Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([F:14])([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10](N)=[O:11])=[CH:5][CH:4]=1.S(=O)(=O)(O)[OH:16]>>[Cl:1][C:2]([F:14])([F:13])[C:3]1[NH:8][C:7](=[O:9])[C:6]([C:10]([OH:16])=[O:11])=[CH:5][CH:4]=1
Reactant: NC(=O)c1ccc(C(F)(F)Cl)[nH]c1=O
Reactant: O=S(=O)(O)O
Product: O=C(O)c1ccc(C(F)(F)Cl)[nH]c1=O
Temperature: 0 °C

Procedure:
11.0 g (49.4 mmol) of 6-[chloro(difluoro)methyl]-2-oxo-1,2-dihydropyridine-3-carboxamide were heated in 77 ml of 50% strength sulfuric acid. The mixture was then added to ice water, and the precipitate was filtered off with suction and dried. This gave 7.2 g (65% of theory) of a yellowish powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[C:22]2[N:21]=[C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:24])[CH:19]=[N:18][C:17]=2[C:16]([C:30]([OH:32])=O)=[CH:15][CH:14]=1.[NH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1>C(Cl)Cl.CO>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([NH:33][C:30]([C:16]2[C:17]3[N:18]=[CH:19][C:20]([N:23]([CH2:25][CH2:26][N:27]([CH3:28])[CH3:29])[CH3:24])=[N:21][C:22]=3[C:13]([C:3]3[C:2]([Cl:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=3[Cl:12])=[CH:14][CH:15]=2)=[O:32])[CH:35]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)O)c3ncc(N(C)CCN(C)C)nc23)c1Cl
Reactant: Nc1cccnc1
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(Cl)c(-c2ccc(C(=O)Nc3cccnc3)c3ncc(N(C)CCN(C)C)nc23)c1Cl

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-dichloro-3,5-dimethoxy-phenyl)-2-[(2-dimethylamino-ethyl)-methyl-amino]-quinoxaline-5-carboxylic acid (Step 85.1) and 3-aminopyridine. Title compound: ESI-MS: 555.0/557.2 [M+H]+; tR=3.16 min (System 1); TLC: Rf=0.20 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.[P:19]([O:26]CC)([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22]>CN(C=O)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][P:19](=[O:26])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[CH:4][CH:5]=2)=[O:10])=[CH:12][CH:13]=1
Reactant: CCOP(OCC)OCC
Reactant: COc1ccc(C(=O)c2ccc(CBr)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(C(=O)c2ccc(OC)cc2)cc1)OCC
Temperature: 150 °C
Reaction time: 10 h
Yield: 72 %

Procedure:
(4-(bromomethyl)phenyl)(4-methoxyphenyl)methanone, 32-c, (3 g, 10 mmol) and triethyl phosphite (2 g, 11.9 mmol) was dissolved in DMF (20 ml), and then stirred for 10 h at 150° C. The resulting mixture was cooled to ambient temperature, diluted with water (50 ml) and extracted with ethyl acetate (3×50 ml). The organic layer was combined, washed with brine (2×100 ml), dried over Na2SO4 anhydrous, purified by chromatography on silica gel (petroleum ether/ethyl acetate=1:1.5). The pure product, 32-d, was obtained as a colorless oil (2.6 g, 72% yield). 1H NMR (300 MHz, CDCl3) δ 1.20-1.27 (m, 6H), 2.80-2.88 (d, J=22.8, 2H) 3.81 (s, 3H), 3.93-4.07 (m, 4H), 6.86-6.90 (m, 2H), 7.31-7.35 (m, 2H), 7.62-7.93 (m, 4H). LC-MS 363 [MH]+.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[CH2:25]O)[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:30])=O.[Na+].[Cl-]>ClCCl.CN(C=O)C>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[CH2:25][Cl:30])[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cc2cc(C(F)(F)F)ccc2CO)c2cccnc21
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(Cc2cc(C(F)(F)F)ccc2CCl)c2cccnc21
Reaction time: 3 h
Yield: 73.9 %

Procedure:
To a solution of 15 (3.5 g, 10.4 mmol) in dichloromethane (20 mL) was charged DMF (0.04 mL, 0.5 mmol). This solution was cooled under an ice bath. Thionyl chloride (0.85 mL, 11.5 mmol) was then added under 5° C., and the resulting reaction was aged for 3 h at this temperature. Once the reaction was complete, 5% aqueous NaCl (16.5 mL) was added. The organic layer was separated and washed with 5% aqueous NaCl (16.5 mL). The solvent was removed via rotovap, and the crude was purified by silica gel column chromatography (0 to 10% AcOEt/hexane) to give the desired compound 16 as an oil (3.05 g, 74%). 1H NMR (CDCl3, 500 MHz): δ 8.20 (dd, J=5.1, 1.7 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.51 (dd, J=8.1, 1.1 Hz, 1H), 7.18 (s, 1H), 7.12 (dd, J=6.3, 2.7 Hz, 1H), 6.88 (dd, J=7.3, 5.1 Hz, 1H), 4.77 (ABq, J=12.9 Hz, 2H), 3.72 (m, 1H), 3.46 (dd, J=14.2, 4.4, 1H), 3.18 (dd, J=14.2, 8.7 Hz, 1H), 1.67 (s, 9H); 13C NMR (CDCl3, 125 MHz): δ 177.6, 159.1, 146.5, 143.3, 136.6, 131.0, 129.7 (m, 2C), 124.0, 123.0, 123.9 (q, J=271 Hz), 117.4, 126.6, 62.4, 58.8, 46.1, 32.9, 28.6.
Reaction SMILES: [ClH:1].CCOC(C)=O.[N:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:10][CH:9]=1.[H][H]>[Pt]=O.C(O)C>[ClH:1].[NH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:12][CH2:13]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCC(/C=C/c2ccncc2)CC1
Agent: O=[Pt]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CCC2CCNCC2)CC1

Procedure:
A 4 M hydrogen chloride/EtOAc solution (0.88 ml) and platinum oxide (100 mg) were added to an ethanol (25 ml) solution of tert-butyl 4-[(E)-2-pyridin-4-ylvinyl]piperidine-1-carboxylate (1.02 g), followed by stirring in the presence of hydrogen (3.5 atm) for 24 hours. This was purged with argon, diluted with methanol, filtered through Celite, and concentrated under reduced pressure. The solid precipitated was washed with EtOAc/hexane, and dried under reduced pressure to obtain tert-butyl 4-(2-piperidin-4-ylethyl)piperidine-1-carboxylate hydrochloride (850 mg) as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:39])[C@@H:4]([NH:28][C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30])[CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[OH-].[Na+].FC(F)(F)C(O)=O>CO>[CH2:32]([O:31][C:29]([NH:28][C@@H:4]([CH2:5][NH:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22]3[NH:23][CH2:24][CH2:25][CH2:26][N:27]=3)[CH:16]=2)[CH2:11][CH2:10]1)=[O:8])[C:3]([OH:39])=[O:2])=[O:30])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)[C@H](CNC(=O)N1CCN(c2cccc(NC3=NCCCN3)c2)CC1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H](CNC(=O)N1CCN(c2cccc(NC3=NCCCN3)c2)CC1)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of Example 144 in methanol (5 ml) is added 2M aqueous sodium hydroxide solution (5 ml), and the mixture is stirred at 25° C. overnight. The reaction solution is neutralized with trifluoroacetic acid, and purified by CHP-20 (eluent: gradient, 35% to 100% methanol/0.05% aqueous trifluoroacetic acid solution) to give the title compound (8 mg).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:7]=O)=[CH:5][N:6]=1.N1C=CC=CC=1.C(O)(=O)[CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O>N1C=CC=CC=1.O>[CH3:1][C:2]1[S:3][C:4]([CH:7]=[CH:16][C:17]([OH:19])=[O:18])=[CH:5][N:6]=1
Reactant: Cc1ncc(C=O)s1
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: c1ccncc1
Product: Cc1ncc(C=CC(=O)O)s1
Temperature: 25 °C
Yield: 72 %

Procedure:
A mixture of 29 g of 2-methyl-5-thiazolecarboxaldehyde, 30 ml of pyridine, 29 g of malonic acid and 30 drops of pyridine was heated at 100°-110° C. for 5 hours and after cooling to room temperature, the mixture was poured into 500 ml of water. The pH of the solution was adjusted to 3 by addition of N sulfuric acid and the precipitate formed was recovered by vacuum filtration and was dried to obtain 27.8 g of 3-(2-methyl-5-thiazolyl)-2-propenoic acid which were crystallized from 10% aqueous ethanol to obtain 23.8 g of the said product melting at 204° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]=[C:9]([CH2:13][C:14](O)=[O:15])[C:10]([OH:12])=[O:11].[OH-].[Na+]>O>[O:15]=[C:14]1[N:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH:9]([C:10]([OH:12])=[O:11])[CH2:13]1
Reactant: C=C(CC(=O)O)C(=O)O
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CC(=O)N(c2ccccc2)C1
Temperature: 110 °C
Yield: 97.2 %

Procedure:
A mixture of aniline (3.26 g; 34.68 mmol) and 2-methylenesuccinic acid (5.47 g; 41.62 mmol) in water (10 ml) was heated in a sealed tube at 110° C. for 30 hours. After cooling to room temperature, 6N NaOH (13 mL) was added and the resulting precipitate was filtered off. The filtrate was acidified with 6N hydrochloric acid to pH 1 and the resulting precipitate was filtered, washed with water, and dried to yield 6.92 g (97%) of 5-oxo-1-phenypyrrolidine-3-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH3:13])[C:3](=O)[CH2:4][C:5](=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C1C=CC=CC=1.[CH3:21][C:22]([N:25]1[C:29]([NH2:30])=[CH:28][C:27]([CH3:31])=[N:26]1)([CH3:24])[CH3:23]>C(O)(=O)C>[CH3:24][C:22]([N:25]1[C:29]2[N:30]=[C:3]([C:2]([CH3:14])([CH3:13])[CH3:1])[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:28]=2[C:27]([CH3:31])=[N:26]1)([CH3:21])[CH3:23]
Reactant: CCOC(=O)C(=O)CC(=O)C(C)(C)C
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C(C)(C)C)nc2c1c(C)nn2C(C)(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 5,5-dimethyl-2,4-dioxohexanoate (392 mg, 1.958 mmol), benzene (10 mL), 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-amine (300 mg, 1.958 mmol), and acetic acid (2 mL). The crude product was purified by column chromatography (Silica gel, eluent: 0 to 100% EtOAc/hexanes) to give 530 mg (85%) of product. LCMS E-S (M+H)=318.3. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.43-1.52 (m, 12 H), 1.84 (s, 9 H), 2.67 (s, 3 H), 4.50 (q, J=7.07 Hz, 2 H), 7.59 (s, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C@H:12]4[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]4[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[Cl:32]>>[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[CH:3]=[C:4]3[C:9]4=[C:10]([C@H:12]5[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:15][CH2:14][C@H:13]5[N:8]4[CH2:7][CH2:6][CH2:5]3)[CH:11]=2)[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CCC3
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)c(Cl)c3)cc3c1N2CCC3

Procedure:
The title compound was prepared by the method of Example 109 from tert-butyl (±)-cis-2-bromo-5,6,8,9,11,11a-hexahydro-4H-pyrido[3′,4′:4,5]pyrrolo[3,2,1-ij]quinoline-10(7aH)-carboxylate (101.7 mg, 0.26 mmol) and 3,4-dichlorophenylboronic acid (97 mg, 0.52 mmol), after chromatographic purification (91.6 mg, 77%) as a white amorphous solid. 1H NMR (CDCl3, 300 MHz) δ7.57 (d, 1H, J=1.8 Hz), 7.42 (d, 1 H, J=8.4 Hz), 7.31 (dd, 1H, J=2.2, 8.4 Hz), 7.12 (bs, 1H), 7.07 (bs, 1H), 3.62-3.75 (m, 1H), 3.48-60 (m, 1H), 3.15-3.35 (m, 4H), 2.65-2.80 (m, 4H), 2.10-2.20 (m, 2H), 1.85-2.00 (m, 2H), 1.46 (s, 9H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([NH2:13])[CH:7]=1.C([O:17][C:18](=O)[CH:19]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:20](=O)[CH2:21][CH3:22])C.O1CCOCC1.C([O-])(=O)C.[Na+]>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]2[C:7]=1[C:18](=[O:17])[C:19]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=1)=[C:20]([CH2:21][CH3:22])[NH:13]2
Reactant: CCOC(=O)C(Cc1ccc(S(C)(=O)=O)cc1)C(=O)CC
Reactant: COC(=O)COc1ccc(Cl)c(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(Cl)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 130 °C

Procedure:
A mixture of (3-amino-4-chlorophenoxy)acetic acid methyl ester (0.54 g), 2-(4-methanesulfonylbenzyl)-3-oxopentanoic acid ethyl ester (0.78 g), polyphosphoric acid (2.5 mL) and dioxane (10 mL) was heated at 130° C. for 17 hours. The mixture was diluted with water (100 mL) and the pH of this solution adjusted to 4 by the addition of sodium acetate. The mixture was extracted with ethyl acetate and the combined extracts were washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as a honey coloured solid, 1.2 g.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15]Br)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=O)C.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(OC(=O)C)C>[NH2:4][C:5]1[S:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15][N:27]3[CH2:28][CH2:29][CH:24]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)[CH:11]=[CH:10][C:8]=2[N:9]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: CC(=O)Nc1nc2ccc(CCBr)cc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1nc2ccc(CCN3CCC(Cc4ccccc4)CC3)cc2s1
Yield: 67 %

Procedure:
A solution of 3 g of 1-(2-Acetylamino-benzothiazol-6-yl)-2-bromo-ethane and 1.95 g of 4- benzylpiperidin and 3.5 g of K2CO3 in 20 ml of DME was heated at 75° C. for 2 hours. The solution was diluted with ethylacetate and washed with brine, after removal of the solvent the residue was heated at reflux in 50 ml of ethanol containing 5 ml of 5 M NaOH for 1 hour. The solvent was evaporated and the residue taken up in ethylacetate was washed with brine and dried. After removal of the solvent, the reaction produce was chromatographed on silica gel eluting with ethylacetate/cyclohexane ⅓ affording the title compound in 67% yield, m.p. 152-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:13])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].N1C(C)=CC=CC=1C.Br[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1(C)C=CC=CC=1>[C:28]([O:27][C:25](=[O:26])[CH2:24][CH2:23][NH:13][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[C:2]([Cl:1])[CH:3]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: Nc1ccc(OC(F)(F)F)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)OC(=O)CCNc1ccc(OC(F)(F)F)c(Cl)c1
Reaction time: 48 h
Yield: 66.6 %

Procedure:
A solution of 9.26 g (42.4 mmol) of 3-chloro-4-trifluoromethoxy-phenylamine and 4.39 ml (42.4 mmol) of 2,6-lutidine in 50 ml of toluene was treated slowly with 7.30 ml (42.4 mmol) of tert-butyl 3-bromopropionate and stirred 2 days at reflux temperature. The reaction was then partitioned between aqueous 10% KHSO4 and EtOAc (3×). The organic phases were washed with 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (n-heptane:EtOAc 9:1) to yield 9.59 g (60%) of the title compound as brown liquid. MS: 339 (M+, Cl).
Reaction SMILES: [CH3:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[C:11](=[O:13])[CH3:12].[CH3:14]COCC>O1CCCC1>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:14])[CH:9]=2)[CH2:4][C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: CC(=O)[C@H]1Cc2ccccc2[C@H]1C
Reactant: CCOCC
Solvent: C1CCOC1
Product: CC(=O)C1=C(C)c2cc(C)ccc2C1
Yield: 84 %

Procedure:
1-(3,5-Dimethyl-inden-2-yl)ethanone is prepared by the same procedure as cis-1-(2,3-dihydro-1-methyl-1H-inden-2-yl)ethanone in Example 4b. A mixture of dry ether and tetrahydrofuran is used as solvent. Yield 84%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]([O:11][C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:18])=[O:5]
Reactant: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccc(C(=O)Cl)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
To a solution of 2-fluoro-4-hydroxybenzoic acid (1.87 g, 12 mmol) in 30 mL pyridine was added acetic anhydride (1.84 g, 18 mmol) and catalytic amount of DMAP and the reaction mixture was stirred at rt for 15 h. The pyridine was removed under reduced pressure; the residue was dissolved in EtOAc (100 mL), washed with 1N HCl (20 mL), water (20 mL) and dried over anhydrous Na2SO4. Removal of solvent gave 2-fluoro-4-acetoxybenzoic acid in 57% yield (1.35 g). To a suspension of 2-fluoro-4-acetoxybenzoic acid (1.33 g, 6.71 mmol) in 10 mL anhydrous dichloromethane was added oxalyl chloride (2.56 g, 20.13 mmol). Two drops of DMF was added and the reaction mixture was stirred at rt for 3 h. The solvent and excess oxalyl chloride were removed under reduced pressure to give 1.48 g of 2-fluoro-4-acetoxybenzoyl chloride which was used in next step without purification. To a solution of 2′-hydroxyacetophenone (0.93 g, 6.83 mmol) in 15 mL anhydrous pyridine was added 2-fluoro-4-acetoxybenzoyl chloride (1.48 g, 6.83 mmol) and the reaction mixture was stirred at rt for 15 h under nitrogen atmosphere. Then the reaction mixture was poured into 100 mL 2N HCl, extracted with EtOAc (200 mL). The crude compound was purified by column chromatography (Silica Gel 230-400 mesh; 20% EtOAc in hexanes as eluent) to give 4-acetoxy-2-fluorobenzoic acid 2-acetyl phenyl ester (1.14 g, 53%). The ester compound (0.74 g, 2.34 mmol) was dissolved in 10 mL anhydrous THF. Potassium tert-butoxide (0.53 g, 4.68 mmol) was added in portions and stirred at rt under nitrogen for 1 h. A yellow solid was formed. The reaction mixture was quenched with 15 mL saturated aqueous ammonium chloride. EtOAc (100 mL) was added and the organic phase was separated and dried over anhydrous Na2SO4. Removal of solvent gave crude product (0.725 g) which was used in next step without further purification. This crude compound (0.72 g, 2.62 mmol) was dissolved in 10 mL glacial AcOH, conc. HCl (1 mL) was added and the reaction mixture was stirred at 110° C. for 4 h. The reaction mixture was cooled to rt. The solid was isolated by filtration, washed with AcOH and dried under vacuum to give 126 mg (21%) over 2 steps. MS (ES) m/z: 256.89 (M), 255.86 (M−1); Mp. 287-289° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:16]1([CH2:2][CH2:3][CH2:4][S:5][S:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)SCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)SCCCN2CCOCC2)cc1

Procedure:
Toluene-4-thiosulfonic acid S-(3-chloro-propyl) ester (61.7 g, 233 mmol, 1.00 eq.), morpholine (22.2 g, 255 mmol, 1.09 eq.) and potassium carbonate (33.8 g, 240 mmol, 1.06 eq.) were stirred together in acetonitrile (1 L) for 64 hours at 50° C. The mixture was concentrated, then partitioned between ethyl acetate and water. The organic solution was washed with water (2×), dried using MgSO4, and concentrated to produce a light yellow oil weighing 61.5 g (84%).
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH2:3]1.[C:18]([O:22][C:23]([NH:25][C:26]1[S:30][C:29]([C:31]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=2[F:38])=[N:28][C:27]=1[C:39](O)=[O:40])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:29]1[S:30][C:26]([NH:25][C:23](=[O:24])[O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[C:27]([C:39](=[O:40])[NH:14][C:9]2[CH:10]=[N:11][N:12]([CH3:13])[C:8]=2[N:4]2[CH2:5][CH2:6][CH2:7][C:2]([F:17])([F:1])[CH2:3]2)[N:28]=1
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(F)(F)C1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCCC(F)(F)C1
Yield: 20 %

Procedure:
Following the procedure for Example 55, starting with 3,3-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25, gave tert-butyl 2-(2,6-difluorophenyl)-4-(5-(3,3-difluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (57 mg, 20%). 1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.67 (s, 1H), 7.71 (s, 1H), 7.41-7.32 (m, 1H), 7.11-7.01 (m, 2H), 3.76 (s, 3H), 3.32 (t, J=11.0 Hz, 2H), 3.19-3.13 (m, 2H), 2.10-1.97 (m, 2H), 1.94-1.85 (m, 2H), 1.53 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:18]=[C:19]=[S:20])[CH:13]1[O:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)C>[Br:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:19](=[S:20])[N:18]([CH2:12][CH:13]1[CH2:14][CH2:15][CH2:16][O:17]1)[C:4]2=[O:6]
Reactant: S=C=NCC1CCCO1
Reactant: Nc1ccc(Br)cc1C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1c2cc(Br)ccc2[nH]c(=S)n1CC1CCCO1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A mixture of 2-amino-5-bromobenzoic acid (8.0 g, 37.0 mmol), tetrahydrofurfuryl isothiocyanate (5.0 g, 34.9 mmol) and triethylamine (5.0 mL, 3.6 g, 35.6 mmol) in ethanol (48 mL) was heated at reflux for 2 h. The reaction mixture was then allowed to cool to room temperature and filtered. The resulting filter cake was washed with 50 mL of cold ethanol, followed by 50 mL of hexanes to provide 10.8 g of the title compound of Step A as a solid melting at 230-232° C. 1H NMR (400 MHz, Me2SO-d6): δ 1.63-2.0 (m,4H), 3.58-3.68 (m,1H), 3.74-3.82 (m,1H), 4.32 (dd,1H), 4.39-4.50 (m,1H), 4.58 (dd,1H), 7.37 (d,1H), 7.91 (d,1H), 8.02 (s,1H), 13.1 (br s,1H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:7]=[C:6]([CH2:8][CH:9]2[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:5][N:4]=1.F[B-](F)(F)F.[CH3:24][O+](C)C>>[CH3:24][O:16][C:14]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]([CH2:8][C:6]2[O:5][N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:7]=2)[N:15]=1
Reactant: C[O+](C)C
Reactant: O=C1CCCCC(Cc2cc(C(F)(F)F)no2)N1
Agent: F[B-](F)(F)F
Product: COC1=NC(Cc2cc(C(F)(F)F)no2)CCCC1

Procedure:
The title product of Example 119 is reacted with trimethyloxonium tetrafluoroborate by the method of Example 3 to generate the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:19]=[CH:18][N:17]=1
Reactant: Clc1ccnc(Cl)c1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cccc2cc(Oc3ccnc(Cl)c3)ccc12
Temperature: 90 °C

Procedure:
6-Hydroxynaphtoic acid (10.0 g, 53.1 mmol), 2,4-dichloropyridine (9.44 g, 63.8 mmol) and cesium carbonate (51.9 g, 159 mmol) were combined in DMSO (266 mL) and the reaction mixture was heated at 90° C. for 16 h. After cooling to RT, water was added and the aqueous layer was acidified to pH=4-5. The title compound was isolated by filtration and dried under vacuum.