24][C:25]=1[CH3:26]>>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)[O:24][C:25]=1[CH3:26]
Reactant: Cc1cc(C=O)oc1C
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: Cc1cc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)oc1C

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4,5-dimethylfuran-2-carbaldehyde was carried out according to General Synthetic Method 6. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4,5-dimethylfuran-2-yl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:7][CH:6]([CH3:8])[CH2:5][C:4](Cl)([Cl:9])[C:3]1=[O:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[OH:11]
Reactant: CC1CC(Cl)(Cl)C(=O)C(Cl)(Cl)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc(Cl)c(O)c(Cl)c1
Yield: 57.7 %

Procedure:
120 g (0.48 mol) of 2,2,6,6-tetrachloro-4-methylcyclohexanone and 2 g (0.008 mol) of triphenylphosphine were introduced into the reactor used in Example 1. The reaction mixture was heated at 160°-170° C., under stirring; the reaction was terminated when the evolution of hydrogen chloride from the reaction mixture ceased. The reaction mixture was distilled under reduced pressure to yield 49 g of 2,6-dichloro-4-methylphenol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:11][C:12]=2[OH:13])=[CH:3][N:2]=1.[C:20]([C:22]1[CH:23]=[C:24]([S:29]([N:32](CC2C=CC(OC)=CC=2OC)[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1F)#[N:21].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:20]([C:22]1[CH:23]=[C:24]([S:29]([NH:32][C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[O:13][C:12]1[CH:11]=[CH:10][C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:8][C:7]=1[C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)#[N:21]
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2ccc(F)c(C#N)c2)c(OC)c1
Reactant: Oc1ccc(-c2ccccc2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: N#Cc1cc(S(=O)(=O)Nc2nncs2)ccc1Oc1ccc(-c2ccccc2)cc1-c1ccnnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
3-Pyridazin-4-ylbiphenyl-4-ol (Preparation 4, 50 mg, 0.2 mmol) and 3-cyano-N-(2,4-dimethoxybenzyl)-4-fluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 15, 87.3 mg, 0.2 mmol) were dissolved in dimethylsulfoxide (2 mL). Potassium carbonate (83 mg, 0.6 mmol) was added and the reaction stirred at room temperature for 16 hours. The crude material was partitioned between ethyl acetate (20 mL) and water (20 mL), the organic layer separated, concentrated in vacuo, dissolved in trifluoroacetic acid (1 mL) and the solution stirred for 16 hours at room temperature. The reaction was concentrated in vacuo then purified by reverse phase column chromatography (ISCO™, 12 g, C18, 20:1 water:acetonitrile to 1:4 water:acetonitrile). The appropriate fractions were combined and concentrated in vacuo to afford the title compound as a white solid (25 mg, 24%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][O:27][CH2:28][CH3:29])[N:14]([CH2:15][C:16]([NH:19][C:20]([NH:22][CH:23]([CH3:25])[CH3:24])=[O:21])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([O:30]CC3C=CC=CC=3)=[CH:5][C:4]=2[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:26][O:27][CH2:28][CH3:29])[N:14]([CH2:15][C:16]([NH:19][C:20]([NH:22][CH:23]([CH3:24])[CH3:25])=[O:21])([CH3:17])[CH3:18])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([OH:30])=[CH:5][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOCc1nc2c(N)nc3cc(O)ccc3c2n1CC(C)(C)NC(=O)NC(C)C
Temperature: 25 °C
Yield: 77 %

Procedure:
N-[2-(4-Amino-7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-isopropylurea (0.94 g, 1.66 mmol) was dissolved in 100 mL of warm ethanol and then cooled back to ambient temperature. 10% Palladium on carbon (0.35 g) was added and the mixture was shaken overnight under 50 psi (3.4×105 Pa) of hydrogen. The reaction was filtered through CELITE filter agent, and the filter pad was washed sequentially with ethanol and methanol. The filtrate was concentrated under reduced pressure. The resulting off white solid was purified by flash column chromatography on silica gel (eluting with 90:10:1 dichloromethane/methanol/aqueous ammonium hydroxide) to provide 0.53 g of N-[2-(4-amino-2-ethoxymethyl-7-hydroxy-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]-N′-isopropylurea as an off-white powder, m.p. 163-168° C.