Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[C:7]12([CH2:17][NH:18][C:19]([C:21]3[C:22]4[N:23]([N:27]=[C:28]([CH2:30][CH2:31][C:32]#[N:33])[CH:29]=4)[CH:24]=[CH:25][CH:26]=3)=[O:20])[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2.O>CS(C)=O>[C:7]12([CH2:17][NH:18][C:19]([C:21]3[C:22]4[N:23]([N:27]=[C:28]([CH2:30][CH2:31][C:32]5[NH:33][N:3]=[N:2][N:1]=5)[CH:29]=4)[CH:24]=[CH:25][CH:26]=3)=[O:20])[CH2:14][CH:13]3[CH2:15][CH:9]([CH2:10][CH:11]([CH2:12]3)[CH2:16]1)[CH2:8]2
Reactant: N#CCCc1cc2c(C(=O)NCC34CC5CC(CC(C5)C3)C4)cccn2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cccn2nc(CCc3nnn[nH]3)cc12
Temperature: 130 °C

Procedure:
NaN3 (65 mg, 0.48 mmol) and NH4Cl (26 mg, 0.48 mmol) are added to a solution of 2-(2-cyano-ethyl)-pyrazolo[1,5-a]pyridine-4-carboxylic acid (adamantan-1-ylmethyl)-amide (58 mg, 0.16 mmol) in DMSO at rt. The mixture is heated to 130° C. for 6 h. Additional NaN3 (65 mg, 0.48 mmol) is added, and the mixture is heated for 14 h. The mixture is cooled to rt. H2O is added and pH is adjusted to about 7. The aqueous layer is extracted with EtOAc (3×15 mL), dried over Na2SO4 and the solvent is removed to dryness. The crude product is purified by PTLC (eluted with 2% MeOH in DCM) to give the title compound. 1H NMR (CDCl3): 8.49-8.47 (d, 1H), 7.52-7.50 (d, 1H), 6.79-6.69 (t, 1H), 6.69 (s, 1H), 6.40 (b, 1H), 3.44-3.41 (m, 2H), 3.31-3.29 (m, 2H), 3.20-3.19 (m, 2H), 2.00 (b, 3H), 1.74-1.60 (m, 12H). LC-MS m/z (M+H+): 406.07.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:21][C:18]2[CH:17]=[N:16][C:15]([C:12]3[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])=[CH:10][CH:11]=3)=[CH:20][N:19]=2)=[O:38])=[CH:34][CH:35]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)cn2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2cnc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cn2)cc1
Temperature: 50 °C
Reaction time: 20 h
Yield: 74.8 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]pyrazin-2-amine (7s) (350 mg, 1.16 mmol) and 4-(dimethylamino)pyridine (15.0 mg, 123 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 20 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=7/1) to give Compound 11s (478 mg, 869 μmol, 74.8%) as a yellow foamy solid. Rf=0.19 (n-hexane/ethyl acetate=6/1); 1H NMR (400 MHz, DMSO-d6) δ 0.14 (s, 6H), 0.19 (s, 6H), 0.91 (s, 9H), 0.94 (s, 9H), 3.66 (s, 2H), 6.75-6.82 (AA′BB′, 2H), 6.91-6.97 (AA′BB′, 2H), 7.17-7.24 (AA′BB′, 2H), 7.93-8.00 (AA′BB′, 2H), 8.90 (d, 1H, J=1.4 Hz), 9.28 (d, 1H, J=1.4 Hz), 10.99 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.8, 17.9, 25.46 (3C), 25.47 (3C), 41.8, 119.6 (2C), 120.2 (2C), 127.5 (2C), 128.2, 129.2, 130.4 (2C), 134.9, 138.7, 146.3, 147.0, 153.8, 156.2, 170.3; IR (KBr, cm−1) 417, 517, 575, 638, 681, 708, 781, 806, 839, 914, 1009, 1051, 1103, 1167, 1260, 1354, 1416, 1468, 1508, 1545, 1605, 1670, 2857, 2886, 2930, 2955, 3034, 3063; HRMS (ESI+) m/z 550.2930 ([M+H]+, C30H44N3O3Si2+ requires 550.2916).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[N:7]([C:9]([CH2:23][N:24]([C:26](=[O:31])[C:27]([Cl:30])([F:29])[F:28])[CH3:25])([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH2:10][CH:11]([OH:14])CO)[CH3:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:32])[N:7]([C:9]([CH2:23][N:24]([C:26](=[O:31])[C:27]([Cl:30])([F:28])[F:29])[CH3:25])([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH2:10][CH:11]=[O:14])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC(CC(O)CO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C)C(=O)C(F)(F)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CC(CC=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C)C(=O)C(F)(F)Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
tert-Butyl[1-{[(2-chloro-2,2-difluoroacetyl)-methylamino]-methyl}-1-(3,4-dichlorophenyl)-3,4-dihydroxybutyl]methylcarbamate (323 mg) was dissolved in a mixture solvent of tetrahydrofuran (3 mL) and water (3 mL). Sodium periodate (266 mg) was added thereto, and the mixture was stirred for 1.5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby give the title compound (291 mg, 96%). The compound was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]([NH2:22])=[N:19][C:18]=1[CH3:23])=[O:16])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:17]1[S:21][C:20]2=[N:22][C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)=[CH:2][N:19]2[C:18]=1[CH3:23])=[O:16])[CH3:13]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CCO
Product: CCOC(=O)c1sc2nc(-c3ccc(F)cc3)cn2c1C
Temperature: 95 °C
Yield: 28.9 %

Procedure:
2-Bromo-1-(4-fluoro-phenyl)-ethanone (200 mg, 0.92 mmol) and 2-amino-4-methyl-thiazole-5-carboxylic acid ethyl ester (186.2 mg, 0.92 mmol) were heated in 5 ml of ethanol at 95° C. for 5 hours. After addition of 80 mg of 2-bromo-1-(4-fluoro-phenyl)-ethanone and further heating for 9 hours at 95° C. the mixture was evaporated. Addition of potassium hydrogensulfate solution, extraction with ethyl acetate and purification by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) yielded 81 mg (32%) of the desired product. MS (mass spectrum): M+H+=305.07.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([C@@H:37]([O:39]C(=O)C)[CH3:38])=[O:36]>>[OH:39][C@@H:37]([CH3:38])[C:35]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)cc1F
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c[nH]c23)cc1F

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A139) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6]O.P(Br)(Br)[Br:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH2:6][Br:14]
Reactant: BrP(Br)Br
Reactant: COc1cc(CO)cc(OC)c1
Product: COc1cc(CBr)cc(OC)c1
Temperature: 80 °C

Procedure:
22 g of 3,5-dimethoxybenzyl alcohol were reacted with 50 ml of phosphorus tribromide with ice cooling and the reaction mixture was heated for 30 minutes at 80° C. For workup, the reaction mixture was poured into ice water and extracted with methyl-tert-butyl ether. The organic phases were combined, dried, and concentrated. 23 g of 3,5-dimethoxybenzyl bromide were obtained as an oil.
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[C:7](=[O:20])[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:21]([NH:28][C:29]([NH:5][C:6]1[C:7](=[O:20])[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[CH:15]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCCn1c2c(cc(N)c1=O)CCCC2
Reactant: O=C=NCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCn1c2c(cc(NC(=O)NCc3ccccc3)c1=O)CCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
3-Amino-1-butyl-5,6,7,8-tetrahydro-1H-quinolin-2-one acetic acid salt (6-001-01) (5 mg, 0.018 mmol) was dissolved in methylene chloride (1 mL), and to the reaction mixture were added benzylisocyanate (2.5 μL, 0.02 mmol) and 4-dimethylaminopyridine (2.4 mg, 0.02 mmol), and the reaction mixture was stirred at room temperature for 4 h. To the reaction mixture was added diluted hydrochloric acid (0.1 mol/L, 3 mL), and the reaction mixture was extracted with ethyl acetate (10 mL), washed with brine (3 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (toluene/ethyl acetate) to give 1-benzyl-3-(1-butyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)urea (6-005) (5.0 mg, 79%) as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[C:25]([O:28][C@@H:29]([CH3:33])[C:30](Cl)=O)(=[O:27])[CH3:26]>O1CCCC1>[C:25]([O:28][C@H:29]([C:33]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:24])[C:10]2[N:11]=[C:12]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[S:13][C:14]=2[C:15](=[O:16])[N:17]=1)[CH3:30])(=[O:27])[CH3:26]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Solvent: C1CCOC1
Product: CC(=O)O[C@@H](C)c1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (100 mg, 0.273 mmol) in Tetrahydrofuran (THF) (1363 μl) was added (1S)-2-chloro-1-methyl-2-oxoethyl acetate (82 mg, 0.545 mmol). The mixture was stirred at room temperature overnight, then additional (1S)-2-chloro-1-methyl-2-oxoethyl acetate (1 equiv.) was added and stirring was continued at 60° C. for 2 h. The mixture was quenched with methanol and concentrated. The residue was purified by reversed-phase HPLC to provide (1S)-1-[4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)-7-oxo-4,7-dihydro[1,3]thiazolo[4,5-d]pyrimidin-5-yl]ethyl acetate. (11 mg, 9%); LC/MS: MS (ES+) m/e 463 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37 (d, J=6.3 Hz, 3H), 1.71 (s, 3H), 2.40 (s, 3H), 3.51-3.54 (m, 4H), 3.67 (m, 4H), 5.48-5.61 (m, 2H), 5.69 (q, J=6.3 Hz, 1H), 6.56 (d, J=7.6 Hz, 1H), 7.16 (m, 1H), 7.38 (d, J=7.8 Hz, 1H).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[OH:10][C:11]1[C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>C(O)(=O)C.O>[N+:6]([C:17]1[CH:16]=[C:12]([C:13]([OH:15])=[O:14])[C:11]([OH:10])=[C:19]([CH:18]=1)[C:20]([OH:22])=[O:21])([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(C(=O)O)c1O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1cc([N+](=O)[O-])cc(C(=O)O)c1O
Reaction time: 0.17 h

Procedure:
A mixture of 40 ml of sulfuric acid and 33 ml of nitric acid is stirred for 10 minutes and then 10 ml of acetic acid is added. To this is added a suspension of 10 g of 2-hydroxyisophthalic acid (Org. Syn., Vol. 5, p. 617) in 20 ml of acetic acid slowly with cooling in a water bath. A 10 ml portion of acetic acid is added. The reaction mixture is dissolved in water and extracted with ether. The ether is washed with saturated saline, dried over sodium sulfate and evaporated giving 5-nitro-2-hydroxyisophthalic acid as an orange oil.
Reaction SMILES: [Mg].BrCCBr.Br[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:8]=1.[S:21]1[CH2:25][CH2:24][C:23](=[O:26])[CH2:22]1.[Cl-].[NH4+]>O1CCCC1>[CH:16]1([O:15][C:9]2[CH:8]=[C:7]([C:23]3([OH:26])[CH2:24][CH2:25][S:21][CH2:22]3)[CH:12]=[CH:11][C:10]=2[O:13][CH3:14])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1ccc(Br)cc1OC1CCCC1
Reactant: O=C1CCSC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1ccc(C2(O)CCSC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirring suspension of magnesium turnings (3.45 g) in dry tetrahydrofuran (60 mL) is treated with 1,2-dibromoethane (0.8 mL), and the mixture is stirred under a nitrogen atmosphere for 30 minutes. It is then treated dropwise with a solution of 4-bromo-2-cyclopentyloxyanisole (25 g); which is prepared as described in Reference Example 4 in tetrahydrofuran (20 mL), and the resulting solution is heated at reflux for 30 minutes. The solution is then cooled to room temperature and treated with a solution of tetrahydrothiophen-3-one (6.9 mL) in tetrahydrofuran (20 mL), and allowed to stand for 16 hours. It is then treated with saturated aqueous ammonium chloride solution (50 mL), and the mixture is partitioned between water (100 mL) and dichloromethane (100 mL). The aqueous phase is further extracted with dichloromethane (100 mL). The combined organic phases are dried over magnesium sulphate and evaporated. The resulting residue is subjected to flash chromatography on silica gel, using a mixture of ethyl acetate and toluene as eluent to give 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxytetrahydrothiophene, in the form of a viscous oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8](Cl)=[O:9])[CH2:4][CH2:3]1.[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][N:27]([C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:9])[CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]
Reactant: CN1CCN(C(=O)Cl)CC1
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)N3CCN(C)CC3)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 4-methylpiperazine-1-carbonyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white powder (79% yield). 1H NMR (300 MHz, CDCl3) δ 8.01, 7.83, 6.96, 3.77-3.73, 3.51-3.44, 3.42-3.38, 3.36-3.33, 2.44-2.41, 2.31, 1.75-1.62, 1.48, 0.92. MS (ES+) m/z 404.4 (M+1).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12](Cl)=[O:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3].[NH2:15][CH:16]1[C:23](=[O:24])[N:22]2[CH:17]1[S:18][CH2:19][C:20]([CH3:28])=[C:21]2[C:25]([OH:27])=[O:26]>C(OCC)(=O)C>[N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:15][CH:16]2[C:23](=[O:24])[N:22]3[CH:17]2[S:18][CH2:19][C:20]([CH3:28])=[C:21]3[C:25]([OH:27])=[O:26])=[O:13])=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCc1ccc(CC(=O)Cl)cc1
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CN=[N+]=[N-])cc3)C2SC1

Procedure:
A mixture of p-azidomethylphenylacetyl chloride (0.6 g) and 7-amino-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (0.6 g) in 250 ml of ethyl acetate was refluxed for 50 minutes after which the solvent was removed under vacuum yielding an oily residue which was purified by chromatography using 60 g of silica gel and benzene-acetone as the eluant to give 7-[[2-[4-(azidomethyl)phenyl]acetyl]amino]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. M.P. 154°-155° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=2[NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.Br[CH2:22][CH2:23][OH:24].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:13]=[CH:14][C:15]=2[N:16]([CH2:22][CH2:23][OH:24])[S:17]([CH3:20])(=[O:19])=[O:18])[C:9]([O:11][CH3:12])=[O:10])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(OCC2CC2)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(N(CCO)S(C)(=O)=O)c(OCC2CC2)c1
Temperature: 110 °C
Yield: 66.6 %

Procedure:
A mixture of methyl 3-(cyclopropylmethoxy)-4-(methylsulfonamido)benzoate (1 g, 3.34 mmol), 2-bromoethanol (0.835 g, 6.68 mmol), and K2CO3 (0.923 g, 6.68 mmol) in CH3CN (12 ml) was heated at 110° C. under microwave irradiation for 12 hours. After cooling the solvent was evaporated and the residue was dissolved in EtOAc and filtered; the solvent was evaporated and the residue was purified by flash chromatography (eluent: EtOAc/petroleum ether 1/1) to give methyl 3-(cyclopropylmethoxy)-4-(N-(2-hydroxyethyl)methylsulfonamido)benzoate as a light brown oil (0.764 g, 2.225 mmol, 66.6% yield, /ESI+ 365.9 [MNa]+).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:26])[C:6]1[CH:15]=[C:14]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)[CH:13]=[C:8]([C:9]([O:11]C)=[O:10])[CH:7]=1.Cl>O.CCO>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:14]1[CH:13]=[C:8]([C:9]([OH:11])=[O:10])[CH:7]=[C:6]([CH:15]=1)[C:5]([OH:26])=[O:4]
Reactant: COC(=O)c1cc(C(=O)OC)cc(-c2ccc3ccccc3c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(C(=O)O)cc(-c2ccc3ccccc3c2)c1
Temperature: 25 °C

Procedure:
A solution of LiOH (1.5 mmol) in water (1 ml) was added to 5-(naphthalene-2-yl)-isophthalic acid dimethylester (160 mg, 0.5 mmol) suspended in 5 ml EtOH. The mixture was stirred at room temperature. The reaction was monitored by TLC until completion. 1.5 ml 1 M HCl solution was added and the precipitation was collected. The product was used in next step without further purification
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]3[CH2:22][N:21]([CH:23]4[CH2:28][CH2:27][C:26]([OH:35])([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH2:25][CH2:24]4)[CH2:20][CH2:19][N:18]3C(OC(C)(C)C)=O)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C@@H:17]3[NH:18][CH2:19][CH2:20][N:21]([CH:23]4[CH2:28][CH2:27][C:26]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)([OH:35])[CH2:25][CH2:24]4)[CH2:22]3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCN(C2CCC(O)(c3ccccn3)CC2)C[C@@H]1C(=O)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@H]1CN(C2CCC(O)(c3ccccn3)CC2)CCN1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The faster running isomer of tert-butyl (2R)-2-{[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl}-4-(4-hydroxy-4-pyridin-2-ylcyclohexyl)piperazine-1-carboxylate (45 mg) was dissolved in dichloromethane (6 ml). Trifluoroacetic acid (1 ml) was added and the solution stirred at room temperature for 2 hours and allowed to stand over the weekend. The mixture was partitioned between saturated aqueous sodium bicarbonate (10 ml) and dichloromethane (2×100 ml) and combined organics were concentrated in vacuo and adsorbed onto silica for purification by chromatography eluting with 0-15% methanol/dichloromethane. This gave one isomer of 4-((3R)-3-{[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl}piperazin-1-yl)-1-pyridin-2-ylcyclohexanol as a light brown solid (31%, 85%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>C1COCC1>[Cl:11][C:12]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:13]=1[S:22]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1)(=[O:24])=[O:23]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)c(O)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a solution of 4-amino-2,6-dichlorophenol (Aldrich, 5.9 g, 33 mmol) in 30 mL of THF was added 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (4.19 g, 15 mmol). The mixture was stirred overnight. The reaction mixture was filtered and washed with EtOAc. The filtrate was washed with 2N HCl, twice with a brine solution, dried over Na2SO4 and concentrated. The residue was purified by chromatography (20%-25% EtOAc/hexanes) to give 5.7 g (90%) of product.
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].O=[C:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:2]([NH:4][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h
Yield: 70 %

Procedure:
Ethylamine HCl (6.14 g, 75.376 mmol, 1.5 eq) and tert-butyl 4-oxopiperidine-1-carboxylate (10.0 g, 50.25 mmol, 1.0 eq) were dissolved in MeOH (200 ml); acetic acid (0.2 ml) was added and stirring was carried out for 2 hours at RT. NaBH3CN (6.3 g, 100.50 ml, 2.0 eq) was then added in portions at 0° C. and the mixture was stirred for 14 hours at RT. The reaction mixture was concentrated and the residue was taken up in sat. sodium hydrogen carbonate solution (150 ml) and extracted with DCM (2×400 ml). The combined org. phases were washed with sat. NaCl solution (200 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, 1% MeOH in DCM). Yield: 70% (8.0 g, 35.08 mmol)
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[C:14]([Cl:19])[C:13]([C:20]([OH:22])=O)=[CH:12]2)([CH3:4])([CH3:3])[CH3:2].[CH:24]([N:27]1[C:40]2[C:39](=[O:41])[CH2:38][C:32]3([CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[CH2:31][C:30]=2[CH:29]=[N:28]1)([CH3:26])[CH3:25]>>[Cl:19][C:14]1[C:13]([C:20]([N:35]2[CH2:34][CH2:33][C:32]3([CH2:38][C:39](=[O:41])[C:40]4[N:27]([CH:24]([CH3:26])[CH3:25])[N:28]=[CH:29][C:30]=4[CH2:31]3)[CH2:37][CH2:36]2)=[O:22])=[CH:12][C:11]2[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:23])[CH:10]=2)[N:15]=1
Reactant: CC(C)n1ncc2c1C(=O)CC1(CCNCC1)C2
Reactant: CC(C)(C)OC(=O)COc1ccc2nc(Cl)c(C(=O)O)cc2c1
Product: CC(C)n1ncc2c1C(=O)CC1(CCN(C(=O)c3cc4cc(OCC(=O)OC(C)(C)C)ccc4nc3Cl)CC1)C2

Procedure:
6-(2-tert-butoxy-2-oxoethoxy)-2-chloroquinoline-3-carboxylic acid and 1-isopropyl-4,6-dihydrospiro[indazole-5,4′-piperidin]-7(1H)-one were coupled by a method analogous to that described for Example 1 to give tert-butyl 2-(2-chloro-3-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-ylcarbonyl)quinolin-6-yloxy)acetate. This material (30 mg, 0.053 mmol) was suspended in ammonia (2 mL, 10 mmol, 7 M in methanol) and stirred at room temperature for 18 hours. The reaction was concentrated to give the title compound (27 mg, 100%). +ESI (M+H) 510.4.