Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:6][CH:7]([N:9]2[C:22]3[CH:21]=[C:20]([C:23](=[S:25])[NH2:24])[CH:19]=[CH:18][C:17]=3[S:16][C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH3:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26](N)[CH2:27][CH2:28][CH2:29][CH3:30].S>C(O)C>[CH2:26]([NH:24][C:23]([C:20]1[CH:19]=[CH:18][C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]([CH:7]([CH3:8])[CH2:6][N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:22]=2[CH:21]=1)=[S:25])[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCN
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Agent: S
Solvent: CCO
Product: CCCCCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Temperature: 100 °C

Procedure:
A suspension of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2 g) and pentylamine (3 cc) in absolute ethanol (30 cc) is saturated with hydrogen sulphide and then heated for 2 hours at a temperature in the region of 100° C. After cooling, the mixture is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The pasty residue is taken up with ethyl ether (50 cc) and distilled water (15 cc). The organic phase is separated, dried over potassium carbonate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual viscous yellow oil is purified by chromatography on a column (height: 35 cm; diameter: 2.6 cm) of silica gel (0.2-0.063 mm), eluting with ethyl acetate (300 cc) and collecting 25-cc fractions. Fractions 3 to 9 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. N-Pentyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide (2.25 g) is thereby obtained in the form of a yellow oil. 0.55 g of this product is dissolved in isopropyl ether (20 cc), and a 3.3N solution (0.6 cc) of hydrochloric acid in isopropyl ether is introduced dropwise and with stirring. The precipitate formed is drained, washed with isopropyl ether (3×5 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. N-Pentyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide hydrochloride (0.56 g) is thereby obtained in the form of a pale yellow powder, m.p. 155°-160° C. (melts forming a paste).
Reaction SMILES: [OH:1]O.[CH3:3][N:4]1[C@@H:20]2[CH2:21][C:9]3[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]4[O:14][C@H:15]5[C:16]([O:22]C)=[CH:17][CH:18]=[C:19]2[C@:7]5([C:8]=34)[CH2:6][CH2:5]1.[NH4+].[OH-]>C(O)=O.OS(O)(=O)=O.O>[CH3:3][N:4]1[C@@H:20]2[CH2:21][C:9]3[CH:10]=[CH:11][C:12]([O:24][CH3:25])=[C:13]4[O:14][CH:15]5[C:16]([CH:17]=[CH:18][C@:19]2([OH:1])[C@:7]5([C:8]=34)[CH2:6][CH2:5]1)=[O:22]
Reactant: OO
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 40 °C
Yield: 86 %

Procedure:
Hydrogen peroxide (30%, 1.3 mL, 13 mmol) is added to a solution of thebaine O-1 (3.11 g, 10 mmol) in a mixture of formic acid (88%, 1.3 mL) and H2SO4 (0.7%, 4.1 mL). The mixture is heated at 40° C. (bath temperature) for 6.5 h, cooled, diluted with water (10 mL), and made basic with concentrated NH4OH. The precipitate is filtered, washed with H2O and dried (MgSO4). The product is recrystallized from EtOH—CHCl3 to yield O-5 (2.70 g, expected yield 86%). See Iijima, I.; Minamikawa, J.; Jacobson, A. E.; Brossi, A.; Rice, K. C.; J. Med. Chem. (1978) 21, 398.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[C:8](=[O:17])[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:3]([OH:5])=[O:4].C(N(CC)CC)C.P(Cl)(OCC)(OCC)=O.[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1>O1CCCC1>[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39]([NH:1][CH:2]([CH2:6][C:7]2[C:8](=[O:17])[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:3]([OH:5])=[O:4])=[O:40])=[CH:37][CH:36]=1
Reactant: NC(Cc1cc2ccccc2[nH]c1=O)C(=O)O
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CCOP(=O)(Cl)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC(Cc1cc2ccccc2[nH]c1=O)C(=O)O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
1.2 Grams of 2-amino-3-(2-quinolon-3-yl)propionic acid and 0.8 ml of triethylamine were suspended in 10 ml of tetrahydrofuran, then under stirring condition at a room temperature, a solution containing 1.0 g of diethyl chlorophosphate in 10 ml of tetrahydrofuran was added dropwise thereto, and the reaction mixture was stirred at a room temperature for 3 hours. To this reaction mixture was added a solution containing 1.0 g of p-chlorobenzoic acid in 10 ml of tetrahydrofuran dropwise and the whole reaction mixture was further stirred at a room temperature for 10 hours. After completion of the reaction, the crystals precipitated were removed by filtration, the filtrate was concentrated and to the residue was poured a saturated sodium hydrogencarbonate aqueous solution, then extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride aqueous solution and dried with sodium sulfare. The solvent was removed by distillation and the residue was recrystallized from ethanol-water to obtain 0.9 g of 2-(4-chlorobenzoylamino)-3-(2-quinolon-3-yl)propionic acid in the form of white powder product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.O>CS(C)=O>[N+:14]([C:11]1[CH:12]=[CH:13][C:8]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[CH:9][CH:10]=1)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: C1COCCN1
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)cc1
Temperature: 100 °C

Procedure:
A mixture of 24.5 g morpholine and 13.3 g 1-Fluoro-4-nitro-benzene in 30 ml DMSO was heated to 100° C. for 4 h. This solution was poured on to 300 ml of water and the resulting precipitate was collected by filtration to yield a bright yellow crystalline product, which was dried in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].S(=O)(=O)(O)O.[CH2:29](O)[CH2:30]CC>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH2:23][CH2:29][CH3:30])=[O:20])=[CH:17][CH2:16][CH2:15][CH2:14]1)(=[O:11])=[O:12]
Reactant: CCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Reactant: CCCCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)C1=CCCCC1S(=O)(=O)Nc1ccc(F)cc1F
Temperature: 82.5 °C
Reaction time: 168 h

Procedure:
To a solution of ethyl 6-[N-(2,4difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate obtained in Example 3 (Compound 3, 180 mg) in 1-butanol (5 ml), a concentrated sulfuric acid (0.12 ml) was added and the mixture was stirred at 80 to 85° C. for 7 days. After cooling, the reaction mixture was diluted with ethyl acetate (60 ml) and washed with water (60 ml). The ethyl acetate layer was washed with water (60 ml×5), dried over anhydrous magnesium sulfate and then evaporated under reduced pressure to dryness. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1/4) and then crystallized from diisopropyl ether to yield butyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-1-cyclohexene-1-carboxylate (Compound 33, 52 mg) as white crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=2[N:5]=1)[CH3:3].Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[N:30]1[C:22]([NH:1][C@H:2]([C:4]2[N:8]([C:9]3[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=3)[C:12]#[N:13])[C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]=3[N:5]=2)[CH3:3])=[C:23]2[C:27]([NH:26][CH:25]=[N:24]2)=[N:28][CH:29]=1
Reactant: C[C@H](N)c1nc2ccccc2n1-c1cccc(C#N)c1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1-c1cccc(C#N)c1
Temperature: 90 °C
Yield: 36.3 %

Procedure:
A mixture of 3-[2-((S)-1-aminoethyl)benzoimidazol-1-yl]benzonitrile (54 mg, 0.21 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (69 mg, 0.29 mmol) and DIPEA (65 mL, 0.37 mmol) in n-butanol (0.5 mL) was heated at 90° C. in a sealed vial for 16 h. After cooling to RT, the crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a gradient 20-98%, 0.1% HCO2H in acetonitrile/water) to afford 170 as a white solid (29 mg, 37%). LCMS (Method K): RT 3.03 min [M+H]+ 381.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.90 (1H, s), 8.25-7.49 (8H, m), 7.32-7.17 (2H, m), 7.09 (1H, d, J=7.84 Hz), 5.60 (1H, s), 1.64 (3H, d, J=6.81 Hz)
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][C:4]([S:7]([NH:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[CH:17]=[N:16][CH:15]=[CH:14]3)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:22]C1C=CC=C(C(OO)=O)C=1.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[Cl:22][C:17]1[C:18]2[C:13](=[CH:12][C:11]([NH:10][S:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:21])=[CH:6][CH:5]=3)(=[O:8])=[O:9])=[CH:20][CH:19]=2)[CH:14]=[CH:15][N:16]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc3cnccc3c2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Nc2ccc3c(Cl)nccc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
In chloroform (100 ml) was dissolved 3.0 g of 6-(4-toluenesulfonylamino)isoquinoline (Preparation Example 21), and m-chloroperbenzoic acid (2.57 g) was added thereto under ice-cooling, followed by stirring at room temperature overnight. The solvent was evaporated, and the resulting crystals were washed with diethyl ether, collected by filtration and dried, to give pale yellow crystals. The obtained crystals were suspended in chloroform (83 ml), and phosphorus oxychloride (19 ml) was added thereto, followed by heating under reflux for 5 hours. After cooling, the solvent was evaporated, and the residue was basified with an aquesou sodium bicarbonate in an ice-bath, followed by extracting with ethyl acetate, The extract was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified by silica gel column, to give crude crystals of the title compound (1.630 g, 49.40%). The crude crysatals were recrystallized from ethanol, to give the title compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)=[C:6]([Cl:19])[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([Cl:19])[CH:5]=1)[NH:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20]
Reactant: CC(C)C=O
Reactant: COC(=O)c1ccc(N=Cc2cccc(Br)c2)c(Cl)c1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)c2c(c1)C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 4-[(3-bromo-benzylidene)-amino]-3-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-8-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]([OH:15])=O)=[CH:11][C:10]([O:16][CH3:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(#N)C.[NH2:21][C:22]1[C:30]([C:31](O)=[O:32])=[C:29]2[C:25]([CH:26]=[N:27][NH:28]2)=[CH:24][C:23]=1[CH3:34].S(Cl)(C)(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:15][C:31](=[O:32])[C:30]4[C:29]5[NH:28][N:27]=[CH:26][C:25]=5[CH:24]=[C:23]([CH3:34])[C:22]=4[N:21]=3)=[CH:11][C:10]([O:16][CH3:17])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2cn[nH]c2c(C(=O)O)c1N
Reactant: COc1cc(C(=O)O)n(-c2ncccc2Cl)n1
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1cc(-c2nc3c(C)cc4cn[nH]c4c3c(=O)o2)n(-c2ncccc2Cl)n1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a solution of 2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carboxylic acid (40 g, 157 mmol) and acetonitrile (1000 mL) was added 6-amino-5-methyl-1H-indazole-7-carboxylic acid (30 g, 157 mmol). To the resulting brown suspension were added sequentially pyridine (57 mL, 706 mml) and dropwise mesylchloride (43 mL, 549 mmol). The reaction mixture was stirred for 6 h at 50° C. and 15 hours at ambient temperature. The reaction mixture was concentrated in vacuo. The residue was suspended in water and stirred for 15 min. The resulting yellow suspension was filtrated. The filtercake was washed sequentially with water and heptane/AcOEt 2:1 and dried to afford the title compound as beige powder, which was submitted to the next step without further purification. LC/MS: 409 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]=[C:34]=[S:35])([CH3:26])[CH3:25]>O1CCCC1>[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:22])[F:23])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)=[S:35])([CH3:26])[CH3:25]
Reactant: Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Reactant: CC(C)c1ccccc1N=C=S
Solvent: C1CCOC1
Product: CC(C)c1ccccc1NC(=S)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Yield: 45.4 %

Procedure:
To a stirred solution of 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)aniline (0.10 g, 0.31 mmol) in tetrahydrofuran (5 mL) was added 1-isopropyl-2-isothiocyanatobenzene (0.10 g, 0.56 mmol). The solution was heated to reflux for 24 hours The solvent was removed under reduced pressure, then triturated with methanol to generate a white solid which was filtered and air-dried to provide the title compound (0.070 g, 45%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([C@@H:45]([CH2:50][OH:51])[C:46]([O:48][CH3:49])=[O:47])([CH3:44])[C:25]1=[O:52])[CH:21]1[CH2:23][CH2:22]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:60][S:61](Cl)(=[O:63])=[O:62]>C(Cl)Cl>[Si:1]([O:18][CH2:19][C@@H:20]([N:24]1[C@H:29]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[C@@H:28]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=2)[CH2:27][C@@:26]([C@@H:45]([CH2:50][O:51][S:61]([CH3:60])(=[O:63])=[O:62])[C:46]([O:48][CH3:49])=[O:47])([CH3:44])[C:25]1=[O:52])[CH:21]1[CH2:22][CH2:23]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)[C@H](CO)[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](COS(C)(=O)=O)[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-methyl 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-hydroxypropanoate (132 mg, 0.173 mmol; Example 270, Step A) and triethylamine (97 μL, 0.69 mmol) in DCM (2.2 mL) was added a solution of methanesulfonyl chloride (27 μL, 0.35 mmol) in DCM (2.2 mL) at 0° C. Then the reaction was allowed to warm to rt and stirred for 3 h. The reaction was quenched (water), extracted (2×EtOAc) and washed (brine). The combined organic layers were dried (Na2SO4) and concentrated under the reduced pressure to provide a crude mesylated compound, (S)-methyl 2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-(methylsulfonyloxy)propanoate.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[N+:15]([C:18]1[CH:27]=[CH:26][C:21]([O:22][CH2:23][CH2:24]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:24][CH2:23][O:22][C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:27][CH:26]=3)[CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(CC2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(OCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1ccc(CC2CCN(CCOc3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 95 %

Procedure:
From a mixture of 4-(4-methylbenzyl)piperidine (2.27 g, 12.0 mmol), 2-(4-nitrophenoxy)ethyl bromide (1.42 g, 6.0 mmol), K2CO3 (130 mg) and KI (120 mg) in toluene (25 mL) was obtained 2.02 g (100%) of the title compound as a viscous oil. 1H NMR (CDCl3): 1.25-1.38 (m, 2H), 1.46-1.56 (m, 1H), 1.63-1.67 (m, 2H), 2.01-2.09 (m, 2H), 2.314 (s, 3H), 2.498 (d, 2H), J=7), 2.797 (t, 2H), J=6), 2.94-2.98 (m, 2H), 4.171 (t, 21, J=6), 6.950 (d, 26, J=9), 7.059 (AB, 4H, J=8), 8.191 (d, 2H, J=9). The hydrochloride, mp. 180-1° C.
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([C:21]([C:24]4([C:27]5[CH:28]=[C:29]6[C:34](=[CH:35][CH:36]=5)[N:33]=[CH:32][CH:31]=[CH:30]6)[CH2:26][CH2:25]4)=[CH:22][N:23]=3)[CH:20]=2)=[CH:11][C:10]=1[F:37]>>[F:37][C:10]1[CH:11]=[C:12]([C:15]2[CH:16]=[N:17][C:18]3[N:19]([C:21]([C:24]4([C:27]5[CH:28]=[C:29]6[C:34](=[CH:35][CH:36]=5)[N:33]=[CH:32][CH:31]=[CH:30]6)[CH2:26][CH2:25]4)=[CH:22][N:23]=3)[CH:20]=2)[CH:13]=[CH:14][C:9]=1[C:15]1[CH:12]=[CH:11][C:3]([C:1]([N:19]([CH3:20])[CH3:18])=[O:2])=[N:17][CH:16]=1
Reactant: Fc1cc(-c2cnc3ncc(C4(c5ccc6ncccc6c5)CC4)n3c2)ccc1Br
Reactant: O=C(O)C(F)(F)F
Product: CN(C)C(=O)c1ccc(-c2ccc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cc2F)cn1

Procedure:
This compound was prepared as a TFA salt starting from 6-{1-[6-(4-bromo-3-fluorophenyl)imidazo[1,2-a]pyrimidin-3-yl]cyclopropyl}quinoline using procedures analogous to those for Example 85. LCMS: (M+H)=529.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[NH:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:41][C:42]([O:44][CH3:45])=[O:43].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:29])[C:21]3[C:20](=[O:30])[N:19]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:18](=[O:39])[N:17]([CH2:41][C:42]([O:44][CH3:45])=[O:43])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3[nH]c(=O)n(COC(=O)C(C)(C)C)c(=O)c3n2-c2ccccc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1nc(N1CCN(C(=O)OC(C)(C)C)CC1)n2-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-[7-(2-Chlorophenyl)-1-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester (107 mg) was dissolved in N,N-dimethylformamide (2 ml), and methyl bromoacetate (0.025 ml) and potassium carbonate (50 mg) were added to the solution. Then, the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, and the mixture was washed with water. The organic layer was concentrated to give 139 mg of the title compound.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([Br:18])[CH:12]=1)[CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.ClCl.[OH-].[Na+]>C(O)(=O)C>[CH3:2][N:3]([CH2:10][C:11]1[CH:16]=[C:15]([Cl:1])[C:14]([OH:17])=[C:13]([Br:18])[CH:12]=1)[CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CN(Cc1ccc(O)c(Br)c1)C1CCCCC1
Reactant: Cl
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(Cc1cc(Cl)c(O)c(Br)c1)C1CCCCC1
Temperature: 0 °C

Procedure:
3.6 gm of N-methyl-N-cyclohexyl-3-bromo-4-hydroxy-benzylamine hydrochloride were dissolved in 50 ml of 90% acetic acid and admixed with a solution of 0.85 gm of chlorine in 15 ml of glacial acetic acid while cooling with ice water. After stirring for a short time, the solution was poured into a mixture of ice and 10 N sodium hydroxide solution and extracted three times with methylene chloride. The organic phase was evaporated to dryness. The residue was purified by means of column chromatography over silicgel with ethyl acetate as the eluant, yielding N-methyl-N-cyclohexyl-3-bromo-5-chloro-4-hydroxy-benzylamine, m.p. 136°-138° C., of the formula ##STR24## after recrystallization from ethanol/ether.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][CH:12]([OH:22])[CH2:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)[CH3:9].[CH3:23][S:24][CH2:25][C:26](Cl)=[O:27]>CN(C)C=O>[CH3:23][S:24][CH2:25][C:26](=[O:27])[NH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH:12]([OH:22])[CH2:11][O:10][CH2:8][CH3:9])=[CH:21][CH:20]=1
Reactant: CCOCC(O)COc1ccc(N)cc1
Reactant: CSCC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCC(O)COc1ccc(NC(=O)CSC)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
Dissolved in 4 ml of dimethylformamide were 2.00 g of triethylamine and 2.11 g of 4-(3-ethoxy-2-hydroxypropoxy)aniline. To the solution was added 1.25 g of methylmercaptoacetyl chloride with ice-cooling and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and the residue was extracted with chloroform. The chloroform layer was washed with water and concentrated. The resulting residue was purified by silica gel column chromatography using a 1:5 ethanol-chloroform mixture, giving 2.85 g of 4-(3-ethoxy-2-hydroxypropoxy)phenylcarbamoylmethyl methyl sulfide in 95.3% yield.
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1.[NH2:27][C@H:28]([CH3:31])[CH2:29][OH:30].FC(F)(F)C(O)=O>C(O)CCC>[OH:30][CH2:29][C@H:28]([N:27]1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH:12][C:13]([C:15]2[CH:20]=[C:19]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:18]=[CH:17][N:16]=2)=[O:14])[CH:9]=[CH:10][CH:11]=1)[CH3:31]
Reactant: O=C(Nc1cccc(-c2nnco2)c1)c1cc(-c2cccnc2)ccn1
Reactant: C[C@@H](N)CO
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: C[C@H](CO)n1cnnc1-c1cccc(NC(=O)c2cc(-c3cccnc3)ccn2)c1
Temperature: 150 °C
Yield: 23 %

Procedure:
A suspension of N-(3-(1,3,4-oxadiazol-2-yl)phenyl)-3,4′-bipyridine-2′-carboxamide (210 mg, 0.61 mmol), (R)-2-amino-1-propanol (0.3 mL), and trifluoroacetic acid (0.05 mL) in n-butanol was heated in a microwave to 150° C. for 1 hour. The solvent was removed under reduced ressure and the residue was purified by reverse-phase HPLC to give (R)—N-(3-(4-(1-hydroxypropan-2-yl)-4H-1,2,4-triazol-3-yl)phenyl)-3,4′-bipyridine-2′-carboxamide as a white powder (55 mg, 0.138 mmol, 23% yield).