Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OS(O)(=O)=O.O=S(=O)=O.[O:10]=[C:11]1[O:17][C@H:16]([C@H:18]([CH2:20][OH:21])[OH:19])[C:14]([OH:15])=[C:12]1[OH:13].[CH3:22][C:23]([CH3:25])=O>>[CH3:22][C:23]1([CH3:25])[O:19][C@H:18]([C@H:16]2[O:17][C:11](=[O:10])[C:12]([OH:13])=[C:14]2[OH:15])[CH2:20][O:21]1
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(C)=O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: CC1(C)OC[C@@H]([C@H]2OC(=O)C(O)=C2O)O1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
55 g of 24% strength oleum were added dropwise to 480 ml of acetone (water content about 1.4%) at -10° C. 120 g of L-ascorbic acid were introduced into the resulting mixture at about 0° C., and the reaction mixture was stirred for 6 h at 0° C. It was then cooled to -15° C. and the crystals formed were filtered off under suction. The resulting filter cake was pressed dry, washed with twice 100 ml of ice cold acetone and dried at room temperature under reduced pressure from a water pump.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3][CH:2]=1.CCN(C(C)C)C(C)C.Cl[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:35][C:36]2[CH:41]=[CH:40][C:39]([F:42])=[C:38]([C:43]([F:46])([F:45])[F:44])[CH:37]=2)=[C:31]([CH:34]=1)[C:32]#[N:33]>C(Cl)Cl>[F:42][C:39]1[CH:40]=[CH:41][C:36]([O:35][C:30]2[CH:29]=[CH:28][C:27]([CH2:26][S:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:5]4[CH:6]=[N:1][CH:2]=[N:3][CH:4]=4)[C:9](=[O:15])[N:10]=3)=[CH:34][C:31]=2[C:32]#[N:33])=[CH:37][C:38]=1[C:43]([F:44])([F:45])[F:46]
Reactant: N#Cc1cc(CCl)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Reactant: O=c1[nH]c(=S)[nH]cc1Cc1cncnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cc(CSc2nc(=O)c(Cc3cncnc3)c[nH]2)ccc1Oc1ccc(F)c(C(F)(F)F)c1
Temperature: 60 °C
Yield: 38.4 %

Procedure:
To a suspension of 5-(5-pyrimidinylmethyl)-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (38 mg, 0.173 mmol) and DIPEA (0.079 mL, 0.455 mmol) in DCM (1 mL), was added 5-(chloromethyl)-2-{[4-fluoro-3-(trifluoromethyl)phenyl]oxy}benzonitrile (50 mg, 0.152 mmol). The solution was heated at 60° C. overnight. Purification via MDAP then afforded the title compound (30 mg, 38.5% yield). LCMS: rt=3.14 min, [M+H+]=514
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=O)=[C:5]2[SH:24])[CH2:3][CH2:2]1.[CH:25]1([N:28]2C3C(=CC(F)=C(F)C=3)C(=O)C3C(O)=C(C#N)SC2=3)C[CH2:26]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]3[C:19]([OH:21])=[C:26]([C:25]#[N:28])[S:24][C:5]2=3)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(S)n(C2CC2)c2c(OC)c(F)c(F)cc2c1=O
Reactant: N#Cc1sc2c(c1O)c(=O)c1cc(F)c(F)cc1n2C1CC1
Product: COc1c(F)c(F)cc2c(=O)c3c(O)c(C#N)sc3n(C3CC3)c12

Procedure:
The title compound is prepared from ethyl 1-cyclopropyl-6,7-difluoro-2-mercapto-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (See US 2008071086, which is hereby incorporated by reference for its teachings regarding this and other compounds, see also, Hashimoto, et al., 2007) using a procedure analogous to that describing the preparation of 9-cyclopropyl-6,7-difluoro-3-hydroxyl-4-oxo-4,9-dihydrothieno[2,3-b]quinoline-2-carbonitrile. (Chiba, et al., JP 03-223289) The crude product is purified by recrystallization from DMF to give the title compound as a white solid. 1H NMR: δ 1.04 (m, 2H), 1.27 (m, 2H), 3.90 (m, 1H), 4.02 (d, J=1.5 Hz, 3H), 7.89 (dd, J=10.0 Hz, 8.5 Hz, 1H). 19F NMR: δ −145.0 (d, J=22.5 Hz, 1F), −138.9 (d, J=22.5 Hz, 1F). LCMS (APCI): m/z calcd for C16H10F2N2O3S ([M]+) 348. found 349 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[K+]>O.CS(C)=O>[C:12]1([CH2:11][C:2]([CH3:18])([CH3:1])[C:3](=[O:10])[CH:4]([N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: CC(C)(Cc1ccccc1)C(=O)Cn1cncn1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(Cc1ccccc1)C(=O)C(Cc1ccccc1)n1cncn1
Temperature: 50 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
48.6 g (0.2 mol) of 3,3-dimethyl-4-phenyl-1-(1,2,4-triazol-1-yl)-butan-2-one, 27.9 g (0.22 mol) of benzyl chloride and 12.3 g (0.22 mol) of potassium hydroxide in 15 ml of water are dissolved in 300 ml of dimethylsulphoxide. The reaction mixture is stirred for a further 8 hours at 50° C. and then poured onto water. The mixture is extracted with ethyl acetate. The organic phase is concentrated and the residue is purified by column chromatography (silica gel/ethyl acetate: cyclohexane =3:1). 54.5 g (81.8% of theory) of 1,5-bisphenyl-2,2-dimethyl-4-(1,2,4-triazol-1-yl)-pentan-3-one of melting point 45°-50° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:12][CH3:13])[C:9](N)=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)([CH2:12][CH3:13])[C:9]([OH:21])=[O:10])=[CH:4][CH:3]=1
Reactant: CCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1
Reactant: O=S(=O)(O)O
Product: CCC(Cn1cncn1)(C(=O)O)c1ccc(Cl)cc1
Temperature: 10 °C

Procedure:
To a 500 mL flask was charged 95 g (0.34 mole) of 2-(4-chlorophenyl)-2-[(1,2,4-triazol-1-yl)methyl]butyramide and 95 g (0.97 mole) of 95% sulfuric acid and 95 g of ice. The reaction was stirred at reflux for 55 hours, after which the reaction was cooled to 10° C. and partitioned between ethyl acetate and water. The mixture was treated with 200 g of 10% sodium hydroxide which resulted in a pH 10 aqueous phase. The organic phase was extracted with 200 ml of water, then 200 ml of 10% sodium hydroxide and again with 200 mL of water. The aqueous phases were combined and washed with ethyl ether then acidified to pH 5 at which point a solid formed. The solid was filtered, washed with water, dried and gave 73 g (77% yield) of a white solid, Example 1 of Table 1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:19])[NH:13][NH:14][C:15]=2[CH:16]([CH3:18])[CH3:17])=[C:6]([CH3:20])[CH:5]=1.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>O1CCCC1>[CH2:21]([O:28][C:29]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[C:12](=[O:19])[NH:13][NH:14][C:15]=2[CH:16]([CH3:17])[CH3:18])=[C:6]([CH3:20])[CH:5]=1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: Cc1cc(CCN)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CCNC(=O)OCc2ccccc2)ccc1Cc1c(C(C)C)[nH][nH]c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 4-{[4-(2-aminoethyl)-2-methylphenyl]methyl}-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (0.3 g) in tetrahydrofuran (5 mL) was added N-(benzyloxycarbonyloxy)succinimide (0.33 g), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution twice, water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.34 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1.[CH:25](O)([CH3:27])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([O:19][CH:25]([CH3:27])[CH3:26])=[O:18])(=[O:12])=[O:11])=[C:7]([CH3:23])[C:6]=2[CH:24]=1
Reactant: Cc1c(S(=O)(=O)Nc2cccc(C(=O)O)c2)sc2ccc(Cl)cc12
Reactant: CC(C)O
Product: Cc1c(S(=O)(=O)Nc2cccc(C(=O)OC(C)C)c2)sc2ccc(Cl)cc12
Yield: 57 %

Procedure:
The product was prepared from 3-{[(5-chloro-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (21 mg, 0.055 mmol) (Intermediate 19) and isopropyl alcohol (6.0 mg, 0.100 mmol) according to the General Procedure 7, described in Example 107, using a slightly modified reaction time (2 days). The title compound was obtained in 57% yield (13.3 mg). 1H NMR (500 MHz, CDCl3) δ ppm 1.30 (d, J=6.32 Hz, 6 H) 2.45 (s, 3 H) 5.18 (spt, J=6.32 Hz, 1 H) 6.89 (s, 1 H) 7.35 (dd, J=8.06, 7.65 Hz, 1 H) 7.41 (ddd, J=8.06, 2.35, 1.18 Hz, 1 H) 7.44 (dd, J=8.73, 1.94 Hz, 1 H) 7.68 (dd, J=2.35, 1.50 Hz, 1 H) 7.71 (dd, J=8.73, 0.61 Hz, 1 H) 7.71 (dd, J=1.94, 0.61 Hz, 1 H) 7.83 (ddd, J=7.65, 1.50, 1.18 Hz, 1 H). MS (ESI+) m/z 424 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:19]([OH:20])[C:18]3[CH:17]=[CH:16][N:15]=[C:14](F)[C:13]=3[C:12]2=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>CCN(C(C)C)C(C)C.C(O)CCC>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:19]([OH:20])[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([NH:23][CH2:24][C:25]4[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=4)[C:13]=3[C:12]2=[O:22])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccncc1
Reactant: CC(C)(C)c1ccc(N2C(=O)c3c(ccnc3F)C2O)cc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(N2C(=O)c3c(ccnc3NCc3ccncc3)C2O)cc1
Temperature: 170 °C

Procedure:
A mixture of 2-(4-tert-butyl-phenyl)-4-fluoro-1-hydroxy-1,2-dihydro-pyrrolo[3,4-c]pyridin-3-one (0.11 g, 0.38 mmol, Step B) and 4-(aminomethyl)pyridine (0.070 mL, 0.68 mmol) in 0.70 mL of DIEA and 1.0 ml of BuOH was subjected to microwave heating at 170° C. for 17 min. The volatiles were removed under reduced pressure, and the residue was purified by flash column chromatography (0 to 5% of MeOH in CH2Cl2) to provide the titled compound as an off-white solid. MS (ES+): 389.1 (M+H)+. Calc'd for C23H24N4O2-388.46.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[N:10]([O-])=O.[Na+].O.O.[Sn](Cl)(Cl)(Cl)Cl>O.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][NH2:10])[CH:8]=1
Reactant: O=N[O-]
Reactant: Cc1ccc(Cl)cc1N
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Cl)cc1NN
Reaction time: 0.75 h
Yield: 152.2 %

Procedure:
To a stirred suspension of 5-chloro-2-methylaniline (1.436 g, 10.14 mmol, 1. eq) in 10 mL water at 0° C. was added 10 mL concentrated hydrochloric acid. To this reaction mixture was added dropwise a solution of sodium nitrite (0.791 g, 11.5 mmol, 1.13 eq) in 5 mL water. The reaction mixture was stirred at 0° C. for 2 hours while tin chloride dihydrate (5.8826 g, 25.839 mmol, 2.55 eq), dissolved in 8 mL concentrated hydrochloric acid, was slowly added. Water was added as needed to maintain the stirring while solids formed. The reaction was kept at 0° C. for 45 minutes. The white solids were filtered and rinsed with two 50 mL portions of diethyl ether, then dried under vacuum to provide 1.49 g (76%) of (5-chloro-2-methylphenyl)hydrazine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 10.08 (s, 3H), 7.98 (s, 1H), 7.13 (d, 1H), 6.97 (s, 1H), 6.91 (d, 1H), 2.14 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:24]=[N:25][C:26](Cl)=[C:27]([Br:29])[CH:28]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.[CH3:31][OH:32]>C[O-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([C:23]3[CH:24]=[N:25][C:26]([O:32][CH3:31])=[C:27]([Br:29])[CH:28]=3)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2cnc(Cl)c(Br)c2)CC1)c1ccc(F)cc1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Product: COc1ncc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)N[C@H](C)c3ccc(F)cc3)CC2)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-4-(5-Bromo-6-chloro-pyridine-3-sulfonylamino)-cyclohexanecarboxylic acid [(R)-1-(4-fluoro-phenyl)-ethyl]-amide (Example 144, 484 mg, 0.933 mmol) was dissolved in a solution of NaOMe in MeOH (0.5M, 28 ml, 13.99 mmol). The reaction mixture was stirred overnight at room temperature. LCMS indicated that the reaction was complete and it was concentrated in vacuo then taken up in EtOAc and purified via column chromatography using a biotage SP1, 40+M column, with 50% EtOAc in heptane as calculated gradient to yield the title compound as a white solid (313 mg, 65%). [M+H]=516.0
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([C:10]#[N:11])=[C:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.[N+]([CH3:16])([O-])=O.N12CCCN=C1CCCCC2>C(#N)C>[CH3:1][O:2][C:3]([C:4]1([C:10]#[N:11])[C:5]2([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:16]1)=[O:12]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)C(C#N)=C1CCCC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1(C#N)CC12CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62 %

Procedure:
To a solution of cyano-cyclopentylidene-acetic acid methyl ester (20.8 g, 126 mmol), in acetonitrile (500 mL) was added nitromethane (34 mL, 630 mmol, 5 eq) followed by dropwise addition of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (18.8 mL, 126 mmol). The reaction solution turned orange upon the addition of DBU. The reaction mixture was stirred at room temperature for 16 hours. Another portion of DBU (1 mL) was added and stirred for 1 hour. The reaction mixture was partitioned between ether (1 L) and 1N HCl (400 mL) and the layers separated. The organic layer was washed with 1N HCl (2×300 mL), brine (2×200 mL), dried over sodium sulfate, filtered and evaporated. The residue was chromatographed on a wet-packed silica gel column eluting with 4-6% ethyl acetate/hexanes. The appropriate fractions were combined and evaporated to furnish 14.0 g (62%) of 1-cyano-spiro[2.4]heptane-1-carboxylic acid methyl ester as a clear oil: 1H NMR (300 MHz, CDCl3) δ 1.64 (d, J=5.0 Hz, 1H), 1.70-1.88 (m, 7H), 2.14 (d, J=5.0 Hz, 1H), 2.1-2.19 (m, 1H), 3.82 (s, 3H); MS (APCI) m/z 180 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18]C)[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=2)=[N:10]1.[Cl:29]N1C(=O)CCC1=O.O>CN(C=O)C>[Cl:29][C:16]1[C:17]2[N:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=3[F:8])[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[C:12]=2[C:13](=[O:18])[NH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2-c1c(F)cccc1F
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(-c2nn(-c3c(F)cccc3F)c3c(Cl)c[nH]c(=O)c23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
To a solution of (4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (322.3 mg) obtained in Step A of Example 39 in DMF (10 mL) was added N-chlorosuccinimide (252 mg) at 0° C., and the mixture was allowed to be warmed to room temperature, and stirred for 1 day, and then at 100° C. for 1 day, and cooled to room temperature. The reaction mixture was added to water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/hexane/methanol) to give the title compound (156 mg).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[Cl:34]N1C(=O)CCC1=O>O1CCCC1.C(OCC)(=O)C>[Cl:34][C:22]1[CH:23]=[C:24]([C:26]2[S:27][C:28]([CH:31]([OH:33])[CH3:32])=[CH:29][N:30]=2)[NH:25][C:21]=1[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([S:4]([CH:1]2[CH2:3][CH2:2]2)(=[O:5])=[O:6])=[CH:8][CH:9]=1)[CH2:14][CH:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(O)c1cnc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)c1cnc(-c2cc(Cl)c(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)s1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[2-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)-1,3-thiazol-5-yl]ethanol (300 mg) in tetrahydrofuran (5 mL) was added N-chlorosuccinimide (82.3 mg) at 0° C., and the mixture was stirred at 50° C. overnight. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate, and washed with saturated aqueous sodium hydrogen carbonate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give a mixture of the title compound and a positional isomer thereof (210 mg). The mixture of the obtained positional isomers was dissolved in hexane-2-propanol (700:300, volume ratio, 18.8 mL), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRY LTD.). Using hexane-2-propanol (700:300, volume ratio) as a mobile phase, the solution was eluted at flow rate 60 mL/min and at 30° C., and the fraction was separated at retention time 22.0 min, and concentrated. The obtained solid was dissolved in ethyl acetate and the insoluble material was filtered off. The filtration was concentrated to give the title compound (85.9 mg, yield 27%) as a colorless amorphous solid. MS: 521 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[H-].[Na+].[Cl:11][C:12]1[CH:17]=[C:16]([N+]([O-])=O)[CH:15]=[CH:14][N:13]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([O:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:15]=[CH:14][N:13]=1
Reactant: Oc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: Clc1cc(Oc2ccccc2Cl)ccn1
Yield: 64.7 %

Procedure:
Using the method of Example 3, Step A, 2-chlorophenol (811 mg, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol), and 2-chloro-4-nitropyridine (1.00 g, 6.31 mmol) were reacted to provide 2-chloro-4-(2-chlorophenoxy)pyridine (0.98 g, 95% yield) as an oil. 1H NMR (CDCl3) δ 8.25 (d, 1H), 7.52 (d, 1H), 7.36 (t, 1H), 7.28 (t, 1H), 7.17 (d, 1H), 6.74-6.77 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([O:13]C3C=CC=CC=3)=[O:12])[C:5]=2[C:4]2([C:31]3[C:22](=[CH:23][C:24]4[O:29][CH2:28][CH2:27][O:26][C:25]=4[CH:30]=3)[O:21][CH2:20]2)[C:3]1=[O:32].O.[OH-].[Li+]>O1CCCC1.O>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]([OH:13])=[O:12])[C:5]=2[C:4]2([C:31]3[C:22](=[CH:23][C:24]4[O:29][CH2:28][CH2:27][O:26][C:25]=4[CH:30]=3)[O:21][CH2:20]2)[C:3]1=[O:32]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)Oc3ccccc3)cccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(C(=O)O)cccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
To a solution of phenyl 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylate (2.00 g, 4.65 mmol) in tetrahydrofuran (50 mL) and water (10 mL) was added lithium hydroxide monohydrate (1.00 g, 23.8 mmol) at ambient temperature. The reaction mixture was stirred at ambient temperature for 18 h and concentrated in vacuo. The residue was neutralized to pH 4-5 with 10% w/v hydrochloric acid. The resultant precipitate was filtered and washed with diethyl ether to afford 1′-methyl-2′-oxo-1′,2,2′,3-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indole]-4′-carboxylic acid (1.40 g, 85%): mp 297-299° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.54-7.43 (m, 3H), 7.32-7.28 (m, 1H), 6.31 (s, 1H), 6.03 (s, 1H), 4.77 (ABq, 2H), 4.12-4.02 (m, 4H), 3.15 (s, 3H); MS (ES+) m/z 376.0 (M+23).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][CH2:21][CH2:22][CH3:23])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[CH:40][C:36]=1[C:37](Cl)=O>C(Cl)Cl>[CH3:33][O:34][C:35]1[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=[CH:40][C:36]=1[CH2:37][NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([NH:13][C:14]2[C:17](=[O:18])[C:16](=[O:19])[C:15]=2[NH:20][CH2:21][CH2:22][CH3:23])[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCCNc1c(N[C@@H](Cc2ccc(N)cc2)C(=O)O)c(=O)c1=O
Reactant: COc1ccc(C(=O)Cl)c(OC)c1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCNc1c(N[C@@H](Cc2ccc(NCc3ccc(OC)c(OC)c3OC)cc2)C(=O)O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.3 %

Procedure:
To the derivatised resin (5), (120 mg) was added DCM (5 ml), DIPEA (0.1 ml, 0.6 mmol) and 2,3,4-trimethoxybenzoyl chloride (138 mg, 0.6 mmol). The solution was agitated for 12 h at RT then filtered and washed thoroughly with DCM. The resin was treated with 60% trifluoroacetic acid in DCM (1.5 ml) for 3 h with agitation and then filtered. The filtrate was evaporated in vacuo to give the crude product which was purified by preparative HPLC to afford the title compound (0.5 mg).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12](=O)[N:11]2[CH:16]=[CH:17][NH:18][C:10]=12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][C:12]1[N:11]2[CH:16]=[CH:17][N:18]=[C:10]2[C:9]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:14][CH:13]=1
Reactant: O=C(c1ccccc1)c1ccc(=O)n2cc[nH]c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccc(Cl)n2ccnc12
Yield: 87.5 %

Procedure:
1.0 g (4.20 mmol) of 8-Benzoylimidazo[1,2-a]pyridin-5(1H)-one (example L, step 2) and 20.0 g (130.44 mmol) of phosphoric trichloride are dissolved in 20 ml toluene and refluxed for 1 h. The solvent is evaporated under vacuum; the crude is dissolved in 200 ml ethyl acetate and extracted with 100 ml saturated sodium hydrogen carbonate solution and 100 ml water. The organic phase is dried over magnesium sulfate, filtrated and concentrated. Petrolether is added to the residue and the precipitate is filtrated to yield 943 mg (87.5% of th.) (5-Chloroimidazo[1,2-a]-pyridin-8-yl)(phenyl)methanone.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([Cl:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:25])[NH:7][C:6]=2[CH:5]=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O>CC#N.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>[Cl:23][C:22]1[C:17]([N:14]2[CH2:15][CH2:16][N:11]([C:8]3[NH:9][C:10]4[C:2]([C:35]5[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=5)=[CH:3][C:4]([C:26]([F:28])([F:27])[F:29])=[CH:5][C:6]=4[N:7]=3)[C@H:12]([CH3:25])[CH2:13]2)=[N:18][CH:19]=[C:20]([Cl:24])[CH:21]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2c(Br)cc(C(F)(F)F)cc2[nH]1
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: CC#N
Solvent: O
Product: C[C@@H]1CN(c2ncc(Cl)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)c2[nH]1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of 4-bromo-2-[(2R)-4-(3,5-dichloro-pyridin-2-yl)-2-methyl-piperazin-1-yl]-6-trifluoromethyl-1H-benzoimidazole (204 mg, 0.4 mmol, Example 149b), 4-trifluoromethylphenylboronic acid (152 mg, 0.8 mmol, Aldrich), Pd(PPh3)4 (46 mg, 0.04 mmol, Aldrich) and Na2CO3 (2 mL, 0.8 mmol, 0.4 M in H2O) in MeCN (4 mL) was heated at 90° C. with stirring for 16 h. Water (10 mL) was added and the mixture was extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% EtOAc/hexane to give the title compound. MS (ESI, pos. ion) m/z: 574 (M+1).