Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]([CH:14](Br)[C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=1)=[O:16])[C:10]([O:12][CH3:13])=[O:11]>C(Cl)Cl>[CH3:26][O:25][C:19]1[CH:18]=[C:17]([C:15](=[O:16])[C:14]#[C:9][C:10]([O:12][CH3:13])=[O:11])[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COC(=O)C(Br)C(Br)C(=O)c1ccc(OC)c(OC)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C#CC(=O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
A solution of triethylamine (27 mg) in methylene chloride (0.5 ml) was added to a solution of methyl 2,3-dibromo-4-(3,4-dimethoxyphenyl)-4-oxobutanoate (49 mg, 0.1 mmol), prepared above, in methylene chloride (0.5 ml). The mixture was stirred at room temperature for 15 min and then heated under reflux with stirring for 2 hr. The mixture was then treated by a conventional method, and the crude product was purified by column chromatography on silica gel (hexane/ethyl acetate) to give the title compound as a yellow crystal (21 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[N:6]([CH2:7][CH2:8][NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:17][C:18]([S:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)(=[O:23])=[O:22])=[CH:19][CH:20]=3)[C:13]([C:31]3[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=3)[C:34]#[N:35])=[CH:12][N:11]=2)[C:5](=[O:39])[NH:4][C:3]1=[O:40].C[Si]([N:46]=[N+:47]=[N-:48])(C)C.C([Sn](=O)CCCC)CCC.Cl.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH:46]1[C:34]([C:33]2[CH:32]=[C:31]([C:13]3[C:14]([C:16]4[S:17][C:18]([S:21]([C:24]5[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=5)(=[O:23])=[O:22])=[CH:19][CH:20]=4)=[N:15][C:10]([NH:9][CH2:8][CH2:7][N:6]4[C:2]([CH3:41])([CH3:1])[C:3](=[O:40])[NH:4][C:5]4=[O:39])=[N:11][CH:12]=3)[CH:38]=[CH:37][CH:36]=2)=[N:35][N:48]=[N:47]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(C#N)c2)c(-c2ccc(S(=O)(=O)c3ccc(F)cc3)s2)n1
Agent: CCCC[Sn](=O)CCCC
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)NC(=O)N1CCNc1ncc(-c2cccc(-c3nnn[nH]3)c2)c(-c2ccc(S(=O)(=O)c3ccc(F)cc3)s2)n1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3-(2-(2-(5,5-dimethyl-2,4-dioxoimidazolidin-1-yl)ethylamino)-4-(5-(4-fluorophenylsulfonyl)thiophen-2-yl)pyrimidin-5-yl)benzonitrile (110 mg, 0.19 mmol), trimethylsilyl azide (178 mg, 1.52 mmol) and dibutyltin oxide (47 mg, 0.19 mmol) in N,N-dimethylformamide (5 mL) was heated at 120° C. for 24 h. After cooling to rt, 10 mL of aqueous hydrochloric acid (10%) was added and the resulting mixture was stirred for 30 min. Saturated sodium bicarbonate was added to adjust to pH 5 and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (3×50 mL), dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuo and the product purified by flash chromatography eluting with methanol (containing 10% acetic acid)/dichloromethane (1:20). MS (M+H)+ 634.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.Cl.[NH2:13][OH:14]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[N:13][OH:14])[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: Cn1nc(Cl)cc(C=O)c1=O
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CO
Product: Cn1nc(Cl)cc(C=NO)c1=O
Temperature: 70 °C
Yield: 73.6 %

Procedure:
To a solution of 6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine-4-carbaldehyde (2 g, 11.59 mmol, Preparation #30) in MeOH (30 mL) was added a solution of hydroxylamine hydrochloride (0.966 g, 13.91 mmol) in water (5 mL) and heated to about 70° C. for 1 h. The mixture was cooled to RT and solids obtained were collected by filtration to afford the 6-chloro-2-methyl-3-oxo-2,3-dihydropyridazine-4-carbaldehyde oxime 1.6 g, (73.6%) as an off white solid. 1H NMR (400 MHz, DMSO) δ 12.316 (s, 1H), 8.092 (s, 1H), 7.675 (s, 1H), 3.651 (s, 3H); MS m/z: 185.7 (M−H)−
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Br:20])=[CH:4][N:3]=1.[N:21]1([CH2:27][C:28]2[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])(=O)C.[NH4+]>C(O)C>[Br:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:32]([C:31]3[CH:30]=[CH:29][C:28]([CH2:27][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[CH:35][CH:34]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=O)[C@@H]1[C@H](Nc2c(Br)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2

Procedure:
(1S,2S,3R,4R)-3-(2,3-Diamino-5-bromo-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (40.0 mg, 0.118 mmol), 4-morpholin-4-ylmethyl-benzaldehyde (26.7 mg, 0.130 mmol) and ammonium acetate (59.4 mg, 0.771 mmol) were heated in ethanol (5 mL) at 70° C. for 18 hours. The reaction mixture was concentrated and the product was purified by reverse phase chromatography (Gilson) to afford, following neutralization with saturated sodium bicarbonate solution and filtration, the title compound 35 mg (57%). mp: 217-219° C., 1H NMR (300 MHz, DMSO-d6): 13.27 (s, 1H), 8.10 (d, J=9 Hz, 2H), 8.03 (s, 1H), 7.76 (s, 1H), 7.48 (d, J=8 Hz, 2H), 7.22 (s, 1H), 7.16 (d, J=8 Hz, 1H), 6.41 (br s, 1H), 6.37 (br s, 1H), 5.23 (t, J=8 Hz, 1H), 3.59 (br s, 4H), 3.53 (s, 2H), 2.89 (s, 1H), 2.78 (s, 1H), 2.39 (br s, 4H), 2.25 (d, J=8 Hz, 1H), 1.90 (s, 1 h), 1.39 (d, J=8 Hz, 1H). MS: 523, 525 (M+H), HPLC: 1.82 min (G method).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[I:17][CH2:18][C:19](Cl)=[O:20]>O>[I:17][CH2:18][C:19]([NH:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1)=[O:20]
Reactant: O=C(Cl)CI
Reactant: NC(=O)c1cc(N)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: NC(=O)c1cc(NC(=O)CI)ccc1O
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To an ice-cooled, stirred solution of 5-Aminosalicylamide (10.0 grams, 0.073 mol), in 300 mL of water containing NaHCO3 (42.0 grams, 0.5 mol), iodoacetyl chloride (18.4 grams, 0.09 mol) is added dropwise over 15 min. After stirring at 0-5° C. for 1 hr., the solution is acidified with cold 6 N HCI. The precipitate is collected and dried in vacuo over NaOH pellets, to afford 21.3 grams (96% yield) of crude 5-(iodoacetamido)salicylamide.
Reaction SMILES: O=[CH:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].CN(C)C=O.[NH:17]1[CH2:22][CH:21]=[CH:20][CH2:19][CH2:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.O1CCCC1>[N:17]1([CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:18][CH:19]=[CH:20][CH2:21][CH2:22]1
Reactant: C1=CCNCC1
Reactant: CC(C)(C)OC(=O)NCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCN1CC=CCC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.8 %

Procedure:
To 1,1-dimethylethyl N-(2-oxoethyl)carbamate (2.0 g, 13 mmol) were added N,N-dimethylformamide (50 mL), tetrahydrofuran (50 mL), 1,2,3,6-tetrahydropyridine (1.2 mL, 13 mmol) and sodium triacetoxyborohydride (5.3 g, 25 mmol), and the mixture was stirred at room temperature for 14 hours. To the reaction solution was added ethyl acetate, and the resulting mixture was washed with a 0.5 M aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate to ethyl acetate:methanol=8:2) and further purified with amino silica gel column chromatography (hexane:ethyl acetate=9:1 to ethyl acetate) to obtain the title compound (1.2 g, yield 41%).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.O>[N:7]1([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: C1COCCN1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#CCC(=O)N1CCOCC1
Temperature: 0 °C

Procedure:
500 mg (5.88 mmol) Cyanoacetic acid are dissolved in 30 ml dimethylformamide, 563 mg (6.47 mmol) morpholine, 794 mg (5.88 mmol) 1-hydroxy-1H-benzotriazole hydrate and 718 mg (5.88 mmol) 4-dimethylaminopyridine are added. The reaction mixture is stirred at 0° C., then 1.12 g (5.88 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride are added. The reaction mixture is stirred at room temperature for 18 hours, then water and ethyl acetate are added. The organic phase is dried over sodium sulfate and evaporated to dryness in vacuo. The residue is purified by preparative HPLC.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH:12]([C@@H:15]1[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17][C@H:16]1[O:22][CH2:23][C:24]([O:26][CH2:27][CH:28]1[CH:33]=[CH:32][CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:29]1)=[O:25])([CH3:14])[CH3:13]>C(Cl)Cl>[CH:12]([C@@H:15]1[CH2:20][CH2:19][C@@H:18]([CH3:21])[CH2:17][C@H:16]1[O:22][CH2:23][C:24]([O:26][CH2:27][CH:28]1[CH:33]2[O:6][CH:32]2[CH2:31][N:30]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH2:29]1)=[O:25])([CH3:14])[CH3:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCC(=O)OCC1C=CCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OCC(=O)OCC1CN(C(=O)OC(C)(C)C)CC2OC12
Yield: 66.6 %

Procedure:
A solution of 3-chloroperoxybenzoic acid (0.9 g, 5.2 mmol), tert-butyl 3-((1R,2S,5R)-2-isopropyl-5-methyl-1-cyclohexyloxy)acetoxymethyl-1,2,3,6-tetrahydropyridine-1-carboxylate (0.5 g, 1.2 mmol), and methylene chloride (150 ml) was stirred at room temperature for 20 h. An extra portion of 3-chloroperoxybenzoic acid (1.1 eq) was added and the mixture refluxed for 2h. The reaction mixture was extracted with 1M sodium hydroxide and water, dried over magnesium sulphate and evaporated to dryness in vacuo. The residue was purified on a silica gel column (Eluent: heptane/ethyl acetate (5/1)) to give tert-butyl 3-((1R,2S,5R) 2-isopropyl-5-methyl-1-cyclohexyloxy)acetoxymethyl-4,5-epoxypiperidine-1-carboxylate as an oil (Yield: 0.34 g, 66%).
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]([CH3:10])[C:7](Cl)=[O:8])(=[O:3])[CH3:2].C(OC([C@@H](N[C@H](C([N:30]1[N:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[S:32][C@H:31]1[C:41]([OH:43])=[O:42])=O)C)CCC1C=CC=CC=1)=O)C>ClCCl>[C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([N:30]1[N:34]=[C:33]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[S:32][CH:31]1[C:41]([O:43][CH2:33][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:42])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H](C)C(=O)Cl
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1N=C(c2ccccc2)S[C@H]1C(=O)O
Solvent: ClCCl
Product: CC(=O)SC[C@@H](C)C(=O)N1N=C(c2ccccc2)SC1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
3-Acetylthio-2-(S)-methylpropanoyl chloride (2.3 g) in dichloromethane (30 ml) was added over 5 minutes to a stirred mixture of the product of Example 1, step a) (3.6 g) and polyvinylpyridine (2.4 g) in dichloromethane (60 ml). The mixture was stirred at room temperature for 20 hours and 3-acetylthio-2-(S)-methylpropanoyl chloride (1.2 g) was then added. The mixture was stirred for a further 2 hours, filtered and the filtrate stirred with a saturated solution of sodium bicarbonate for 1 hour. The organic phase was separated, washed with water, dried and evaporated to a gum. The residue was purified by flash chromatography to give the sub-title product (4.4 g) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[CH2:31]([NH2:33])[CH3:32]>>[CH2:31]([NH:33][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[C:10]=2[N:11]=1)[CH3:32]
Reactant: CCN
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1C
Product: CCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3ccccc3C)c2n1
Yield: 82.2 %

Procedure:
Following the general procedure outlined in Example 126, the product of Example 121 (200 mg, 0.47 mmol), and ethylamine (1.18 mL, 2.36 mmol) were reacted to give the crude material. Purification by flash chromatography eluting with EtOAc/hexane/triethylamine (30/70/2, v/v/v), followed by recrystallization from dichloromethane and hexane, gave the desired product 150 mg (82%). LC-MS: 389.2 (MH+, m/z), 2.39 (Rt, min).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=O>>[Cl:14][C:15]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: O=c1cc(N2CCN(Cc3cccc(Cl)c3Cl)CC2)nc[nH]1

Procedure:
6-[4-(2,3-Dichloro-benzyl)-piperazin-1-yl]-3H-pyrimidin-4-one was prepared using Procedure A from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,3-dichlorobenzaldehyde. Mass spectrum (ES) MH+=339.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27]>C(Cl)Cl>[F:24][C:25]([F:30])([F:29])[C:26]([OH:28])=[O:27].[F:23][C:20]([F:21])([F:22])[C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1ccc(C2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-(4-trifluoromethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 0.0060 mol) in CH2Cl2 (19.0 mL), trifluoro acetic acid (3.46 g, 0.0303 mol) was added at 0° C. and the mixture was allowed to stir at RT overnight. CH2Cl2 and TFA were removed under reduced pressure and the crude product was filtered and washed with diethyl ether (2×20 mL) to obtain 4-(4-trifluoromethyl-phenyl)-piperidine trifluoro acetic acid salt with (1.58 g, 83%).
Reaction SMILES: O.[C:2]1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28]>CO>[OH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:2])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CCCCCCCCCCCCCO
Solvent: O
Solvent: CO
Product: COC(=O)CCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 72 h

Procedure:
p-Toluenesulfonic acid monohydrate (0.28 g, 1.45 mmol) was added to a solution of the above 14-hydroxy-tetradecanoic acid (7.10 g, 29.1 mmol) in methanol (150 mL) and the resulting solution was stirred at room temperature for 3 days. Methanol was removed under reduced pressure; the residue was dissolved in ethyl acetate (170 mL); washed with 5% aqueous solution of sodium carbonate (3×50 mL) and brine (25 mL); dried over anhydrous magnesium sulfate and evaporated in vacuo to give methyl 14-hydroxy-tetradecanoate as white solid.
Reaction SMILES: [CH3:1][CH:2]([NH2:9])[CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.ClC(Cl)C.Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl>>[N:9]([CH:2]([CH3:1])[CH2:3][C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)=[C:15]=[O:17]
Reactant: CC(N)Cc1cccs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: CC(Cc1cccs1)N=C=O
Reaction time: 1 h

Procedure:
To a solution of 1-methyl-2-thiophen-2-ylethylamine (2 g, 14.2 mmol) in dichloroethane (30 ml) triethylamine (4.3 g, 42.6 mmol) and triphosgene (2.1 g, 7.1 mmol) were added. The reaction mixture stirred for 1 h and concentrated on rotary evaporator. Diethyl ether is added, and the resulting mixture is filtered. Ether solution is concentrated, and the resulting oil is used in the next step without purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([OH:12])=[CH:5]2.O[CH:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1.PPP.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([O:12][CH:18]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17]1)=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: Oc1cnc2ccc(Br)cc2c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: PPP
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(Oc2cnc3ccc(Br)cc3c2)C1
Temperature: 50 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
To a solution of 6-bromoquinolin-3-ol (500 mg, 2.232 mmol), tert-butyl 3-hydroxypyrrolidine-1-carboxylate (418 mg, 2.232 mmol) and triphosphine (875 mg, 3.35 mmol) in THF (10 ml) was added DEAD (0.424 ml, 2.68 mmol) at 0° C. Then the mixture was stirred at 50° C. for 6 h under N2. The mixture was diluted with ether and filtered. The filtrate was concentrated. The residue was purified by silica gel chromatography eluted with Hex/EA (from 100% to 95%) to afford the title compound (650 mg, 67% yield) as brown gel.
Reaction SMILES: C[O:2][CH:3]=[CH:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1.C(O)=O>C1(C)C=CC=CC=1>[CH2:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][CH2:5][CH2:4][CH:3]=[O:2])[CH2:8][CH2:9]2)[CH2:14][CH2:15]1)[CH2:20][CH3:21]
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=COC)CC2)CC1
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCC=O)CC2)CC1

Procedure:
In 500 ml of toluene was dissolved 50.0 g (171 ml ) of the crude 1-methoxy-4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butene obtained by the procedures in the fourth step, 78.7 g (1710 mmol) of formic acid was added thereto, and then they were heated to reflux for 4 hours. The reaction mixture was washed with 300 ml of saturated aqueous sodium bicarbonate solution twice and with 500 ml of water five times, and the solvent was distilled off under a reduced pressure to obtain 45.1 g of a crude 4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butanal.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[CH3:19])=[C:8]([Cl:20])[CH:7]=1.[CH3:29][O:30][C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:8]1[CH:7]=[C:6]([NH:5][CH2:4][C:3]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:2]=2[C:36]2[CH:37]=[CH:38][C:33]([C:31]([O:30][CH3:29])=[O:32])=[CH:34][CH:35]=2)[CH:11]=[CH:10][C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH3:19]
Reactant: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2Br)cc1Cl
Reactant: COC(=O)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
N-(2-bromo-4-(trifluoromethyl)benzyl)-2,4′-dichloro-2′-methyl-[1,1′-biphenyl]-4-amine (324 mg, 0.66 mmol), (4-(methoxycarbonyl)phenyl)boronic acid (143 mg, 0.80 mmol), Pd(dppf)Cl2 (54 mg, 0.07 mmol), and K2CO3 (183 mg, 1.33 mmol) were dissolved in 1,4-dioxane (6 mL) and water (1.5 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: Br[CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[N-:20]=[N+:21]=[N-:22].[Na+].O>CN(C)C=O>[N:20]([CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCC(N=[N+]=[N-])C(=O)O
Temperature: 80 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To the solution of 2-bromohexadecanoic acid (1.00 g) in N,N-dimethylformamide (DMF, 15 ml) was added sodium azide (0.86 g), and the mixture was stirred at 80° C. for 12 hours. To the reaction mixture, after having been cooled to room temperature, was then added water. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was separated, washed twice with brine, dried over anhydrous sodium sulfate. The solvent was removed by distillation to give 2-azidohexadecanoic acid (0.73 g). To the solution of 2-azidohexadecanoic acid in DMF were added N-hydroxysuccinimide (74 mg) and N,N'-dicyclohexylcarbodiimide (146 mg), and the mixture was stirred for 12 hours. Precipitates produced was removed by filtration, and the filtrate was concentrated to give the active ester of 2-azidohexadecanoic acid. To the active ester in DMF were further added 6-(4'-N-glycylspicaminyl-amino)purine hydrochloride (246 mg) and triethylamine (0.72 ml), and the mixture was stirred for 12 hours. The solvent was removed by distillation, and the residue was subjected to chromatography on a silica gel column with an eluent system of chloroform-methanol (6:1) to give SPK229 in the yield of 185 mg.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15](O)[CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:11][CH:10]=1>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[CH:11][CH:10]=1
Reactant: Oc1ccccc1
Reactant: OC(CCn1ccnc1)c1ccc(Br)cc1
Product: Brc1ccc(C(CCn2ccnc2)Oc2ccccc2)cc1

Procedure:
Phenol was reacted with 1-(4-Bromo-phenyl)-3-imidazol-1-yl-propan-1-ol* following the procedure set out in Example 48B to give the title compound. LC/MS: (PS-A2) Rt 2.30 [M+H]+ 357.26, 359.27. *This starting material can be made by the method described in Example 47A.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH:17]=[C:16]([C@@:18]([OH:25])([CH2:23][CH3:24])[C:19]([F:22])([F:21])[F:20])[N:15]=[N:14]3)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:26]([NH2:28])=[O:27])[CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>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>[OH:25][C@@:18]([C:16]1[N:15]=[N:14][N:13]([CH2:12][C:8]2[CH:7]=[C:6]3[C:11]([C:2]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[CH3:29])=[CH:3][C:4]([C:26]([NH2:28])=[O:27])=[N:5]3)=[CH:10][CH:9]=2)[CH:17]=1)([C:19]([F:22])([F:21])[F:20])[CH2:23][CH3:24]
Reactant: Cc1ccccc1B(O)O
Reactant: CC[C@](O)(c1cn(Cc2ccc3c(Cl)cc(C(N)=O)nc3c2)nn1)C(F)(F)F
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
Product: CC[C@](O)(c1cn(Cc2ccc3c(-c4ccccc4C)cc(C(N)=O)nc3c2)nn1)C(F)(F)F
Temperature: 100 °C

Procedure:
4-chloro-7-({4-[(2S)-1,1,1-trifluoro-2-hydroxybutan-2-yl]-1H-1,2,3-triazol-1-yl}methyl)quinoline-2-carboxamide (3-14, 8 mg, 0.02 mmol, 1.0 equiv.), (2-methylphenyl)boronic acid (5 mg, 0.04 mmol, 2 equiv.), Pd(PPh3)4 (0.7 mg, 0.0006 mmol, 0.03 equiv.) and 2M aqueous Na2CO3 (0.02 mL, 0.05 mmol, 2.5 equiv.) were suspended in Dioxane (0.4 mL) and the reaction mixture was heated overnight at 100° C. The crude mixture was filtered, concentrated and purified by reverse phase HPLC (H2O/CH3CN gradient w/0.1% TFA modifier) to afford 7-({4-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1H-1,2,3-triazol-1-yl}methyl)-4-(2-methylphenyl)quinoline-2-carboxamide (3-15). LRMS m/z (M+H)+ 470.1 found, 470.2 required.