Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](SC)(=O)[S:2]C.[C:7]([OH:13])(=[O:12])/[CH:8]=[CH:9]/[CH2:10][CH3:11].[OH-].[K+]>>[CH3:1][S:2][CH:9]([CH2:10][CH3:11])[CH2:8][C:7]([OH:13])=[O:12]
Reactant: CC/C=C/C(=O)O
Reactant: CSC(=O)SC
Agent: [K+]
Agent: [OH-]
Product: CCC(CC(=O)O)SC
Temperature: 90 °C
Reaction time: 3 h
Yield: 151.8 %

Procedure:
S,S-dimethyl carbonodithioate (1.467 g, 12.00 mmol) was added with vigorous stirring to a solution of (E)-pent-2-enoic acid (2.002 g, 20 mmol) in 30% KOH solution (prepared from potassium hydroxide (3.87 g, 69 mmol) and Water (10 mL)). The reaction mixture was slowly heated to 90° C. over a period of 20-30 min. Heating was continued for 3 hours before the reaction was cooled down to 25° C. and quenched slowly with HCl. The mixture was then extracted with DCM (3×30 mL), combined organic layer dried and concentrated to give 3-(methylthio)pentanoic acid (2.7 g, 18.22 mmol, 91% yield) as light orange oil: IR (Thin film) 2975, 1701 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.92 (qd, J=7.3, 5.6 Hz, 1H), 2.63 (d, J=7.2 Hz, 2H), 2.08 (s, 3H), 1.75-1.51 (m, 2H), 1.03 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.14, 43.95, 39.78, 27.04, 12.95, 11.29; EIMS m/z 148.
Reaction SMILES: C(OC([N:8]1[CH2:31][CH2:30][C:11]2[N:12]=[C:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:23]([C:13]1[N:14]=[C:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:10]2[CH2:9][NH:8][CH2:31][CH2:30][C:11]=2[N:12]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccccc3)nc(-c3ccc(F)cc3)c2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2nc(Cc3ccccc3)nc3c2CNCC3)cc1
Reaction time: 4 h
Yield: 84.3 %

Procedure:
A solution of the product from Step B (0.131 g, 0.312 mmol) in CH2Cl2 was treated with TFA. After stirring for 4 h, the mixture was concentrated and partitioned between saturated (satd.) aq. NaHCO3 and CH2Cl2 (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (1-7% 2 M NH3 in MeOH/CH2Cl2) to give 0.084 g (84%) of the title compound. MS (ESI): exact mass calcd. for C20H18FN3, 319.15; m/z found, 320.4 [M+H]+. 1H NMR (CDCl3): 7.51 (dd, J=5.4, 8.8, 2H), 7.41 (d, J=7.4, 2H), 7.31-7.27 (m, 2H), 7.22-7.19 (m, 1H), 7.15 (dd, J=8.7, 2H), 4.27 (s, 2H), 3.95 (s, 2H), 3.24 (t, J=6.1, 2H), 2.97 (t, J=6.1, 2H).
Reaction SMILES: C[Li].[C:3]([O:11][CH3:12])(=[O:10])[C:4]#[C:5][CH2:6][CH2:7][CH:8]=[CH2:9].[CH2:13](O)C>C1COCC1.CCOCC.[Cu]I>[CH3:13]/[C:5](/[CH2:6][CH2:7][CH:8]=[CH2:9])=[CH:4]/[C:3]([O:11][CH3:12])=[O:10]
Reactant: CCO
Reactant: C=CCCC#CC(=O)OC
Agent: [Cu]I
Agent: [Li]C
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC/C(C)=C\C(=O)OC
Temperature: -20 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A suspension of copper(I) iodide (12.38 g, 65 mmol) in 150 mL of dry THF under a nitrogen atmosphere was cooled to −20° C., and methyllithium (1.6 M in ether, 81.5 mL, 130 mmol) was added dropwise over 15 min. The solution was cooled to −78° C., and 4.49 g (32.5 mmol) of the compound from Example 19 in 15 mL of dry THF was added gradually, keeping the temperature below −70° C. After 1 h, 40 mL of ethanol was added cautiously, and the mixture was allowed to warm to room temperature. The mixture was diluted with ether, and washed with satd aq NH4Cl (200 mL), 5N NH3 (4×250 mL), water (200 mL), and brine (200 mL), dried, and the bulk of the solvent was evaporated to give the title compound (6.8 g, 100%) as an oil. The material had only minor solvent contamination and was adequate for use in the next reaction.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1.[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15]>ClCCl>[OH:13][CH:10]1[CH2:11][CH2:12][N:8]([C:20]([C:19]2[CH:23]=[CH:24][CH:25]=[C:17]([N+:14]([O-:16])=[O:15])[CH:18]=2)=[O:21])[CH2:9]1
Reactant: OC1CCNC1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
2.22 g of triethylamine (20 mmol), followed by 1.74 g of pyrrolidin-3-ol (20 mmol), were added to a solution of 3.71 g of 3-nitrobenzoyl chloride (20 mmol) in 40 ml of dichloromethane cooled to 0° C. The reaction medium was stirred at ambient temperature for 2 hours and was then diluted with 50 ml of dichloromethane. The organic phase was washed with 50 ml of a 1 N hydrochloric acid solution and then with 50 ml of a saturated sodium hydrogen carbonate solution, dried over magnesium sulfate and evaporated. 3.78 g of (3-hydroxypyrrolidin-1-yl)-(3-nitrophenyl)methanone were obtained and used without purification in the next step. Yield=80%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:21](OC)=[O:22])=[N:11][N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1>CO>[CH2:1]([O:8][C:9]1[C:10]([C:21]([NH:31][CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)=[O:22])=[N:11][N:12]2[CH2:17][CH:16]([CH3:18])[N:15]([CH3:19])[C:14](=[O:20])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)N(C)C(C)C2
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: CC1Cn2nc(C(=O)NCc3ccc(F)cc3)c(OCc3ccccc3)c2C(=O)N1C
Reaction time: 4 h

Procedure:
To a solution of methyl 3-benzyloxy-5,6-dimethyl-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxylate (72 mg, 0.219 mmol) in MeOH was added 4-fluorobenzylamine (376 μL, 3.28 mmol). The mixture was heated to reflux overnight and then at 110° C. for 4 hours. The mixture was purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA), and collection and concentration of the appropriate fractions afforded the amide as a yellow oil. ES MS (M+1)=423.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH2:21])=[O:20])=[CH:17][CH:16]=2)[N:10]=1.Br[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([NH:21][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[O:20])=[CH:17][CH:16]=2)[N:10]=1
Reactant: NC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Yield: 10.5 %

Procedure:
To a solution of 4-(3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)benzamide (Intermediate-17, 0.100 g, 0.301 mmol) in dry toluene (5 mL) was added 1-bromo-4-(trifluoromethyl)benzene (0.101 g, 0.451 mmol), sodium tert-butoxide (0.058 g, 0.602 mmol), tris(diphynylideneacetone)dipalladium(0) (0.005 g, 0.0006 mmol), 4,5 bis(diphenylphosphino) and 9,9-dimethylxanthene (0.005 g, 0.0009 mmol) under nitrogen atmosphere. The reaction mass was refluxed for 3-4 h. The reaction mass was quenched in water and extracted in ethyl acetate. The organic layer was concentrated to afford crude product which was purified by column chromatography to afford 0.015 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.40 (br s, 1H), 7.84 (t, J=9 Hz, 1H), 7.55 (d, 1H), 7.72-7.75 (m, 3H), 8.02 (d, J=8.1 Hz, 2H), 8.11 (br s, 3H) 10.61 (br s, 1H), 12.70 (br s, 1H). MS (m/z): 475.18 (M−H)−.
Reaction SMILES: C(OC1[CH:12]=[CH:11][C:8]([CH:9]=[CH2:10])=[CH:7][CH:6]=1)(=O)C.[OH-].[K+].C(O[C:20]([O:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O)(C)(C)C>[OH-].[K+].CO>[C:26]([O:25][C:23]([O:22][C:20]1[CH:10]=[CH:9][C:8]([CH:11]=[CH2:12])=[CH:7][CH:6]=1)=[O:24])([CH3:27])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Temperature: 12 °C
Yield: 83.2 %

Procedure:
A solution comprising 2.4 g of potassium hydroxide, 201 g 4-acetoxystyrene and 500 g of methanol was heated at reflux for 2.2 hours. The reaction was cooled to 12° C. and 64 g potassium hydroxide pellets were added over a period of 10 minutes. After warming to 25° C., 314 g di-tertiary-butyl-dicarbonate was introduced over a period of one hour. After an additional 2.3 hours of reaction time, the reaction slurry was washed with water and extracted with ethyl acetate. The ethyl acetate was stripped from the extraction mixture using a rotary evaporator, and the residual oil was charged with 0.26 g phenothiazine inhibitor. Distillation at 0.1 mm Hg yielded 227.2 g (85% yield) 4-tertiary-butoxycarbonyloxystyrene (IV).
Reaction SMILES: [CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Si:40]([O:47][C:48]1[CH:55]=[CH:54][C:51]([CH:52]=[O:53])=[CH:50][CH:49]=1)([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:42])[CH3:41]>O1CCCC1.CCCCCC>[CH2:1]([N:8]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:52]([C:51]2[CH:50]=[CH:49][C:48]([O:47][Si:40]([C:43]([CH3:46])([CH3:45])[CH3:44])([CH3:41])[CH3:42])=[CH:55][CH:54]=2)[OH:53])=[CH:30][CH:29]=1)[CH2:9][C@H:10]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C(O)c2ccc(CCN(Cc3ccccc3)C[C@H](O[Si](C)(C)C(C)(C)C)c3cccc(Cl)c3)cc2)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
To a solution of (2R)-N-benzyl-N-[2-(4-bromophenyl)-ethyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethanamine (2.1 g) in tetrahydrofuran (25 ml) was added a solution of butyllithium in hexane (1.59M, 2.83 ml) dropwise at −70° C. under nitrogen and the mixture was stirred at −70° C. for 30 minutes. To the reaction mixture was added 4-[[tert-butyl(dimethyl)silyl]oxy]benzaldehyde (977 mg) at −70° C., and the mixture was stirred at −70° C. for 1 hour. The mixture was allowed to warm to room temperature and partitioned between ethyl acetate and water. The organic layer was separated, washed with saturated sodium biscarbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=10/1) to give [4-[2-[N-benzyl-N-[(2R)-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)-ethyl]amino]ethyl]phenyl][4-[[tert-butyl(dimethyl)silyl]-oxy]phenyl]methanol (1.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10]([CH:12]=O)=O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:12][CH:10]=[N:9]2
Reactant: Nc1ccc(Br)cc1N
Reactant: O=CC=O
Solvent: CO
Product: Brc1ccc2nccnc2c1
Yield: 51 %

Procedure:
In a round bottom flask under nitrogen was combined 4-Bromo-benzene-1,2-diamine (2.01 g, 10.7 mMol), methanol (50 mL), and glyoxal (40% by wt. 3.1 mL, 26.9 mMol) and the resulting solution stirred overnight. Upon arrival the reaction was concentrated to dryness on a rotary evaporator and purified by flash column chromatography on silica gel using 5-10% ethyl acetate in dichloromethane as eluant to yield 1.14 g (50% yield) of 6-Bromo-quinoxaline as a yellow-orange solid. 1H NMR (DMSO-d6): δ=9.00 (d, 2H, J=2.8 Hz), 8.36 (d, 1H, J=2.2 Hz), 8.07 (d, 1H, J=9.0 Hz), 8.02 (dd, 1H, J=8.8, 2.1 Hz). CHN for C8H5BrN2: calc. C, 45.97; H, 2.41; N, 13.4. found C, 45.99; H 2.09; N 13.09. LC/MS (Method A), rt=1.10 mins., purity=99%, calculated mass=208, [M+H]+=209/21. HPLC (Method C): rt=7.4 mins., purity=98.52% @ 210-370 nm and 98.8% @ 322 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Cl:10][CH2:11][C:12](OCC)(OCC)OCC>C(O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[S:9][C:12]([CH2:11][Cl:10])=[N:1][C:2]=2[CH:7]=1
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1cc(Cl)ccc1S
Solvent: CCO
Product: ClCc1nc2cc(Cl)ccc2s1
Temperature: 60 °C
Yield: 81.1 %

Procedure:
0.966 g of 2-amino-4-chloro-benzenethiol was dissolved in 10 ml of abs. ethanol. 1.44 g of 2-chloro-1,1,1-triethoxy-ethane were added and the reaction was heated at 60° C. overnight. The reaction mixture was then concentrated in vacuo, dissolved in diethyl ether and the organic phase was washed once each with 5% aqueous hydrochloric acid, followed by water and 10% aqueous sodium bicarbonate. The organic layer was dried with magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica with heptanes/dichloromethane afforded 1.071 g of 5-chloro-2-chloromethyl benzothiazole as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22](=[O:24])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:17]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1.[CH:32]([Mg]Cl)([CH3:34])[CH3:33].[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([C:22]([OH:24])([CH:32]([CH3:34])[CH3:33])[CH3:23])[CH:19]=[C:18]([CH2:25][O:26][CH2:27][C:28]([F:29])([F:30])[F:31])[N:17]=2)[CH:6]=[CH:7][C:8]=1[C:9]1[O:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: CC(C)[Mg]Cl
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)=O)n2)ccc1-c1cnc(C)o1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(Nc2nc(COCC(F)(F)F)cc(C(C)(O)C(C)C)n2)ccc1-c1cnc(C)o1
Reaction time: 0.08 h

Procedure:
1-(2-(3-Methoxy-4-(2-methyloxazol-5-yl)phenylamino)-6-((2,2,2-trifluoroethoxy)methyl)-pyrimidin-4-yl)ethanone (60 mg, 0.14 mmol) was dissolved in THF (5 mL) and was added slowly to a solution of isopropyl magnesium chloride (2 M in THF, 0.206 mL, 0.41 mmol) in THF (5 mL). The mixture was stirred for 5 min. The mixture was cooled on an ice bath, ammonium chloride (sat, aq, 5 mL) was added. The mixture was stirred for 5 min. The mixture was extracted with EtOAc (×2). The solvents were evaporated and the residue was purified by column chromatography on silica eluting with a gradient of MeOH in DCM to give the title compound as a solid, 40 mg (61%).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([C:27](=[O:28])[C:26]5[CH:30]=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 68 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.=135-140° C.; 400 MHz 1H NMR (CDCl3) δ: 7.93-7.91 (m, 1H), 7.83-7.82 (m, 1H), 7.67-7.64 (m, 1H), 7.45-7.25 (m, 4H), 4.65-4.5 (bs, 1H), 3.80-3.65 (bs, 1H), 3.55-3.35 (m, 2H), 2.98 (s, 2H), 2.30-2.05 (m, 2H), 2.00-1.67 (m, 2H); LCMS: 518 [M+H].
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:27])[CH2:22][CH2:21]1.C(N(CC)CC)C>ClCCl>[C:1]1([S:7]([N:31]2[CH2:30][CH2:29][N:28]([C:26]([N:23]3[CH2:22][CH2:21][N:20]([C:19]4[CH:18]=[CH:17][N:16]=[CH:15][C:14]=4[F:13])[CH2:25][CH2:24]3)=[O:27])[CH2:33][CH2:32]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(N1CCNCC1)N1CCN(c2ccncc2F)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCN(c2ccncc2F)CC1)N1CCN(S(=O)(=O)c2ccccc2)CC1
Temperature: 5 °C
Reaction time: 18 h
Yield: 63.7 %

Procedure:
Phenylsulphonyl chloride (0.38 g) was added to a mixture of 1-[(3-fluoro-4-pyridyl)piperazin-4-ylcarbonyl]piperazine dihydrochloride (0.65 g) and triethylamine (1.5 ml) in dichloromethane (30 ml) at 5° C. The solution was stirred at 5° C. for 1 hour and at ambient temperature for 18 hours. The solution was evaporated to dryness. The residue was dissolved in dichloromethane (100 ml), and the solution was washed with water (3×10 ml), dried (Na2SO4) and evaporated. The residue was purified by chromatography on alumina (N32-63) using 0.1-0.3% methanol in dichloromethane as eluent. Recrystallisation from ethyl acetate/isohexane gave 1-phenylsulphonyl-4-[1-(3-fluoro-4-pyridyl)piperazin-4-ylcarbonyl]piperazine (0.49 g), as an off-white solid mp 143-145° C: NMR (CDCl3): 3.05 (t, 4H), 3.25 (t, 4H), 3.40 (m, 8H), 6.70 (dd, 1H), 7.60 (m, 3H), 7.78 (s, 2H), 8.20 (dd, 2H); m/z 434 (M+1).
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:25][N:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([NH2:35])[CH:32]=2)[CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:35][C:31]4[CH:32]=[C:33]5[C:28](=[CH:29][CH:30]=4)[CH2:27][N:26]([CH3:25])[CH2:34]5)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Reactant: CN1Cc2ccc(N)cc2C1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1Cc2ccc(Nc3nc4c(NCc5cccnc5N(C)S(C)(=O)=O)cccn4n3)cc2C1

Procedure:
166 f) N-Methyl-N-(3-{[2-(2-methyl-2,3-dihydro-1H-isoindol-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 2-methyl-2,3-dihydro-1H-isoindol-5-ylamine (34.0 mg, 0.229 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as tan foam (0.048 g, 49%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=3.6 Hz, 1H), 7.87-7.81 (m, 2H), 7.53 (s, 1H), 7.33-7.25 (m, 2H), 7.14 (d, J=8.1 Hz, 1H), 6.72 (s, 1H), 6.66 (t, J=7.4 Hz, 1H), 6.30 (d, J=7.6 Hz, 1H), 5.33-5.29 (m, 1H), 4.77 (d, J=6.2 Hz, 2H), 3.94 (s, 2H), 3.88 (s, 2H), 3.32 (s, 3H), 3.09 (s, 3H), 2.60 (s, 3H). MS=479 (MH)+.
Reaction SMILES: [CH:1]1([SH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]Br.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Br:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][S:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrCc1cccc(Br)c1
Reactant: SC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(CSC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of cyclohexylmercaptan (1.09 mL, 8.89 mmol), 3-bromobenzyl bromide (2.22 g, 8.882 mmol) and K2CO3 (2.54 g, 18.38 mmol) in acetone was stirred under argon at room temperature for 4 hrs then filtered. The filtrate was concentrated under reduced pressure. Purification by flash chromatography (0% to 20% EtOAc—hexanes gradient) gave (3-bromobenzyl)(cyclohexyl)sulfane as a colorless oil. Yield (2.02 g, 80%); 1H NMR (400 MHz, CDCl3) δ 7.48 (t, J=1.8 Hz, 1H), 7.33-7.37 (m, 1H), 7.22-7.26 (m, 1H), 7.16 (t, J=7.8 Hz, 1H), 3.68 (s, 2H), tt, J=3.33, 10.0 Hz, 1H), 1.87-1.96 (m, 2H), 1.69-1.77 (m, 2H), 1.53-1.61 (m, 1H), 1.18-1.38 (m, 5H).
Reaction SMILES: C(O[C:4](=[O:36])[C@:5]([O:11][CH2:12][C@@:13]([C:28]1[CH:33]=[C:32]([Br:34])[CH:31]=[CH:30][C:29]=1[F:35])([NH:15][S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26])(=[O:18])=[O:17])[CH3:14])([CH3:10])[C:6]([F:9])([F:8])[F:7])C.[NH3:37]>CO>[Br:34][C:32]1[CH:31]=[CH:30][C:29]([F:35])=[C:28]([C@:13]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])(=[O:17])=[O:18])([CH3:14])[CH2:12][O:11][C@@:5]([CH3:10])([C:6]([F:8])([F:7])[F:9])[C:4]([NH2:37])=[O:36])[CH:33]=1
Reactant: N
Reactant: CCOC(=O)[C@@](C)(OC[C@](C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F)C(F)(F)F
Solvent: CO
Product: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F

Procedure:
A solution of (R)-2-[(R)-2-(5-bromo-2-fluoro-phenyl)-2-(2-nitro-benzenesulfonylamino)-pro-poxy]-3,3,3-trifluoro-2-methyl-propionic acid ethyl ester (26.6 g, 44.2 mmol) in 7N NH3 in MeOH (75 ml) was stirred for 16 h at 50° C. The solvent was removed under reduced pressure and the residual solid re-crystallized from Et2O to give the title compound as yellow crystals: TLC (hexane-EtOAc 1:1): Rf=0.35; UPLC RtH5=1.184 min; ESIMS: 589, 591 [(M+NH4)+]; 1H NMR (360 MHz, CDCl3): δ 7.85 (d, 1H), 7.64 (m, 3H), 7.44 (d, 1H), 7.41 (dd, 1H), 7.26 (m, 1H), 6.68 (br s, 1H), 6.57 (dd, 1H), 6.19 (s, 1H), 5.54 (br s, 1H), 4.24 (d, 1H), 3.93 (d, 1H), 1.79 (s, 3H), 1.67 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[Cl:15][CH2:16][C:17](Cl)=[O:18]>CC(C)=O>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:17](=[O:18])[CH2:16][Cl:15])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CCl)Nc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 8.60 g (0.05 mol) of 4-bromoaniline, 10.60 g (0.10 mol) of Na2CO3, and 6.78 g (0.06 mol) of chloroacetyl chloride in 100 mL of acetone was stirred at ambient temperature for 3 h. The mixture was concentrated in vacuo, and the residue was partitioned between EtOAc and H2O. The organic layer was separated, washed with H2O, dried over Na2SO4, filtered, and evaporated in vacuo to give 11.4 g of analytically pure title compound as light crystals.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8](=O)[CH3:9])=[C:5]([CH3:7])[N:6]=1.[OH-].[NH4+:12].Cl>>[CH3:1][C:2]1[N:12]=[C:8]([CH3:9])[C:4]([OH:3])=[C:5]([CH3:7])[N:6]=1
Reactant: CC(=O)c1oc(C)nc1C
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: Cc1nc(C)c(O)c(C)n1
Reaction time: 3 h
Yield: 60 %

Procedure:
The 2,4-dimethyl-5-acetyloxazole is poured into a Parr Bomb with 20 ml (51 mmol) of concentrated ammonium hydroxide and brought to 180° C. in three hours. Heating is continued for 10 hours, and after cooling the mixture is brought to pH 5 with HCl, extracted into ether, dried over Na2SO4 and stripped in vacuo. The residual solid is crystallized from benzene to give pale yellow crystals (1.3 g, 60%).
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][C:6](=[CH:9][CH2:10][CH:11]=[CH2:12])[CH:7]=[O:8]>O1CCCC1>[C:1]([CH:7]([OH:8])[C:6]([CH3:5])=[CH:9][CH2:10][CH:11]=[CH2:12])#[CH:2]
Reactant: C#C[Mg]Br
Reactant: C=CCC=C(C)C=O
Solvent: C1CCOC1
Product: C#CC(O)C(C)=CCC=C
Reaction time: 3 h
Yield: 401.1 %

Procedure:
To a solution of ethynyl magnesium bromide (prepared from 2.91 g of magnesium) in 100 ml of tetrahydrofuran, was added dropwise 11.0 g of 2-methyl-2,5-hexadienal at a temperature from 0° C to 10° C under cooling with ice-bath. The resulting reaction solution was stirred for 3 hours to complete the reaction and the same after-treatment as in the Reference Example 1 was then carried out to obtain 12.3 g of a colorless oily 1-ethynyl-2-methyl-2,5-hexadienyl alcohol, b.p. 60°-65° C/7 mmHg.