Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13](=[O:40])[CH2:14][O:15][C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([C:27]([NH:29][C@@H:30]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:31](O)=[O:32])=[O:28])[CH:17]=2)=[O:7])[CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH2:74]([O:76][C:77]([N:79]1[CH2:84][CH2:83][NH:82][CH2:81][CH2:80]1)=[O:78])[CH3:75]>CN(C=O)C>[CH2:74]([O:76][C:77]([N:79]1[CH2:80][CH2:81][N:82]([C:31](=[O:32])[C@@H:30]([NH:29][C:27]([C:18]2[CH:17]=[C:16]([O:15][CH2:14][C:13]([N:9]3[CH2:10][CH2:11][CH2:12][C@H:8]3[C:6](=[O:7])[NH:5][CH:1]3[CH2:2][CH2:3][CH2:4]3)=[O:40])[N:20]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:19]=2)=[O:28])[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:83][CH2:84]1)=[O:78])[CH3:75]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(N[C@H](C(=O)O)C1CCCCC1)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@@H](NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NC3CCC3)n(-c3ccccc3)n2)C2CCCCC2)CC1
Reaction time: 12 h

Procedure:
To a mixture of 122 mg (S)-({5-[2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-cyclohexyl-acetic acid in 2.5 ml DMF were added 84 mg HATU, 116 l DIPEA and 32 l 1-ethoxycarbonylpiperazine. After stirring for 12 h it was concentrated and the crude product thus obtained was purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA) to give the title compound. Yield: 60 mg MS (ES+): m/e=692.
Reaction SMILES: [N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])([O-:3])=[O:2].[OH-].[Li+]>CO.C1COCC1.O>[N+:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])([O-:3])=[O:2]
Reactant: CCOC(=O)CCCCCO[N+](=O)[O-]
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)CCCCCO[N+](=O)[O-]
Temperature: 50 °C

Procedure:
19.1 mmol Ethyl 6-nitrooxy-hexanoate were dissolved in 222 ml Methanol/THF 1:1. 37.5 ml 1M Lithiumhydroxide in Water were added to the reaction and the cloudy solution was heated for 18 hours at 50° C. After cooling to room temperature the solution was concentrated in vacuo. The pH level of the solution was brought down to 1 with HCl 25% and extracted two times with TMBE. The organic phases were combined, washed with brine, dried over Na2SO4 and the solvent was removed in vacuo leaving 3.43 g.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=1)=O.[C:17]1([C:23](=O)[CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[O:34]=[C:33]1[NH:35][CH:1]([C:3]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([C:13]([F:16])([F:15])[F:14])[CH:4]=2)[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:32]1
Reactant: COC(=O)c1ccc(C=O)cc1C(F)(F)F
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc1C(F)(F)F

Procedure:
To a solution of methyl 4-formyl-2-(trifluoromethyl)benzoate (Intermediate 82) (180 mg, 0.80 mmol), 1,2-diphenyl-ethanone (222 mg, 0.80 mmol) and urea (145 mg, 2.4 mmol) in ethanol (3 mL) was added conc. HCl (0.2 mL), then the resulting mixture was refluxed for 2 days. The mixture was concentrated in vacuo to give methyl 4-(2-oxo-5,6-diphenyl-1,2,3,4-tetrahydropyrimidin-4-yl)-2-(trifluoromethyl)benzoate, which was used crude. This was taken up in MeOH (3 mL) and 2 N aq. NaOH (3 mL) was added; then the resulting mixture was stirred at 40° C. for 3 hours. The mixture was acidified with aqueous HCl till pH=5 and then followed a standard aqueous/EtOAc workup. Purified by prep-HPLC (0.1% TFA as additive) to give Compound 157 (34 mg, two steps yield 10%) as white solid. 1H NMR (MeOD 400 MHz) δ 7.82 (d, J=8.0 Hz, 1H), 7.72-7.67 (m, 2H), 7.36-7.20 (m, 5H), 7.10-7.05 (m, 3H), 6.88-6.85 (m, 2H), 5.30 (s, 1H). MS (ESI): m/z 439.2 [M+1]+.
Reaction SMILES: CCN(S(F)(F)[F:7])CC.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([N:20]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:37][CH:38]=[CH:39][N:40]=3)=[CH:32][C:31]=2[F:41])[C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:27]O)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:20]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[O:37][CH:38]=[CH:39][N:40]=3)=[CH:32][C:31]=2[F:41])[C@@H:21]2[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]2[CH2:27][F:7])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1F)[C@@H]1CCCC[C@H]1CO
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)cc1F)[C@@H]1CCCC[C@H]1CF
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
DAST (4-dimethylamino-N-methyl-4-stilbazolium tosylate, 9 μL, 0.06 mmol) was added to a solution of 4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (25 mg, 0.05 mmol) in 2 mL anhydrous methylene chloride at −20° C. The reaction was stirred at room temperature for 1 h, then purified by flash chromatography on silica gel with 0 to 50% ethyl acetate in hexane to yield 4-chloro-N-(2-fluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(fluoromethyl)cyclohexyl)benzenesulfonamide (8 mg, 33%). 1H NMR (400 MHz, CDCl3) δ ppm 7.82 (1H, dd, J=8.06, 1.51 Hz), 7.69-7.78 (4H, m), 7.67 (1H, dd, J=10.83, 1.51 Hz), 7.40-7.49 (2H, m), 7.23-7.26 (1H, m), 4.46 (2H, dd, J=34.50, 15.61 Hz), 3.97-4.22 (2H, m), 3.58 (1H, br. s.), 1.75-1.76 (1H, m), 1.59-1.74 (3H, m), 1.46 (2H, br. s.), 0.94-1.30 (3H, m). 19F NMR (376 MHz, CDCl3) δ ppm −111.85 (s), −118.19 (s). Analytical HPLC R.T.=25.91 min. MS [M+H]30 =481, [M+Na+]=503. HRMS [M+H]+ calc'd 481.1164, found 481.1176. Chiral LC: R.T.=6.08 min., >96% ee.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[Li]CCCC.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1C=O.[NH4+].[Cl-].[O:21]1CCC[CH2:22]1>ClCCl.CCOCC>[S:4]1[CH:5]=[CH:6][C:2]([CH:22]([C:15]2[CH:14]=[CH:13][S:12][CH:16]=2)[OH:21])=[CH:3]1
Reactant: Brc1ccsc1
Reactant: O=Cc1cccs1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCOCC
Product: OC(c1ccsc1)c1ccsc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
The solution containing 1.87 mL (20 mmol) of 3-bromothiophene, 3 mL of tetrahydrofuran, and 10 mL of ether was cooled to −78° C. under N2. To the cooled solution was then added 8 mL of n-BuLi ([2.5] M in hexane) drop wise, while maintaining the reaction temperature below −70° C. The reaction solution turned to white cloudy. The suspension was allowed to stir 15 min at <−70° C. After 15 min, a solution containing 1.75 mL (20 mmol) of 2-thiophenecarboxaldehyde and 3 mL of tetrahydrofuran was added drop wise while maintaining the reaction temperature below −70° C. After the addition, the reaction suspension was allowed to stir 1 hr at −78° C. and slowly warmed to −10° C. over 2 hr. After 2 hr, the reaction was stopped by adding 50 mL of a saturated solution of NH4Cl and 100 mL of dichloromethane. The aqueous solution was separated from the organic phase. After removing the aqueous layer, the organic layer was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The concentrated sample was purified by flashy chromatography (hexane:ethyl acetate, from 10 to 15% ethyl acetate over 16 column volume) to obtain 2.12 gm (53.9%) of yellow solids; 1H NMR 500 MHz (CDCl3) δ 7.29 (d, 1H), 7.29 (d, 1H), 7.22 (t, 1H), 7.21 (t, 1H), 7.05 (d, 1H), 7.04 (d, 1H), 5.97 (d, 1H), 2.22 (d, 1 H).
Reaction SMILES: CC(C)([O-])C.[K+].[OH:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][CH:12]=[CH:11]2.Cl[CH:19]([O:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21].O>C(O)(C)(C)C.[I-].[K+]>[N:14]1[C:15]2[C:10](=[CH:9][C:8]([O:7][CH:19]([O:25][CH2:26][CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(Cl)OCC
Reactant: Oc1ccc2ncccc2c1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C(OCC)Oc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.7 %

Procedure:
Potassium t-butoxide (3.15 g) was dissolved in t-butyl alcohol (20 ml) and stirred for 10 minutes at ambient temperature. 6-Hydroxyquinoline (3.0 g) was added, the resulting dark green solution was stirred for 15 minutes, and then ethyl 2-chloro-2-ethoxyacetate (4.22 g, 90% pure) added, followed by a catalytic amount of potassium iodide (0.005 g). The mixture was stirred for 18 hours, poured into water and extracted with chloroform. The organic fraction was washed with brine, water, and dried over magnesium sulphate. The solvent was evaporated to give a brown oil, which was purified by flash chromatography on silica gel, eluting with a gradient of ethyl acetate:hexane (1:2 to 4:1) to give ethyl 2-(6-quinolinyloxy)-2-(ethoxy)acetate as a pale brown oil (3.68 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:24][O:23][C:21](=[O:22])[CH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:19][CH:18]=1
Reactant: COC(=O)Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C2CCNCC2)cc1

Procedure:
The compound is prepared analogously to Example XI.1 using 4-(4-methoxycarbonylmethyl-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (VIII.2) as educt and TFA in DCM instead of HCl. The crude product is used without further purification in the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([F:18])=[CH:20][CH:21]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)cc1)c1ccc(F)cc1
Yield: 77.5 %

Procedure:
To a solution of 4-fluorobenzenesulfonyl chloride (2 g, 10.3 mmol) at room temperature was stirred with pyridine (2.49 mL, 30.8 mmol) and 4-fluoroaniline (1.95 mL, 20.6 mmol) for 2 hrs. The reaction was quenched with 1 M HCl aqueous and then extracted with DCM, filtered through a phase separator and purified by silica gel column chromatography (0-100% DCM in cyclohexane) to give 4-fluoro-N-(4-fluoro-phenyl)-benzenesulfonamide (2.15 g, 78%). LCMS (m/z, Method A) ES+ 270 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:10][CH:9]([CH3:11])[O:8][C:7]([CH3:18])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[CH:19]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([F:28])[CH:27]=1)#[N:21].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:11][C@H:9]1[O:8][C@@:7]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[CH:19]=[C:2]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([F:28])[CH:25]=3)[C:20]#[N:21])[CH:3]=[CH:4][C:5]=2[NH:10]1
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Reactant: CC1Nc2ccc(Br)cc2C(C)(c2ccccc2)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C[C@@H]1Nc2ccc(-c3cc(F)cc(C#N)c3)cc2[C@](C)(c2ccccc2)O1
Temperature: 85 °C
Yield: 13.2 %

Procedure:
A mixture of 6-bromo-2,4-dimethyl-4-phenyl-1,4-dihydro-2H-3,1-benzoxazine (0.6 g, 1.9 mmol), 3-cyano-5-fluorobenzene boronic acid (0.45 g, 2.7 mmol), tetrakis(triphenylphosphine)palladium(0) (0.2 g, 0.17 mmol), sodium carbonate (0.6 g, 5.7 mmol) in a mixture of DME and water (20/5 mL) was subject to a positive nitrogen flow to remove oxygen and then heated to 85° C. under a blanket of nitrogen for 2 hours. The mixture was allowed to cool to ambient temperature. Brine (30 mL) and ethyl acetate (100 mL) were added. The organic layer was separated and aqueous layer was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (MgSO4), and evaporated. The residue was purified by a silica gel column chromatography (hexane:ethyl acetate/4:1) to afford the title compound as off-white solid (0.09 g, 13%): mp 128-129° C.; 1H-NMR (DMSO-d6) δ 8.08 (s, 1H), 7.91 (dt, 1H, J=10.7, 1.9 Hz), 7.71 (d, 1H, J=2.0 Hz), 7.65 (m, 1H), 7.57 (dd, 1H, J=8.8, 2.4 Hz), 7.32-7.36 (m, 2H), 7.24-7.29 (m, 3H), 6.71 (d, 1H, J=1.6 Hz), 6.69 (d, 1H, J=8.3 Hz), 4.33 (m, 1H), 1.84 (s, 3H), 1.24 (d, 3H, J=5.5 Hz); MS (ESI) m/z 357 [M−H]−.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([CH3:17])([CH3:16])[O:10][SiH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH:24]1([C:27]2[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[C:29]([CH3:36])[CH:28]=2)[CH2:26][CH2:25]1>C1(C)C=CC=CC=1.CCCCCC>[Br:1][C:2]1[C:3]([C:9]([CH3:17])([CH3:16])[O:10][SiH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:4]([NH:8][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([CH:24]3[CH2:26][CH2:25]3)=[CH:28][C:29]=2[CH3:36])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1c(N)cccc1Br
Reactant: Cc1cc(C2CC2)ccc1C(=O)Cl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(C2CC2)ccc1C(=O)Nc1cccc(Br)c1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.7 %

Procedure:
To a solution of [3-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenylamine (21.28 g, 67.3 mmol) and anhydrous pyridine (6.5 mL, 80 mmol) in 50 mL of anhydrous toluene was added a solution of 4-cyclopropyl-2-methylbenzoyl chloride (13.25 g, 68.1 mmol) in 50 mL anhydrous toluene dropwise. A precipitate formed immediately upon addition. Stirred the mixture at ambient temperature under nitrogen overnight. Diluted the reaction mixture with 125 mL hexane and filtered off the precipitate. Washed the filtrate with 2×200 mL 1.0 M KHSO4, 2×200 mL 5% NaHCO3, and 250 mL water. Dried the solution over MgSO4 and concentrated in vacuo to obtain N-[3-Bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-4-cyclopropyl-2-methyl-benzamide as a waxy light brown solid (31.54 g, 66.4 mmol). MS (ESI) 474, 476.0 (M+H)+.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:7][S:6][C:5](=[O:8])[N:4]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16].CC(OI1(OC(C)=O)(OC(C)=O)O[C:28](=O)[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]1=2)=O.[H-].[Na+].C1C[O:44][CH2:43][CH2:42]1>C(Cl)Cl>[O:8]=[C:5]1[N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[C@@H:3](/[CH:2]=[CH:42]/[C:43](=[O:44])[CH2:28][C:27]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:7][S:6]1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: C1CCOC1
Reactant: N#CCCCCCCN1C(=O)SC[C@@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CCCCCCCN1C(=O)SC[C@@H]1/C=C/C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-2 (0.65 g, 2.7 mmol) in 15 mL CH2Cl2 was added Dess Martin periodinane (1.4 g, 3.2 mmol) portion wise and the resulting solution was stirred for 2 hours. The solution was concentrated in vacuo, to which toluene was added and concentrated thrice to remove acetic acid. The concentrate was then filtered through celite with CH2Cl2 and concentrated in vacuo. The crude product was then diluted in 7 mL of THF and added to a solution of the Wittig reagent dimethyl 2-oxo-3-phenylpropylphosphonate (1.3 g, 5.3 mmol) and 60% sodium hydride (0.2 g, 5.1 mmol) in 7 mL of THF at 0° C. which had been premixed 30 minutes. The reaction mixture was stirred for 15 minutes at the initial temperature and was allowed to warm up to room temperature for 1 hour. The solution was stored at 4° C. overnight, quenched with saturated aqueous ammonium chloride solution and was extracted with ethyl acetate. The organic phases were then combined, and sequentially washed with H2O, brine and dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by flash chromatography using 40% ethyl acetate/hexanes to yield 350 mg of 4-3 as a colorless oil. 1H NMR (400 MHz, CDCl3): δ 7.37–7.20 (m, 5H), 6.74 (dd, 1H), 6.31 (d, 1H), 4.34 (q, 1H), 3.88 (s, 2H), 3.54–3.44 (m, 2H), 3.01 (dd, 1H), 2.77 (m, 1H), 2.33 (t, 2H), 1.67–1.60 (m, 2H), 1.47–1.30 (m, 4H), 1.28–1.23 (m, 2H); MS (+ESI): m/z 356.9 (M+1)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:39])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](O)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[NH:40]([C:42](OC(C)(C)C)=O)[NH2:41].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.C(OCC)(=O)C.CN(C=O)C>[O:37]1[CH:42]=[N:40][N:41]=[C:36]1[CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:39])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][N:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)O)CC2)c2ncnn12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCc3nnco3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 13 h

Procedure:
A mixture of [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetic acid (0.45 g), tert-butyl hydrazinecarboxylate (0.13 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.19 g), 1-hydroxybenzotriazole (0.13 g) and N,N-dimethylformaldehyde (5 mL) was stirred at room temperature for 13 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in trifluoroacetic acid (5 mL), and the mixture was stirred at room temperature for 1 hr. 1 M Aqueous sodium hydroxide solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was mixed with ethyl orthoformate (0.37 g), methanesulfonic acid (0.016 g) and tetrahydrofuran (7 mL), and the mixture was heated under reflux for 2 hr. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.17 g, 37%).
Reaction SMILES: [C:1](=[NH:25])([O:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=2)=[C:8]([F:24])[CH:7]=1)[NH2:2].[OH:26]/[CH:27]=[C:28](/[CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[N:38][CH:39]=1)\[C:29](OC)=O.[C:40]([O-:43])([O-])=[O:41].[K+].[K+]>CN1C(=O)CCC1>[F:21][C:20]([F:23])([F:22])[C:40]([OH:43])=[O:41].[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][O:3][C:1]3[NH:2][CH:29]=[C:28]([CH2:33][C:34]4[CH:39]=[N:38][CH:37]=[N:36][CH:35]=4)[C:27](=[O:26])[N:25]=3)=[CH:7][C:8]=2[F:24])=[CH:14][C:15]=1[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)/C(=C\O)Cc1cncnc1
Reactant: O=C([O-])[O-]
Reactant: N=C(N)OCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(F)c1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)C(F)(F)F
Product: O=c1nc(OCCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)c(F)c2)[nH]cc1Cc1cncnc1
Temperature: 160 °C
Yield: 82.9 %

Procedure:
The mixture of 2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-3-fluorophenyl)ethyl imidocarbamate (200 mg, 0.380 mmol), methyl (2Z)-3-hydroxy-2-(5-pyrimidinylmethyl)-2-propenoate (147 mg, 0.759 mmol) and K2CO3 (105 mg, 0.759 mmol) in NMP (5 mL) was heated with a microwave reactor at 160° C. for 1.5 h. Purification via MDAP then afforded the title compound (100 mg, 41.5% yield). LCMS: rt=3.42 min, [M+H+]=521
Reaction SMILES: C([O:9][C@H:10]1[CH2:14][C:13]([F:16])([F:15])[CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CO>[F:16][C:13]1([F:15])[CH2:14][C@H:10]([OH:9])[C@@H:11]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=2)[CH2:12]1
Reactant: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1OC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cn1nccc1[C@H]1CC(F)(F)C[C@@H]1O
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a solution of the (1S*,2R*)-4,4-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl benzoate (90 mg, 0.294 mmol) prepared in Example 107d in methanol (3.0 mL), potassium carbonate (60 mg, 0.434 mmol) was added, and the reaction solution was stirred for 30 minutes. To the reaction solution, water (10 mL) was added, and an organic layer was extracted with ethyl acetate (20 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (dichloromethane/methanol=96:4) to yield the title compound (48 mg, 81%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[S:22][C:5]2[NH:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH3:23]N(C)CCN(C)C.C([Li])CCC.CI>O1CCCC1.O>[CH3:1][C:2]1[S:22][C:5]2[N:6]([CH3:23])[C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[N:9]=[C:10]([N:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1
Reactant: CN(C)CCN(C)C
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cc2c(s1)N(C)c1ccccc1N=C2N1CCN(C)CC1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
A solution of 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (3.1 g) (European Patent Publication 0 454 436) in dry tetrahydrofuran (distillated from sodium/benzophenone) was stirred and cooled to -70° C. Tetramethylethylenediamine (1.16 g) was added followed by n-butyllithium (6.25 ml, 0.6M solution), keeping the temperature below -60° C. The deep red solution was stirred for 15 minutes and then methyl iodide (1.42 g) was added. The reaction was allowed to attain room temperature, during which time the red colour discharged. Water was added and the product extracted with ethyl acetate. The solvent was washed with water, dried and evaporated to dryness under reduced pressure. The product was purified by chromatography on Florisil using ethyl acetate as eluent and crystallised from acetronitrile to give the title compound, m.p. 126-128° C.