Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(C)([O-])C.[K+].F[C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(C1C=CC=CC=1)(=O)C>C1COCC1.CCCCCCC>[CH2:1]([O:9][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][C:18]=1[C:26]([F:27])([F:28])[F:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CCCCCCCCO
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CCCCCCC
Solvent: CC(=O)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(C)=O)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 325.8 %

Procedure:
A solution of n-octanol (13.3 g, 0.102 mol), in THF (224 mL) was treated with 1.0 M potassium t-butoxide in THF (112 mL, 1.1 equiv) at room temperature and heated to 65° C. After 15 minutes, a solution of 1-[4-fluoro-3-(trifluoromethyl)phenyl]ethanone (21 g, 1.0 equiv) in THF (224 mL) was charged slowly over 30 minutes. Vigorous gas evolution was noted during the addition. The reaction was monitored by HPLC and deemed complete after 1.5 h. The reaction mixture was cooled to ambient temperature, treated with 10% aqueous citric acid (250 mL), extracted with MTBE (2×500 mL), dried, and concentrated to afford the product (31.99 g, 99.3%, 88.1% AUC by HPLC). This reaction was repeated with slight modification as described above (reducing the amount of THF used to dissolve the acetophenone to 3 mL/g from 10.7 mL/g with improved control of gas evolution) on a 100 g scale to give 137.1 g, >100% yield). The two lots were combined and purified by column chromatography using silica-gel (1 kg), eluted with 10% ethyl acetate: 90% heptane to afford the title product (105 g, 75% yield) as a pale yellow color oil. Impure fractions were collected and provided 22.8 g (16.3% yield) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:11]=2)[O:7][N:6]=1)=[O:4].[BH4-].[Na+]>CO>[OH:20][CH:18]([CH3:19])[CH2:17][CH2:16][C:12]1[CH:11]=[C:10]([C:8]2[O:7][N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:9]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)c1cc(-c2cccc(CCC(C)=O)c2)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(CCC(C)O)c2)on1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a mixture of 5-(3-(3-Oxo-butyl)-phenyl)-isoxazole-3-carboxylic acid methyl ester (860 mg, 3.15 mmol) in methanol (15 mL)at room temperature was added NaBH4 (178 mg, 4.7 mmol) with stirring. After 30 min, the reaction mixture was partitioned between ethyl acetate and 3N HCl. The organic layer was washed with brine, dried over Na2SO4, filtered, evaporated in vacuo to provide the titled compound as a light brown oil (850 mg, 99% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:34]=[CH:33][N:32](COCC[Si](C)(C)C)[N:31]=5)=[C:26]([F:43])[CH:25]=4)=[C:17]3[N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC1C=C([C@@H]2COC(=O)N2C2C=CN3N=CC(C4C=CC(C5N(COCC[Si](C)(C)C)N=CN=5)=C(F)C=4)=C3N=2)C=CC=1F>>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:13][O:12][C:11](=[O:14])[N:10]2[C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[N:34]=[CH:33][NH:32][N:31]=5)=[C:26]([F:43])[CH:25]=4)=[C:17]3[N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[Si](C)(C)CCOCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@H]5c5ccc(F)c(F)c5)nc34)cc2F)n1
Agent: C[Si](C)(C)CCOCn1ncnc1-c1ccc(-c2cnn3ccc(N4C(=O)OC[C@H]4c4ccc(F)c(F)c4)nc23)cc1F
Product: O=C1OC[C@@H](c2ccc(F)c(F)c2)N1c1ccn2ncc(-c3ccc(-c4nc[nH]n4)c(F)c3)c2n1
Yield: 81 %

Procedure:
(R)-4-(3,4-difluorophenyl)-3-(3-(3-fluoro-4-(1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one (16 mg, 81%) was prepared by the procedure described in Example 1, Step 9, using a mixture of (R)-4-(3,4-difluorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-3-yl)phenyl)pyrazolo[1,5-a]pyrimidin-5-yl)oxazolidin-2-one and (R)-4-(3,4-difluorophenyl)-3-(3-(3-fluoro-4-(1-((2-(trimethylsilyl) ethoxy)methyl)-1H-1,2,4-triazol-5-yl)phenyl)pyrazolo [1,5-a]pyrimidin-5-yl)oxazolidin-2-one. LCMS (APCI+) m/z 478.2 [M+H]+.
Reaction SMILES: COC1C=CC(C[N:8]2[C:16]([CH3:18])([CH3:17])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]#[N:20])[CH:14]=3)[C:9]2=[O:21])=CC=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N.O>[CH3:17][C:16]1([CH3:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:19]#[N:20])[CH:14]=2)[C:9](=[O:21])[NH:8]1
Reactant: COc1ccc(CN2C(=O)c3ccc(C#N)cc3C2(C)C)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC1(C)NC(=O)c2ccc(C#N)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
To a solution of 2-(4-methoxy-benzyl)-3,3-dimethyl-1-oxo-2,3-dihydro-1H-isoindole-5-carbonitrile (3.5 g, 11.42 mmol) in MeCN (70 mL) was added CAN (18.79 g, 34.27 mmol) in 30 mL of water at 0° C. The resulting reaction mixture was stirred at 0° C. for 1 hour until all the starting material was consumed. The reaction mixture was extracted between water and EtOAc and the combined organic layers were dried over anhy. MgSO4, filtered, and concentrated under reduced pressure to give a crude product which was purified by column chromatography to afford the title compound (1.06 g, 49.8%) as a solid.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Br[C:15]1[C:16]([F:27])=[CH:17][N:18]=[C:19]2[C:24]=1[N:23]=[C:22]([O:25][CH3:26])[CH:21]=[CH:20]2.OS([O-])(=O)=O.[Na+]>O1CCOCC1>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[N:23]=2)[N:18]=[CH:17][C:16]=1[F:27])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: COc1ccc2ncc(F)c(Br)c2n1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1c(F)cnc2ccc(OC)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.9 %

Procedure:
Diethyl malonate (12.4 mL, 81.7 mmol) was added to a suspension of NaH (3.0 g, 47.9 mmol, 60% in mineral oil) in dioxane (35 mL). The mixture was stirred at rt for 5 min and then heated at 80° C. for 1 h. After cooling to rt, CuBr (1.4 g, 9.6 mmol) and 8-bromo-7-fluoro-2-methoxy-[1,5]naphthyridine (7.0 g, 27.2 mmol, prepared according to WO 2007/122258) were added. The mixture was stirred at 100° C. for 6 h. After cooling to rt, 10% NaHSO4 (100 mL) was added. The mixture was stirred for 30 min at rt. The two layers were decanted and the aq. layer was extracted three times with EA (3×150 mL). The combined org. layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by CC (Hept-EA 3:1 then 1:1) to afford the title intermediate as a yellow oil (8.22 g, 90% yield).
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[C:7]1([OH:13])[CH:12]=[CH:11]C=C[CH:8]=1.O>>[C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2].[CH3:11][CH2:12][CH:7]([O:13][C:1]([CH3:2])=[O:3])[CH3:8]
Reactant: Oc1ccccc1
Solvent: C=COC(C)=O
Solvent: O
Product: CCC(C)OC(C)=O

Procedure:
Using for layer (C) this adhesive composition, and as layer (A) saponified ethylene-vinyl acetate copolymer resin containing 56 mol % of vinyl acetate component, and having [η]=0.96 (in the mixture of phenol/water=85/15, at 30° C., dl/g), which was obtained by saponifying 99.5 mol % of vinyl acetate and as layer (B) poly vinyl acetate resin plasticized with 35 wt % of dioctylphthalate, co-extrusion was carried out at a die temperature of 200° C. to obtain a fine laminated article having five layers of three kinds of resin, (B)/(C)/(A)/(C)/(B). The each thickness of layers was 10 μm for (A), 100 μm for (B) and 5 μm for (C). And the article had a good peel strength of (A)/(B); 1.0 kg/cm (T peel test at 200 mm/min).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:14])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Brc1ccc(N2CCNCC2)nc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Br)cn2)CC1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
To a solution of compound 90a (125 g, 516 mmol) in DCM (300 mL), TEA (104 g, 1.03 mol) was added, followed by (BOC)2O (135 g, 619 mmol) in portions with stirring at 0° C. The resulting mixture was stirred overnight at room temperature. The reaction was then quenched with water (100 mL), and the product was extracted with DCM (3×150 mL). The combined organic layers were concentrated under reduced pressure to obtain compound 90b as a white solid (125 g, 71% yield). Mass Spectrum (LCMS, ESI pos.): Calcd. for C14H20BrN3O2: 342.1 (M+H). found 342.1.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl-].[In+3].[Cl-].[Cl-].O[C:13]([CH:25]1[CH2:27][CH:26]1[C:28]#[N:29])([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH3:14].[CH3:30][S:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[CH:38]2>ClCCl>[CH3:30][S:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]2[C:41]=1[NH:40][CH:39]=[C:38]2[C:13]([CH:25]1[CH2:27][CH:26]1[C:28]#[N:29])([C:15]1[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=1)[CH3:14]
Reactant: CC(O)(c1ccc(C(F)(F)F)cc1)C1CC1C#N
Reactant: CSCc1cccc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc2c(C(C)(c3ccc(C(F)(F)F)cc3)C3CC3C#N)c[nH]c12

Procedure:
0.02 ml (0.24 mmol) of trifluoroacetic acid and 43.3 mg (0.20 mmol) of indium(III) chloride were added to 50.0 mg (0.20 mmol) of the compound from Example 132A and 69.5 mg (0.39 mmol) of the compound from Example 8A in 2 ml of dichloromethane at RT, and the mixture was heated under reflux overnight. It was concentrated and the residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 9.0 mg (11% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]#[N:12].[F:13][C:14]1[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=1>N1C=CC=CC=1>[C:11]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:20]([C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)(=[O:22])=[O:21])[CH:3]=2)[NH:7][N:6]=1)#[N:12]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: N#Cc1n[nH]c2ccc(N)cc12
Solvent: c1ccncc1
Product: N#Cc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 84.3 %

Procedure:
N-(3-Cyano-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 2 from 0.6 g of 5-amino-3-cyano-1H-indazole, 12 ml of pyridine and 0.73 g of 3-fluorobenzenesulfonyl chloride. 1 g of N-(3-cyano-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of a yellow solid melting at 227° C. (analysis C14H9FN4O2S % calculated C, 53.16; H, 2.87; F, 6.01; N, 17.71; O, 10.12; S, 10.14. % found C, 52.86; H, 2.63; F, 5.67; N, 16.04).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][C:13]1[C:18]([NH2:19])=[C:17]([CH3:20])[CH:16]=[C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:14]=1.C(N(CC)C(C)C)(C)C>ClCCCl>[CH2:5]([O:4][C:2](=[O:3])[NH:19][C:18]1[C:13]([CH3:12])=[N:14][C:15]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:16][C:17]=1[CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1cc(N2CCOCC2)nc(C)c1N
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCOCC2)nc(C)c1NC(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 31 %

Procedure:
Benzyl chloroformate (18 mg) was added to a solution of 0.085 M 2,4-dimethyl-6-morpholin-4-yl-pyridin-3-ylamine and 0.17 M N,N-diisopropyl-ethylamine in 1,2-dichloroethane (1 mL). The vial was shaken for 16 hours under argon and concentrated in vacuo. Aqueous sodium hydroxide (1 M, 1 mL) was added and the crude mixture was extracted with isopropyl acetate/tetrahydrofuran (4:1, 2×1 mL). The organic phase was washed with brine (1 mL), concentrated in vacuo and redissolved in 1-propanol/dimethyl sulfoxide (1:1, 0.4 mL) of which 0.2 mL was subjected to preparative LC-MS purification to furnish 4.5 mg (31% yield) of the title compound as an oil. LC-MS (m/z) 342 (MH+); tR=1.58, (UV, ELSD) 99%, 99%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=2[CH3:16])=[CH:4][CH:3]=1.C([O-])([O-])=[O:18].C([O-])([O-])=O.OO.OO.OO.[Na+].[Na+].[Na+].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])O.[Na+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH3:16])=[CH:10][CH:11]=[C:12]([C:14]#[N:15])[N+:13]=2[O-:18])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(C#N)nc1-c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: OO
Solvent: CC#N
Product: Cc1ccc(C#N)[n+]([O-])c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 34.4 %

Procedure:
To a solution of 6-(4-fluorophenyl)-5-methylpyridine-2-carbonitrile (16.76 g, 79 mmol) and sodium percarbonate (24.8 g, 158 mmol) in acetonitrile (200 mL) was added dropwise trifluoromethanesulfonic acid anhydride (66.8 g, 237 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hr and further at room temperature overnight. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted 3 times with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2→1/1) to give the title compound (6.2 g, 40%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:29])[CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[C:16]([C:18]1[N:23]=[CH:22][C:21]([C:24]([O:26]C)=[O:25])=[CH:20][CH:19]=1)=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([N:11]([CH3:29])[CH2:12][CH2:13][CH2:14][N:15]([CH3:28])[C:16]([C:18]1[N:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=1)=[O:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)N(C)CCCN(C)C(=O)OCc2ccccc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(CCCN(C)C(=O)c1ccc(C(=O)O)cn1)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 67.3 %

Procedure:
The compound (1.23 g, 3.08 mmol) obtained in Example 5a was dissolved in methanol (9 mL), a 1 N aqueous sodium hydroxide solution (9.24 mL, 9.24 mmol) was added, and then the mixture was stirred at 50° C. for 10 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added to the resulting residue, the mixture was extracted with water (×2), the aqueous layer was adjusted to pH 3 with 1 N hydrochloric acid, and the mixture was extracted with methylene chloride (×3) and dried with anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (799 mg; yield, 68%) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:22][C:2]1[CH:3]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1)=[O:21]
Reactant: CCOC(=O)c1cc(Br)cc2c1OCC2
Reactant: NC(=O)c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2c1OCC2
Temperature: 100 °C
Reaction time: 24 h
Yield: 26.2 %

Procedure:
1,4-dioxane (20 ml) was added to ethyl 5-bromo-2,3-dihydro-1-benzofuran-7-carboxylate (600 mg), 2-(trifluoromethyl)benzamide (501 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (96 mg), cesium carbonate (1.01 g) and tris(dibenzylideneacetone)dipalladium (114 mg). After degassing, the mixture was stirred at 100° C. under argon atmosphere for 24 hours. The reaction mixture was filtered off on celite, and the solvent was removed under reduced pressure. The resultant residue was purified on silica gel column chromatography to obtain the titled compound (220 mg) as slightly yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17].[Br:18]N1C(=O)CCC1=O.Cl(O)(=O)(=O)=O>ClCCl>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][C:8]([Br:18])=[C:3]([O:2][CH3:1])[C:4]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1-c1ccccc1C
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: COc1ccc(Br)c(OC)c1-c1ccccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.2 %

Procedure:
1,3-Dimethoxy-2-(tol-2-yl)-benzene 1, (10 g, 43.86 mmol), N-bromosuccinimide (8.26 g, 46.4 mmol), and perchloric acid (70%, 0.5 ml) were mixed in dichloromethane (200 ml) and stirred for 4 hrs at room temperature. The reaction mixture was quenched with sodium bicarbonate solution (5%, 100 ml), the dichloromethane layer was washed with water (100 ml), brine (100 ml), and the solvent was removed. The crude product was purified by silica-gel chromatography eluting with hexane and ethyl acetate (0% to 10% ethyl acetate) yielding 10.8 g (80%) of 2.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][NH2:33])[CH:27]=1>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[S:3][C:4]([C:8]([NH:33][CH2:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[O:10])=[C:5]([CH3:7])[N:6]=1
Reactant: Cc1nc(Br)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(Br)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
To a solution of 2-bromo-4-methylthiazole-5-carboxylic acid (2.25 g, 10.00 mmol) and 4-methylmorpholine (1.25 g, 11.00 mmol) in anhydrous dichloromethane (80 mL) was added iso-butyl chloroformate (1.3 mL, 10.0 mmol) dropwise at 0° C. The reaction mixture was stirred at ambient temperature for 2 hours, cooled to 0° C. and pyridin-3-ylmethanamine (1.23 g, 12.00 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 4 hours, diluted with ethyl acetate (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate) to afford the title compound as a yellow solid (1.78 g, 56%): 1H NMR (300 MHz, CDCl3) δ 8.55-8.48 (m, 2H), 7.70-7.64 (m, 1H), 7.29-7.26 (m, 1H), 6.36 (t, J=5.8 Hz, 1H), 4.56 (d, J=5.8 Hz, 2H), 2.63 (s, 3H); MS (ES+) m/z 312.1 (M+1), 314.1 (M+1).
Reaction SMILES: [CH:1]1([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.I[CH3:19].[H-].[Na+].O>CN(C)C=O.ClCCl>[CH:1]1([C:7]2([O:17][CH3:19])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CI
Reactant: OC1(C2CCCCC2)CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC1(C2CCCCC2)CCC2(CC1)OCCO2

Procedure:
To a solution of 8-cyclohexyl-1,4-dioxaspiro[4.5]decan-8-ol (1.143 g) and iodomethane (0.59 ml) in N,N-dimethylformamide (11 ml) was added sodium hydride (60% dispersion in mineral oil) (342 mg) at 0° C. The solution was stirred for 9 hours at 0° C., during which period additional iodomethane (0.59 ml) and sodium hydride (60% dispersion in mineral oil) (344 mg) was added to the mixture. The reaction mixture was added to a mixture of water and dichloromethane. The organic layer was washed with water. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate elution) to give 8-cyclohexyl-8-methoxy-1,4-dioxaspiro[4.5]decane (1.201 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12]C(C#N)=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([OH:22])(=[O:21])[CH3:20].O.S(=O)(=O)(O)O>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[C:11](=[CH:12][C:20]([C:19]([OH:22])=[O:21])=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc2c(-c3cccc(F)c3)n[nH]c2c1
Temperature: 110 °C
Reaction time: 6 h

Procedure:
To 92 mg of 3-(3-fluorophenyl)-1H-6-indazolecarbonitrile were sequentially added 1 ml of glacial acetic acid, 0.5 ml of water and 0.4 ml of concentrated sulfuric acid, and the mixture was stirred at 110° C. for 6 hours. After standing to cool, 35 ml of ethyl acetate was added to the reaction mixture. The mixture was sequentially washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 94 mg of the title compound as bright yellow crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[C:10](OC(=O)C)(=[O:12])C.O>C(O)=O.CO>[CH:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8])=[O:12]
Reactant: O=C(O)C1CCCCN1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CO
Solvent: O=CO
Product: O=CN1CCCCC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of 40 g of a racemic mixture of 2-piperidinecarboxylic acid (0.310 mmol) in 300 mL of formic acid at 0° C. there are added dropwise 200 mL (2.15 mmol) of acetic anhydride. The whole is then stirred at ambient temperature overnight. The reaction mixture is then cooled to 0° C., hydrolysed by the addition of 250 mL of water and stirred for half an hour at 0° C. before being concentrated to dryness. The oil so obtained is taken up in 200 mL of methanol and then concentrated to dryness. The title product is obtained in the form of an oil with a yield of 98%. It is used directly, without further purification, for the following step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1)([O-])=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:8]=1
Reactant: CC(C)(C)OC(=O)Cn1cc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Cn1cc(N)cn1
Yield: 99 %

Procedure:
Tert-butyl (4-nitro-1H-pyrazol-1-yl)acetate (1.0 g, 4.40 mmol) and 10% palladium on carbon (0.100 g) in methanol (20 ml) were stirred under an atmosphere of hydrogen for 2 hours and then the mixture was filtered through Celite and the filtrate evaporated to give tert-butyl (4-amino-1H-pyrazol-1-yl)acetate