Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][CH2:6][CH:5]([CH2:8][O:9][C:10]2[C:15]([CH3:16])=[CH:14][N:13]=[C:12]([CH2:17][OH:18])[C:11]=2[CH3:19])[CH2:4][O:3]1.[OH-].[Na+].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([S:29]([O:18][CH2:17][C:12]2[C:11]([CH3:19])=[C:10]([O:9][CH2:8][CH:5]3[CH2:6][O:7][C:2]([CH3:20])([CH3:1])[O:3][CH2:4]3)[C:15]([CH3:16])=[CH:14][N:13]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Cc1cnc(CO)c(C)c1OCC1COC(C)(C)OC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCc2ncc(C)c(OCC3COC(C)(C)OC3)c2C)cc1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 88 %

Procedure:
To a tetrahydrofuran (30 ml) solution of (4-((2,2-dimethyl-1,3-dioxan-5-yl)methoxy)-3,5-dimethylpyridin-2-yl)methanol (738 mg, 2.61 mmol), powdered sodium hydroxide (313 mg, 7.84 mmol) was added and the mixture was stirred at room temperature for 35 minutes. The mixture was further stirred for 10 minutes under ice-cool and p-toluenesulfonyl chloride (1.09 g, 5.74 mmol) was added little by little for one minute. The reaction mixture was stirred at room temperature for 17 hours and 40 minutes and diluted with tetrahydrofuran, and then insoluble substance was removed by filtration. To the filtrate, silica gel was added, and the mixture was concentrated, and subjected to silica gel column chromatography (elution solvent: n-heptane/ethyl acetate=1/1) to obtain the title compound (1.00 g, 88%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH2:29])[CH3:28].C(N(CC)CC)C.ClCCl>C(#N)C>[F:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([NH:29][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH3:28]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(N)c1ccccc1-c1cc(F)ccc1F
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC(C)c2ccccc2-c2cc(F)ccc2F)cc1
Yield: 89.2 %

Procedure:
4-Methoxybenzenesulfonyl chloride (326 mg, 1.6 mmol) was added to a solution of 1-(2′,5′-difluoro-1,1′-biphenyl-2-yl)ethylamine (350 mg, 1.5 mmol) and triethylamine (418 uL, 3 mmol) in acetonitrile. The reaction was stirred at ambient temperature for 16 hours, whereupon dichloromethane was added and the reaction washed with water. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated, and purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane (35 min), to afford the product (540 mg, 89%) as a white solid, m.p. 143-144° C.;
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([F:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)=[N+]=[N-].[C:18](Cl)(=[O:27])[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.N1C=CC=CC=1.[Pd]>[CH2:20]([O:19][C:18]([NH:1][C@H:4]1[C@@H:9]([F:10])[CH2:8][CH2:7][N:6]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5]1)=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H](N=[N+]=[N-])C1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
A mixture of cis-tert-butyl 3-azido-4-fluoropiperidine-1-carboxylate (1.40 g, 5.73 mmol) and 10% Pd/C (0.61 g, 0.57 mmol) in MeOH (20 mL) was charged 1 atmosphere H2 and stirred at room temperature for 1 hour. The catalyst was removed by filtration and washed with methanol. The filtrate was concentrated in vacuo. The residue obtained was dissolved in pyridine (10 mL) and benzyl carbonochloridate (1.61 mL, 11.46 mmol) was added. The reaction was stirred at room temperature for 2 hours. The pyridine was removed in vacuo, and the residue was dissolved in ethyl acetate (30 mL), washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (hexane:ethyl acetate 3:1) to give cis-tert-butyl 3-(benzyloxycarbonylamino)-4-fluoropiperidine-1-carboxylate (0.44 g, 22%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Li][CH2:8][CH2:9][CH2:10]C.[B:12]([O-:18])([O-])[O:13][CH:14]([CH3:16])[CH3:15]>C1COCC1>[CH3:1][N:2]1[C:6]([B:12]2[O:13][C:14]([CH3:15])([CH3:16])[C:9]([CH3:10])([CH3:8])[O:18]2)=[CH:5][CH:4]=[N:3]1
Reactant: [Li]CCCC
Reactant: Cn1cccn1
Reactant: CC(C)OB([O-])[O-]
Solvent: C1CCOC1
Product: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.6 %

Procedure:
To a 5° C. solution of 5.00 mL (60.9 mmol) n-methylpyrazole in 100 ml THF was added dropwise 381 mL (60.9 mmol) 1.6M n-BuLi in hexanes. The reaction mixture was warmed to room temperature, and after 1 hr at room temperature, the reaction mixture was cooled to −78° C. 18.4 mL (79.0 mmol) isopropyl borate was added. After 1.00 h at −78° C., the reaction mixture was quenched with 12.0 mL of 2N HCl. The resulting solution was concentrated in vacuo and azotroped with toluene. The resulting crude material was dissolved in 11 mL THF. 6.57 g (55.6 mmol) pincol and 1.00 g of molecular sieves were added. After 24.0 hr at room temperature, the reaction mixture was filtered and concentrated. The resulting residue was dissolved in 100 mL hexanes, washed twice with water, dried over NaSO4, filtered, and concentrated in vacuo to afford 5.90 g (51%) 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 1H NMR (CD3OD, 400 MHz) 7.45 (d, 1H, J=1.92); 7.67 (d, 2H, J=1.92 Hz); 4.04 (s, 3H); 1.35 (s, 12H). ESMS+1 for C10H17BN2O2: 209.1. To a sealed vessel containing 9.20 g (19.8 mmol) 2-(4-iodophenyl)-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide, 4.95 g (23.8 mmol) 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole, 0.133 g (0.476 mmol) tricyclohexylphosphine, and 0.181 g (0.198 mmol) Pd2(dba)3 was added 52.8 mL dioxane and 26.5 mL of 1.27M K3PO4. After 12.0 h at 100° C., the reaction mixture was cooled to room temperature and extracted three times with CH2Cl2 and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 50-100% EtOAc:hexane). The resulting solid was recrystallized from n-butylchloride to afford 5.00 g (60%) 2-[4-(1-methyl-1H-pyrazol-5-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CDCl3, 400 MHz) 8.23 (d, 1H, J=2.74 Hz); 7.51 (d, 1H, J=1.83 Hz); 7.38 (m, 4H); 7.22 (m, 2H); 6.79 (br d, 1H, J=7.15 Hz); 6.30 (d, 1H, J=2.01 Hz); 5.13 (m, 1H); 4.38 (q, 2H, J=8.05 Hz); 3.90 (s, 3H); 3.63 (s, 2H); 1.43 (d, 3H, J=6.78). HRMS (ES) exact mass calcd for C21H21F3N4O2: 419.1682, Found: 419.1690.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:24][C@@H:23]([CH3:25])[N:13]2[C:14]3[CH:15]=[C:16]([CH2:21][OH:22])[CH:17]=[CH:18][C:19]=3[CH2:20][C@@H:12]2[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].I[CH3:27]>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:24][C@@H:23]([CH3:25])[N:13]2[C:14]3[CH:15]=[C:16]([CH2:21][O:22][CH3:27])[CH:17]=[CH:18][C:19]=3[CH2:20][C@@H:12]2[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(CO)cc3N21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCc1ccc2c(c1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 50 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
Sodium hydride (55-65% dispersion in mineral oil, 27 mg, 0.67 mmol) was added to a solution of (4R,10aR)-7-hydroxymethyl-4-methyl-3,4,10,10a-tetrahydro-1H-pyrazino[1,2-a]indole-2-carboxylic acid tert-butyl ester (200 mg, 0.63 mmol) in N,N-dimethylformamide (5 mL) at r.t., then after 1 h iodomethane (89 mg, 0.63 mmol) was added and the reaction mixture was stirred 2 h at 50° C. After cooling another portion of sodium hydride (27 mg, 0.67 mmol) was added, then after the addition of a second equivalent of iodomethane (89 mg, 0.63 mmol) the reaction mixture was stirred 2 h at 50° C. After cooling the reaction mixture was poured onto ice and extracted with ether (30 mL), the organic layer was washed with half-saturated brine, dried (MgSO4), and concentrated. Chromatography on SiO2 (Hexane/EtOAc 3:1) yielded the title compound (109 mg, 52%). Light yellow oil, ISP-MS: m/e=333.3 ([M+H]+).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[C@@H:6]([CH2:16][OH:17])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:14])[OH:13])[NH2:10])([CH3:3])[CH3:2].C([O:22][C:23](=O)[C@@H:24]([CH3:39])[NH:25]C(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N)(C)C>>[CH:1]([O:4][C:5](=[O:18])[C@@H:6]([CH2:16][OH:17])[NH:7][C:8](=[O:15])[C@H:9]([CH2:11][C:12](=[O:13])[OH:14])[NH:10][C:23](=[O:22])[C@@H:24]([CH3:39])[NH2:25])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)[C@@H](CO)NC(=O)[C@@H](N)CC(=O)O
Reactant: CC(C)OC(=O)[C@@H](C)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N
Product: CC(C)OC(=O)[C@@H](CO)NC(=O)[C@H](CC(=O)O)NC(=O)[C@@H](C)N

Procedure:
This compound was prepared from 1.9 g α-L-aspartyl-D-serine isopropyl ester and 2.2 g N-benzyloxycarbonyl-D-alanine N-hydroxysuccinimide ester in a manner similar to Example 16 (C) and (D). Yield: 1.8 g, m.p.: 222.5°-234° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH:8]1([C:12]2[C:13]([N:21]3[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[C:14]3[CH:20]=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1.C(Cl)[Cl:35]>>[ClH:35].[CH:8]1([C:12]2[C:13]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[C:14]3[CH:20]=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCN(c2c(C3CCC3)cnc3[nH]ncc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: c1nc2[nH]ncc2c(N2CCNCC2)c1C1CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
TFA (0.60 mL, 7.83 mmol) was added to a solution of tert-butyl 4-(5-cyclobutyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.14 g, 0.39 mmol) in DCM (10 mL) and stirred at room temperature for 1 hour. The solvent was removed. The resulting residue was dissolved in DCM (0.5 mL), and 2N HCl in ether (2 mL) was added. The solid formed was collected by filtration to give 5-cyclobutyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine hydrochloride (0.125 g, 97%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:7][CH2:6][CH2:5]2.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>CN(C)C=O>[N+:11]([C:10]1[CH:9]=[C:8]2[C:4](=[CH:3][C:2]=1[S:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1)[CH2:5][CH2:6][CH2:7]2)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1cc2c(cc1Br)CCC2
Reactant: Sc1ccccn1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc2c(cc1Sc1ccccn1)CCC2

Procedure:
4.8 g. of 5-bromo-6-nitroindan, 4.5 g. of potassium tert.-butylate, 4.4 g. of 2-pyridinethiol are heated in 50 ml. of absolute dimethylformamide for 3 hours under nitrogen to 80°. The mixture is concentrated under vacuum; the residue is combined with ethyl acetate and extracted four times with water. The ethyl acetate phase is concentrated, and the residue is purified on a silica gel column (system: cyclohexane/ethyl acetate 4:1). After crystallization from ethanol, 3.3 g. of 5-nitro-6-(2-pyridylthio)indan is obtained, m.p. 74°.
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].C(=O)([O-])[O-:7].[K+].[K+].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>C(Cl)Cl>[CH2:2]([O:4][N:5]([C:15](=[O:16])[C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[F:12])[OH:7])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CCON
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Product: CCON(O)C(=O)c1ccccc1F
Yield: 128.7 %

Procedure:
To a mixture of 35 g (0.36 moles) ethoxyamine hydrochloride, 51 g (0.37 moles) potassium carbonate and ice chips (about 100 g) which had been stirred for several minutes, 50 g (0.32 moles) 2-fluoro-benzoylchloride in methylene chloride (about 50 ml) were added dropwise. The reaction mixture was allowed to come to room temperature and then was stirred at room temperature for about three to four hours. The aqueous and methylene chloride layers were separated. The methylene chloride layer was dried with magnesium sulfate, filtered and stripped under reduced pressure to give about 82 g of the above-identified product as a clear light yellow liquid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:25][C:11]3[N:12]([CH3:24])[C:13](=[O:23])[N:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:15](=[O:16])[C:10]=3[C:9]=2[CH3:26])=[CH:4][CH:3]=1.[F:27][C:28]([F:40])([F:39])[O:29]C1C=C(B(O)O)C=CC=1.[C:41]([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH3:24][N:12]1[C:11]2[S:25][C:8]([C:5]3[CH:6]=[CH:7][CH:2]=[C:3]([O:29][C:28]([F:40])([F:39])[F:27])[CH:4]=3)=[C:9]([CH3:26])[C:10]=2[C:15](=[O:16])[N:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:41])=[O:20])[C:13]1=[O:23]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)CCn1c(=O)c2c(C)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCn1c(=O)c2c(C)c(-c3cccc(OC(F)(F)F)c3)sc2n(C)c1=O
Temperature: 100 °C
Yield: 63.8 %

Procedure:
To a solution of ethyl 3-(6-bromo-1,5-dimethyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (See Compound 24, Step 4, 150 mg, 0.415 mmol) in toluene (3 mL) was added (3-(trifluoro methoxy)phenyl)boronic acid (102 mg, 0.498 mmol) and aq. Cs2CO3 solution (1 M, 0.5 mL). The reaction was degassed under nitrogen gas (3×) then Pd(PPh3)4 (24 mg) was added. The reaction was heated at 100° C. for 18 h, cooled to RT then diluted with EA (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (4:1) to give ethyl 3-(1,5-dimethyl-2,4-dioxo-6-(3-(trifluoromethoxy)phenyl)-1,2-dihydrothieno[2,3-d]pyrimidin-3 (4H)-yl)propanoate (120 mg, 63.8% yield) as a yellow solid. LCMS: MH+ 457 and TR=2.045 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])=[CH:4][C:3]=1[F:15].Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>>[N+:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][C:17](=[O:18])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]3=[O:14])=[CH:4][C:3]=2[F:15])=[CH:25][CH:24]=1)([O-:28])=[O:27]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Product: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1

Procedure:
50.3 Using general method G, 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (prepared according to WO 2003045912) was activated with 4-nitrophenyl chloroformate to give [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester. Pale pink solid.
Reaction SMILES: [CH3:1][C:2]([CH3:20])=[CH:3][CH2:4][C@H:5]1[O:7][C@@:6]1([C@@H:9]1[C@:14]2([O:16][CH2:15]2)[CH2:13][CH2:12][C@@H:11]([OH:17])[C@H:10]1[O:18][CH3:19])[CH3:8].[CH3:21][S-:22].O>CN(C=O)C>[O:7]1[CH:5]([CH2:4][CH:3]=[C:2]([CH3:20])[CH3:1])[C:6]1([CH:9]1[CH:10]([O:18][CH3:19])[CH:11]([OH:17])[CH2:12][CH2:13][C:14]1([CH2:15][S:22][CH3:21])[OH:16])[CH3:8]
Reactant: CO[C@@H]1[C@H](O)CC[C@]2(CO2)[C@H]1[C@@]1(C)O[C@@H]1CC=C(C)C
Reactant: C[S-]
Solvent: O
Solvent: CN(C)C=O
Product: COC1C(O)CCC(O)(CSC)C1C1(C)OC1CC=C(C)C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
Fumagillol (3.00 g) was dissolved in DMF (6 ml), to which was added thiomethoxide (2.23 g). The mixture was stirred for 30 minutes, to which was added water to suspend the reaction. The product was extracted with isopropylether. The extract solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, then the residue was purified by means of a silica gel column chromatography (carrier 150 g, developing solvent : ethyl acetate - hexane=1:2), followed by recrystallization from hexane to afford 2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylthiomethyl-1,4-cyclohexanediol (2.43 g:yield 69%) as colorless powder, m.p. 52° to 53° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][OH:17])(=[O:13])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH2:3]([CH2:10][S:11]([NH:14][CH2:15][CH2:16][O:17][C:19]1[N:24]2[CH:25]=[CH:26][N:27]=[C:23]2[CH:22]=[CH:21][CH:20]=1)(=[O:13])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=S(=O)(CCc1ccccc1)NCCO
Reactant: Clc1cccc2nccn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(CCc1ccccc1)NCCOc1cccc2nccn12
Yield: 39.4 %

Procedure:
To a suspension of 60% sodium hydride in oil (0.20 g, 5 mmoles) in dimethylformamide (20 ml) was added 2-(N-benzylmethylsulfonylamino)-1-ethanol (1.14 g, 5 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added 5-chloroimidazo[1,2-a]pyridine (0.763 g, 5 mmoles) with stirring under ice-cooling, followed by stirring at 80° C. for 16 hours. After cooling, water was added to the reaction mixture, which was extratced with ethyl acetate and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent:ethyl acetate/hexane (1:1)→ethyl acetate/hexane (2:1)] to obtain 0.68 g of the desired product (39.4%, pale yellow oily product).
Reaction SMILES: [NH2:1][C:2](=[O:20])[CH:3]([NH:9]C(=O)OCC1C=CC=CC=1)[CH2:4][C:5]([F:8])([F:7])[F:6].[H][H]>CO.[Pd]>[NH2:9][CH:3]([CH2:4][C:5]([F:8])([F:7])[F:6])[C:2]([NH2:1])=[O:20]
Reactant: NC(=O)C(CC(F)(F)F)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)C(N)CC(F)(F)F
Yield: 93.5 %

Procedure:
A solution of benzyl 1-amino-4,4,4-trifluoro-1-oxobutan-2-ylcarbamate (175 mg, 0.603 mmol) and Pd—C (10%, 55 mg) in MeOH (5 mL) was hydrogenated under balloon hydrogen for 2 h. The mixture was filtered through celite. The filtrate was concentrated in vacuo to give 2-amino-4,4,4-trifluorobutanamide (88 mg).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br.BrCC1[C:47]([Cl:52])=[N:48][CH:49]=[CH:50][CH:51]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:47]([Cl:52])=[N:48][CH:49]=[CH:50][CH:51]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Clc1ncccc1CBr
Agent: Br
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cccnc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-2-chloropyridine hydrobromide and isolated as light yellow gum. MS (m/e): 408.3 (MH+).
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]([C:12]#[N:13])[S:10][CH:11]=1.C(=O)=O.CC(C)=O.[Cl:21][CH2:22][C:23](N(OC)C)=[O:24].Cl>O1CCCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:12]#[N:13])[S:10][C:11]=1[C:23](=[O:24])[CH2:22][Cl:21]
Reactant: N#Cc1cc(Br)cs1
Reactant: CON(C)C(=O)CCl
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: N#Cc1cc(Br)c(C(=O)CCl)s1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
Butyllithium (2.5 M solution in hexanes; 14.5 mL, 36.3 mmol) was added under nitrogen over approximately 5 min to a solution of 4-bromo-thiophene-2-carbonitrile (5.95 g, 31.6 mmol) in 300 mL of anhydrous tetrahydrofuran at dry ice-acetone temperature. After the addition, the reaction was stirred at dry ice-acetone temperature for 30 min. 2-Chloro-N-methoxy-N-methyl acetamide (4.80 g, 32.7 mmol) in 40 mL of anhydrous tetrahydrofuran was then added dropwise over 30 min. After the addition, the reaction was stirred at dry ice-acetone temperature for 4 h. 6 M HCl (36 mL) was added and the reaction allowed to warm to room temperature. The reaction was concentrated under reduced pressure to remove the tetrahydrofuran. The residue was partitioned between ethyl acetate and water. Saturated sodium chloride was added to aid in the separation of an emulsion. The organic layer was separated, washed with water, saturated sodium chloride, dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified on 800 g of silica gel (230-400 mesh) using a gradient of 30% methylene chloride in hexane to 60% methylene chloride in hexane as the eluent. Isolation of the major component gave 4-bromo-5-(chloroacetyl)thiophene-2-carbonitrile (1.81 g, 22%) as a white solid, mp 126-128° C.; MS (ESI) m/z 262.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: Cc1oc(C(=O)O)cc1-c1c(Br)cnn1C
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.7 %

Procedure:
To a solution of 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (200 mg, 0.70 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (270 mg, 0.70 mmol) [prepared according to Preparation 6] and diisopropylethylamine (0.61 ml, 3.51 mmol) in DCM at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (361 mg, 0.77 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-methyl-2-furancarboxamide (232 mg, 0.32 mmol, 46% yield) as a clear oil: LCMS (ES) m/e 615, 617 (M+H)+.