Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7].[CH3:12][CH2:13][N:14](CC)CC.C(N)C>C(Cl)Cl>[CH2:13]([NH:14][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH3:12]
Reactant: CCN(CC)CC
Reactant: COc1cccc(C(=O)Cl)c1
Agent: CCN
Solvent: ClCCl
Product: CCNC(=O)c1cccc(OC)c1
Reaction time: 1 h

Procedure:
To a solution of 3-methoxybenzoyl chloride (commercially available from Aldrich, 5 mL, 35 mol) and Et3N (10 mL) in 100 mL of DCM was added and EtNH2 (2 M/THF, 30 mL, 60 mmol) dropwise for 30 min at 0° C. and the resulting solution was stirred for additional 1 h. The reaction mixture was washed with aq. NaHCO3 and brine, consecutively. The organic layer was dried over Na2SO4 and concentrated in vacuo, yielding oily residue, which was subjected to column chromatography to yield Example A175a (6.2 g, >95%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([C:39]([C:41]2[C:49]3[C:44](=[CH:45][C:46]([Cl:50])=[CH:47][CH:48]=3)[NH:43][CH:42]=2)=[O:40])[CH2:35][CH2:34]1>C(Cl)Cl>[Cl:50][C:46]1[CH:45]=[C:44]2[C:49]([C:41]([C:39]([N:36]3[CH2:35][CH2:34][CH:33]([NH:32][C:4](=[O:6])[C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[F:1])[CH2:38][CH2:37]3)=[O:40])=[CH:42][NH:43]2)=[CH:48][CH:47]=1
Reactant: NC1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: O=C(O)c1ccccc1F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
To a stirred solution of 50 mg (0.36 mmol) 2-fluoro-benzoic acid in 5 ml CH2Cl2 were added 90 mg (0.47 mmol) EDC, 63 mg (0.47 mmol) HOBt, 60 μl (0.47 mmol) Et3N and 100 mg (0.36 mmol) (4-amino-piperidin-1-yl)-(6-chloro-1H-indol-3-yl)-methanone. The mixture was stirred overnight at RT and then poured onto water and extracted with CH2Cl2. The combined organic phases were dried over Na2SO4 and concentrated in vacuo. Flash chromatography (ethyl acetate) afforded 82 mg (57%) N-[1-(6-Chloro-1H-indole-3-carbonyl)-piperidin-4-yl]-2-fluoro-benzamide of as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]2[CH:11]([CH:28]3[CH2:30][CH2:29]3)[O:12][C:13]3[CH:18]=[CH:17][C:16](B4OC(C)(C)C(C)(C)O4)=[CH:15][C:14]=3[C:3]=12.Br[C:32]1[C:33]([N:52]([CH3:57])[S:53]([CH3:56])(=[O:55])=[O:54])=[CH:34][C:35]2[O:39][C:38]([C:40]3[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=3)=[C:37]([C:47]([NH:49][CH3:50])=[O:48])[C:36]=2[CH:51]=1>CN(C=O)C.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:1][C:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]2[CH:11]([CH:28]3[CH2:30][CH2:29]3)[O:12][C:13]3[CH:18]=[CH:17][C:16]([C:32]4[C:33]([N:52]([CH3:57])[S:53]([CH3:56])(=[O:55])=[O:54])=[CH:34][C:35]5[O:39][C:38]([C:40]6[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=6)=[C:37]([C:47]([NH:49][CH3:50])=[O:48])[C:36]=5[CH:51]=4)=[CH:15][C:14]=3[C:3]=12
Reactant: CC1(C)OB(c2ccc3c(c2)-c2c(Cl)c4ccccc4n2C(C2CC2)O3)OC1(C)C
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(Br)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(c3)-c3c(Cl)c5ccccc5n3C(C3CC3)O4)cc12
Temperature: 100 °C
Yield: 52.2 %

Procedure:
A mixture of 12-chloro-6-cyclopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6H-benzo[5,6][1,3]oxazino[3,4-a]indole (40 mg, 0.10 mmol), 5-bromo-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (45 mg, 0.10 mmol), K3PO4-3H2O (80 mg, 0.30 mmol) and Pd(dppf)Cl2 (7 mg, 0.01 mmol) in 2 mL of DMF was heated in a sealed tube under microwave condition at 100° C. for 20 minutes, and then the mixture was purified using prep-HPLC to provide Compound 131 (35 mg, yield: 55.1%). 1H-NMR (CDCl3, 400 MHz) δ 8.39 (s, 1H), 7.96˜7.93 (t, J=8.0 Hz, 2H), 7.85 (s, 1H), 7.64 (d, J=6.8 Hz, 2H), 7.40 (d, J=4.4 Hz, 2H), 7.30 (d, J=7.2 Hz, 1H), 7.23˜7.20 (m, 4H), 5.94 (s, 1H), 5.77 (d, J=7.2 Hz, 1H), 3.29 (s, 3H), 3.00 (d, J=4.8 Hz, 3H), 2.62 (s, 3H), 1.55˜1.50 (m, 1H), 0.66˜0.60 (m, 4H). MS (M+H)+: 670.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[N:11][C:12]1[CH:17]=[C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])[CH:15]=[CH:14][C:13]=1[OH:26])([O-])=O.NCCNCCN>C1(C)C(C)=CC=CC=1>[OH:26][C:13]1[CH:14]=[CH:15][C:16]([C:18]([CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:19])=[CH:17][C:12]=1[N:11]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[N:1]1
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Agent: NCCNCCN
Solvent: Cc1ccccc1C
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(-n2nc3ccccc3n2)c1
Yield: 92 %

Procedure:
Example 1 is repeated, except that an equivalent amount of 2-nitro-2'-hydroxy-5'-tert.-octylazobenzene (93% pure) is used instead of 2-nitro-2'-hydroxy-5'-methylazobenzene and a mixture of 60 g of xylene and 40 g of diethylenetriamine instead of 80 g of xylene and 20 g of diethylenetriamine. The hydrogenation is carried out at 45° C. The title product is isolated in a yield of 92% of theory. Melting point: 101°-103° C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([OH:15])[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH:21]=1.O>CN(C=O)C>[CH:1]1([CH2:7][CH:8]([O:15][CH2:19][C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])[CH:21]=2)[CH2:9][O:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(CI)cc1-c1ccccc1C
Reactant: CCCCOC[C@@H](O)CC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOCC(CC1CCCCC1)OCc1ccc(C(=O)OC)c(-c2ccccc2C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62 %

Procedure:
To a solution of (S)-3-cyclohexyl-1-butoxy-2-propanol (example 1308D, 1.0 g) in DMF (15 mL) was added NaH (0.184 g of a 60% oil dispersion). After 15 min, the reaction was chilled to 0° C., and 4-iodomethyl-2-(2-methylphenyl)benzoic acid, methyl ester (example 1308E, 1.54 g) was added. After 45 min, the reaction was poured into water (150 mL), and extracted with EtOAc (2×75 mL). The organic extracts were washed with brine (20 mL), dried (MgSO4), filtered and concentrated. The residue was purified by silica gel chromatography eluting with 5% EtOAc/hexane to give a colorless oil (1.18 g, 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12][CH3:13])=[CH:7][C:4]=1[C:5]#[N:6].C1C(=O)N([Br:21])C(=O)C1>>[Br:21][CH2:11][C:9]1[C:8]([O:12][CH3:13])=[CH:7][C:4]([C:5]#[N:6])=[C:3]([O:2][CH3:1])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C#N)c(OC)cc1C
Product: COc1cc(CBr)c(OC)cc1C#N

Procedure:
2,5-Dimethoxy-4-methylbenzonitrile (4.06 g, 21.5 mmol) is brominates with NBS according to Example 1A to give 4-bromomethyl-2,5-dimethoxybenzonitrile. 1H NMR (400 MHz, CDCl3) δ (ppm) 6.95 (s, 1H), 6.91 (s, 1H), 4.43 (s, 2H), 3.84 (s, 3H), 3.80 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:20])[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[N:6][CH:5]=1.[BH4-].[Na+]>CO>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:20])[CH2:11][NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)CNC(=O)OC(C)(C)C)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(C(O)CNC(=O)OC(C)(C)C)nc1
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
6-(2-tert-Butoxycarbonylamino-acetyl)-nicotinic acid methyl ester (132.7 mg, 0.451 mmol) was dissolved into 3 mL of MeOH. To this was added sodium borohydride (18.96 mg, 0.50 mmol) in one portion. After 0.5 h, the reaction mixture was concentrated on a rotary evaporator. The residue was dissolved into 20 mL of EtOAc. The organic phase was washed with 2×20 mL NH4Cl and 1×20 mL of brine, dried (MgSO4) filtered and concentrated to give 133 mg, 99.5% of 6-(2-tert-butoxycarbonylamino-1-hydroxy-ethyl)-nicotinic acid methyl ester.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[N:5]1([CH2:17][CH:18]=[O:19])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[O:16][CH:15]=[CH:14][C:12]3=2)[CH:7]=[N:6]1.[Cl-].[NH4+]>O1CCCC1>[N:5]1([CH2:17][CH:18]([OH:19])[CH2:1][CH3:2])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]3[O:16][CH:15]=[CH:14][C:12]3=2)[CH:7]=[N:6]1
Reactant: CC[Mg]Br
Reactant: O=CCn1ncc2ccc3occc3c21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)Cn1ncc2ccc3occc3c21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under argon atmosphere, 5 ml of 1.0 M tetrahydrofuran solution of ethylmagnesium bromide was diluted with 5 ml of tetrahydrofuran, a tetrahydrofuran (5 ml) solution of 0.30 g of (1H-furo[2,3-g]indazol-1-yl)acetaldehyde was added dropwise, and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into ammonium chloride aqueous solution and extracted with ethyl acetate. The organic layers were combined, washed with brine and then dried with anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by a silica gel column chromatography to give 0.29 g of 1-(1H-furo[2,3-g]indazol-1-yl)-2-butanol.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:28])[CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[N:26][N:25]=[N:24]3)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:29]1([S:39](Cl)(=[O:41])=[O:40])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.O>C(Cl)Cl>[N:23]1([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH2:15][C:14]([N:11]3[CH2:10][CH2:9][N:8]([S:39]([C:29]4[C:38]5[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=5)[CH:32]=[CH:31][CH:30]=4)(=[O:41])=[O:40])[CH2:13][CH2:12]3)=[O:28])=[CH:22][CH:21]=2)[CH:27]=[N:26][N:25]=[N:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)COc2ccc(-n3cnnn3)cc2)CC1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Solvent: ClCCl
Solvent: O
Product: O=C(COc1ccc(-n2cnnn2)cc1)N1CCN(S(=O)(=O)c2cccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
In a two neck round bottom flask, 2-(4-(1H-tetrazol-1-yl)phenoxy)-1-(piperazine-1-yl)ethanone hydrochloride (compound 3, 0.882 mmoles, 0.286 g, 1 eq) and 1-naphthalene sulfonylchloride (0.882 mmoles, 0.2 g, 1 eq) were charged in DCM (20 mL). TEA (2.646 moles, 0.267 g, 3 eq) was added drop wise to the reaction mixture over a period of 10 min at 0° C. The resulting mixture was stirred for 3 h at room temperature and monitored by TLC. After completion of the reaction, water (10 mL) was added and extracted with DCM (2×20 mL). The combined organic layers were washed with brine (1×20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (Silica gel 60-120, 3:7, Ethyl acetate/Hexane) to obtain the title compound (0.300 g, 71.09%) as off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][NH:10][C:9]2=O)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:9]1[C:8]2[C:13](=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][CH:7]=2)[N:12]=[CH:11][N:10]=1
Reactant: O=c1[nH]cnc2c([N+](=O)[O-])cccc12
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc2c(Cl)ncnc12

Procedure:
A solution of 8-nitroquinazolin-4(3H)-one (Intermediate-7, step-1, 300 mg, 1.57 mmol) in POCl3 (3 mL) was heated at reflux for 2 h. Then the reaction mixture was concentrated and dried to afford 4-chloro-8-nitroquinazoline which was used for the next step without further purification. Then NaH (263 mg, 11.54 mmol, 95%) was added to EtOH (2 mL) at 0° C. and stirred at that temperature for 15 minutes before it was added to a solution of 4-chloro-8-nitroquinazoline in THF (2 mL) at 0° C. Then the reaction mixture was stirred at rt for 4 h. Then the reaction mixture was quenched with water and was extracted with EtOAc. The organic layer was washed with brine, separated, dried, filtered and concentrated. The residue was purified by column chromatography to afford 200 mg of the title product. MS (m/z): 220.23 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:27][Li]>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([NH:13][C:14]2[C:15]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])=[CH:8][CH:9]=1)([CH3:27])[CH3:2]
Reactant: [Li]C
Reactant: CC(=O)c1ccc(CC(=O)Nc2cccnc2Oc2cccnc2)cc1
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(CC(=O)Nc2cccnc2Oc2cccnc2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-Acetyl-phenyl)-N-[2-(pyridin-3-yloxy)-pyridin-3-yl]-acetamide (0.130 grams, 0.374 mmole) in tetrahydrofuran (10 ml) at −78° C. 1.0 M methyl lithium in tetrahydrofuran (1.123 ml, 1.123 mmole) was added and stirred at −78° C. for 30 minutes, allowed to warm to room temperature for 30 minutes and cooled to −78° C. The mixture was quenched with water and extracted with ethyl acetate. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated to a product which was purified by chromatography on silica eluting with 3% methanol/methylene chloride. Recrystalization from ethyl acetate/hexane gave a solid (0.045 g). M.P. 122-124° C.; Anal. calcd. for C21H21N3O3: C, 69.41; H, 5.82; N, 11.50. Found: C, 69.02; H, 6.12; N, 11.30.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.OS(O)(=O)=O.[CH3:18]O>O>[CH3:18][O:11][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)=[O:12]
Reactant: CO
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1n[nH]c2ccccc12
Temperature: 80 °C

Procedure:
To indazole-3-carboxylic acid (40 g, 247 mmol) suspended in methanol (700 mL) was added concentrated H2SO4 (10 mL) slowly while stirring the mixture. The mixture was stirred and refluxed at 80° C. for 24 h. The mixture was cooled, filtered, and concentrated under reduced pressure to afford a pale yellow solid. The solid was suspended in water (700 mL), crushed to fine powder, collected by filtration, and rinsed with water (˜400 mL). The product was suspended in toluene, and evaporated to dryness under reduced pressure, affording indazole-3-carboxylic acid methyl ester as a pale yellow solid (45 g, >95% pure). (m/z): [M+H]+ calcd for C9H8N2O2 177.07; found, 177.0. 1H-NMR (CD3OD, 300 MHz): δ (ppm) 8.0 (1H, d), 7.5 (1H, d), 7.4 (1H, t), 7.2 (1H, t), 3.9 (3H, s).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([CH:9]1[C:14](=[O:15])[O:13][C:12]([CH3:17])(C)OC1=O)=[O:8])=[N+:2]=[N-:3].OCC[C:22]#[N:23].C(=O)=O>ClCl>[C:22]([CH2:17][CH2:12][O:13][C:14](=[O:15])[CH2:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])#[N:23]
Reactant: CC1(C)OC(=O)C(C(=O)CCCN=[N+]=[N-])C(=O)O1
Reactant: N#CCCO
Agent: ClCl
Agent: O=C=O
Product: N#CCCOC(=O)CC(=O)CCCN=[N+]=[N-]

Procedure:
5-(4-Azidobutanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was heated with 3-hydroxypropionitrile (5.25 g, 72.0 mmol) at 80° C. until no more CO2 was released. The reaction mixture was diluted with CH2 Cl2 (100 ml), washed with water (100 ml) and brine (100 ml). After drying and evaporation of solvent, the product was purified by chromatography (SiO2, CHCl3 :MeOH=95:5), 4-azidobutanoylacetic acid 2-cyanoethyl ester was obtained as a yellowish oil (2.86 g, 53.2%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1.S(Cl)([Cl:32])=O>N1C=CC=CC=1.C(Cl)(Cl)Cl.O>[Cl:32][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH2:13][CH2:14][O:15][C:16]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=4)=[CH:19][C:17]=3[CH:18]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CO)cc2)CCO3)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CCl)cc2)CCO3)cc1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a solution of N-(4-hydroxymethylphenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (412 mg, 1.07 mmol) and pyridine (1 drop) in chloroform (5 ml) was dropwise added thionyl chloride (0.14 ml, 1.61 mmol), and the mixture was stirred for 2 hours. The mixture was diluted with water and extracted with chloroform. The extract was washed with saturated sodium chloride solution and dried with magnesium sulfate. The solvent was evaporated, and the resulting powder was washed with hexane-ethyl acetate (1:1) to give N-(4-chloromethyl-phenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (380 mg, 88%) as colorless powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].CS(C)=O.C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH3:1][C:2]1[N:3]([S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH:4]=[CH:5][C:6]=1[CH:7]=[O:8]
Reactant: Cc1c(CO)ccn1S(=O)(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(C=O)ccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 83.7 %

Procedure:
To a mixture of [2-methyl-1-(phenylsulfonyl)-1H-pyrrol-3-yl]methanol (6.35 g), dimethyl sulfoxide (50 mL) and triethylamine (25 mL) was added sulfur trioxide•pyridine complex (4.57 g), and the mixture was stirred at room temperature for 12 hr. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give a white title compound (yield 5.27 g, 84%).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:12]N1C(=O)CCC1=O.O>O1CCCC1>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]2[C:10]([Cl:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1c(Br)cnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Br)cnc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 96.9 %

Procedure:
The compound obtained in Step 3 of Example 36 (323 mg) was dissolved in tetrahydrofuran (6 ml). N-Chlorosuccinimide (225 mg) was added and the mixture was stirred at room temperature for three days. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated to give the title compound (364 mg).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CO.[OH-].[Na+]>[C:5]1([CH2:4][CH2:3][O:2][C:8]2[CH:9]=[CH:10][C:5]([C:4](=[O:11])[C:3]([OH:2])=[O:12])=[CH:6][CH:7]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C(=O)c1ccc(OCCc2ccccc2)cc1
Yield: 112.4 %

Procedure:
A mixture of 4-[(2-phenylethyl)oxy)]-alpha-oxobenzeneacetic acid methyl ester (0.4 g) in methanol and 0.5N sodium hydroxide (8 mL) was treated as in Example 19 and the crude product was crystallized from benzene-hexane to give 0.37 g of 4-[(2-phenylethyl)oxy]-alpha-oxobenzeneacetic acid as a colorless solid, mp 72°-73° C.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH:11]([CH3:12])[CH:10]=[CH:9][CH:8](OCC)[O:7]1)(=[O:3])[CH3:2].S(Cl)([Cl:18])=O>CCOCC>[C:1]([O:4][CH2:5][CH:6]1[CH:11]([CH3:12])[CH:10]([Cl:18])[CH:9]=[CH:8][O:7]1)(=[O:3])[CH3:2]
Reactant: CCOC1C=CC(C)C(COC(C)=O)O1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: CC(=O)OCC1OC=CC(Cl)C1C
Temperature: 25 °C
Reaction time: 4.75 h

Procedure:
To a solution of 0.113 g. (0.53 mmol) of 3-methyl-6-ethoxy-3,6-dihydro-2H-pyran-2-methanol acetate in 2 ml. of ether at 0° was added 0.12 g. (1.0 mmol) of thionyl chloride. The mixture was stirred at 0° for 1 hour, at room temperature for 4.75 hours and concentrated to give 0.098 g. (103%) of the crude chloroenol-ether as a colorless oil (ca. 70% pure by nmr).
Reaction SMILES: O.[OH-].[Li+].[OH:4][C:5]1([C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=3)[N:16]=2)[CH2:7][CH2:6]1.O.CO>C1COCC1>[OH:4][C:5]1([C:24]2[CH:34]=[CH:33][C:27]([O:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)[CH2:6][CH2:7][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[N:15]([C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=3)[N:16]=2)[CH2:9][CH2:10]1
Reactant: O=C([O-])COc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc(C2(O)CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
Lithium hydroxide monohydrate (177 mg, 4.21 mmol) was added to 2-[4-[4-hydroxy-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetate (380 mg, 0.84 mmol) in a mixture of THF (7 mL), water (3.5 mL) and MeOH (3.5 mL). The resulting mixture was stirred at ambient temperature for 16 hours. The solvents were evaporated, then the residues were suspended in water and acidified to pH 4 with 1M citric acid. The resulting precipitate was collected by filtration, washed with water and dried to afford 2-[4-[4-hydroxy-1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl]phenoxy]acetic acid (297 mg, 81%) as a white solid.
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[CH2:12][N:11]([CH2:31][CH2:32][CH2:33][Cl:34])[C@@H:10]1[CH2:35][O:36]CC1C=CC=CC=1)C1C=CC=CC=1.Cl>C(O)C.[Pd]>[Cl:34][CH2:33][CH2:32][CH2:31][N:11]1[CH2:12][C@H:13]([OH:23])[C@@H:14]([OH:15])[C@H:9]([OH:8])[C@H:10]1[CH2:35][OH:36]
Reactant: ClCCCN1C[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)CN1CCCCl
Reaction time: 32 h
Yield: 83.5 %

Procedure:
To a stirred solution of (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)-2-[(benzyloxy)methyl]-1-(3-chloropropyl)piperidine 4 (30 g, 49.98 mmol) in a mixture of ethanol (1.2 lit) and aqueous solution of HCl (1M, 100 mL) was added 10% Pd/C (3 g) and the mixture was degassed for 20 min using nitrogen. The reaction mixture was then stirred under 50 psi hydrogen pressure for 32 h. The reaction mixture was filtrate through celite, washed with ethanol (3×100 mL) and the filtrate was concentrated under reduced pressure to get crude hydrochloride salt of (2R,3R,4R,5S)-1-(3-chloropropyl)-2-(hydroxymethyl)piperidine-3,4,5-triol 5 (10 g, 83%) as black oil.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[C:23]([CH:27]=1)[C:24](O)=[O:25])(=[O:18])=[O:17]>>[CH3:15][S:16]([C:19]1[CH:20]=[CH:21][C:22]([C:28]2[S:29][CH:30]=[CH:31][N:32]=2)=[C:23]([CH:27]=1)[C:24]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:8]=[CH:9][C:10]([C:11]#[N:12])=[CH:13][CH:14]=2)[CH2:2][CH2:3]1)=[O:25])(=[O:17])=[O:18]
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(-c2nccs2)c(C(=O)N2CCN(c3ccc(C#N)cc3)CC2)c1

Procedure:
The title compound was prepared according to the procedure E described for Example 9 from 4-piperazin-1-yl-benzonitrile [68104-63-2] and 5-Methanesulfonyl-2-thiazol-2-yl-benzoic acid (Example O). MS (ISP): 453.5 MH+.