Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:30]O.Cl>CO>[O:3]=[C:4]1[CH:5]=[C:6]([C@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=3)[CH2:9]2)[O:7][NH:30]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(F)c(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(F)c(F)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 47.7 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3,4,5-trifluorophenyl)piperidine-1-carboxylate (810 mg, 2.09 mmol) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.615 mL, 2.09 mmol) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.128 mL, 2.09 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (10.77 mL, 64.62 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3,4,5-trifluoro-phenyl)piperidine-1-carboxylate (355 mg, 48%) was isolated. MS m/z 357 (M+H)+
Reaction SMILES: [C:1](=S)=[S:2].[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N:4]([CH2:5][CH2:6][CH2:7][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[S:15][C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:1]=[S:2]
Reactant: S=C=S
Reactant: NCCCN1c2ccccc2Sc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: S=C=NCCCN1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.8 %

Procedure:
4.2 g of carbon disulfide was added dropwise to a solution of 12.8 g of 10-(3-aminopropyl)phenothiazine and 7.7 ml of triethylamine in 100 ml of tetrahydrofuran. After stirring the solution at room temperature for 2 hours, a solution of 11.3 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran was added dropwise thereto, and the reaction was conducted at room temperature for 5 hours. After removing solvents in vacuo, 50 ml of ethyl acetate was added to the residue, and the crystals precipitated were collected by filtration, and the filtrate was concentrated to obtain 18.6 g of the desired compound (oily).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:20](O)[CH:21]1[O:25][CH2:24][CH2:23][CH2:22]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][O:25]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OCC1CCCO1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(CC1CCCO1)c1cc(F)ccc1F

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.661 mmol) obtained in Example 5 and tetrahydrofurfuryl alcohol (0.13 ml, 1.34 mmol) were dissolved in toluene (3 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (0.320 ml). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the reaction mixture under reduced pressure was separated and purified by flash silica gel chromatography (using a hexane/ethyl acetate mixed solvent) to give a white solid. The white solid was washed with hexane, whereby obtained were the title Isomer 294-A (low polarity) (102 mg, 0.264 mmol, 40%) and the title Isomer 294-B (high polarity) (39 mg, 0.10 mmol, 15%), each as a white powder.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH:19]N>C(O)(=O)C>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:14]=1[NH:19][C:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][C:3]2=1
Reactant: O=C1CCC(C(=O)O)CC1
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)C1CCc2[nH]c3c(Cl)cccc3c2C1
Yield: 83.1 %

Procedure:
A mixture of 4-oxo-cyclohexanecarboxylic acid (3.1 g, 21.7 mmol) and 2-chlorophenylhydrazine hydrochloride (4.0 g, 21.7 mmol) in glacial acetic acid (740 ml) is stirred at reflux for 3 h. The solvent is evaporated and water is added to the residue. The resulting precipitate is filtered off and dried under high vacuum to give the subtitle compound as a brownish solid (4.5 g) in 83% yield. tR (LC-5) 0.88 min; ESI-MS (positive ion): m/z 250.14 [M+H]+ (calcd 249.70 for C13H12NO2Cl). 1H-NMR (DMSO-d6): 1.75 (m, 1H); 2.14 (m, 1H); 2.62 (m, 5H); 6.90 (t, J=7.9 Hz, 1H); 7.02 (d, J=7.3 Hz, 1H); 7.30 (d, J=7.6 Hz, 1H); 7.92 (br s, 1H); 10.9 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]=[O:25])=[CH:4][CH:3]=1.C[Si](C)(C)[C:28]([F:31])([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=4[CH3:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: Cc1cc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(C#N)ccc1N1CCCn2c1nc1c(Cl)ccc(C(O)C(F)(F)F)c12
Reaction time: 0.17 h
Yield: 82.1 %

Procedure:
To a stirred solution of 4-(9-chloro-6-formyl-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl)-3-methylbenzonitrile (68.5 mg, 0.195 mmol) and trimethyl(trifluoromethyl)silane (86.5 μL, 0.585 mmol) in tetrahydrofuran (1.0 mL) was added a solution of tetrabutylammonium fluoride in tetrahydrofuran (1.0 M, 19.5 μL, 0.0195 mmol) at 0° C. After 10 min, hydrochloric acid (1.0 M, 0.3 mL) was added. After 30 min, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a pale yellow solid (67.4 mg, 0.160 mmol, 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:18])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[O:18][C:20]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1OCc1ccccc1
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 88.9 %

Procedure:
A mixture of 3-(benzyloxy)-4-nitrophenol (31.4 g), 2-bromo-5-(methylsulfonyl)pyridine (30.3 g), cesium carbonate (83.6 g) and N,N-dimethylformamide (300 mL) was stirred at 100° C. for 3 h. The mixture was concentrated under reduced pressure. Water was added to the residue and the resulting brown suspension was filtered to give the title compound (45.6 g, 89%) as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C:14](=O)/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[OH:23])=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.O.[NH2:26][NH2:27]>CCO>[CH3:1][C:2]1[N:3]([C:8]2[N:13]=[CH:12][C:11]([C:14]3[CH2:15][CH:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[OH:23])[NH:27][N:26]=3)=[CH:10][CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C)n1-c1ccc(C(=O)/C=C/c2ccccc2O)cn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1ccc(C)n1-c1ccc(C2=NNC(c3ccccc3O)C2)cn1
Reaction time: 0.25 h
Yield: 99.2 %

Procedure:
To a suspension of (2E)-1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-3-(2-hydroxyphenyl)prop-2-en-1-one (0.31 g, 0.97 mmol) in EtOH (8.5 mL) was added hydrazine hydrate (65% solution, 0.146 mL, 1.95 mmol). After stirring for 15 min, the reaction mixture was concentrated to give 2-{3-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-4,5-dihydro-1H-pyrazol-5-yl}phenol as a yellow solid (0.32 g, 99%). LCMS: (FA) ES+ 333.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:16]=3[N:17]=[C:18]([C:20](O)=[O:21])[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:30]1C=CN=C1)=O.N>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[CH:25]=[C:24]([CH2:26][CH3:27])[S:23][C:16]=3[N:17]=[C:18]([C:20](=[O:21])[NH2:30])[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(C(=O)O)nc2s1
Agent: N
Solvent: C1CCOC1
Product: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(C(N)=O)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
4-(4-tert-Butoxycarbonyl-piperazin-1-yl)-6-ethyl-thieno[2,3-d]pyrimidine-2-carboxylic acid (102.3 mg) was dissolved in tetrahydrofuran (0.50 mL) and 1,1′-carbonyl-diimidazole (42.3 mg) was added. The reaction was stirred at room temperature for 30 minutes and ammonia (0.5 M in dioxane, 1.57 mL) was added. The reaction was stirred at room temperature for 8 days and concentrated to dryness. The residue was purified on silica gel (0% to 10% ethyl acetate/hexane over 30 minutes) giving the desired product. Yield=47%, ES-MS: (M+H)+ 392.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[CH2:3][CH2:4][OH:5].[CH3:8][S:9](Cl)(=[O:11])=[O:10]>>[CH3:8][S:9]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:6][CH3:7])(=[O:11])=[O:10]
Reactant: CCC(C)CCO
Reactant: CS(=O)(=O)Cl
Product: CCC(C)CCOS(C)(=O)=O

Procedure:
The title compound was prepared by following the general procedure of Example 43 for mesylation as a colorless oil (384 mg, 67%) from 3-methyl-1-pentanol (300 mg, 2.90 mmol) and methanesulfonyl chloride (500 mg, 4.40 mmol). 1H NMR (CDCl3, 300 MHz) δ0.86-0.95 (m, 6H), 1.15-1.25 (m, 1H), 1.33-1.42 (m, 1H), 1.51-1.60 (m, 2H), 1.76-1.84 (m, 1H), 3.00 (s, 3H), 4.23-4.31 (m, 2H) ppm.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH2:10]1[CH:22]2[CH:13]([C:14](=[O:23])[NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=32)[CH2:12][CH2:11]1>ClCCl>[N+:1]([C:19]1[CH:18]=[CH:17][C:16]2[NH:15][C:14](=[O:23])[CH:13]3[CH2:12][CH2:11][CH2:10][CH:22]3[C:21]=2[CH:20]=1)([O-:4])=[O:2]
Reactant: O=C1Nc2ccccc2C2CCCC12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: O=C1Nc2ccc([N+](=O)[O-])cc2C2CCCC12
Reaction time: 1 h
Yield: 53 %

Procedure:
65% Nitric acid (0.33 ml) is mixed at 0° C. with 96% sulfuric acid (0.44 ml). To this end, a solution of 1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one (1.9 g, 5.3 mmol) in dichloromethane (5 ml) is added in drops. After 1 hour at room temperature, the batch is poured onto ice water, the solid is filtered off and washed with water. Column-chromatographic purification (SiO2) of the filter residue with ethyl acetate-hexane yields 0.65 g (53%) of product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 91.1 %

Procedure:
A mixture of methyl 1-(4-fluorophenyl)-indole-5-carboxylate 7c (0.58 g, 2.15 mmol) and LiOH.H2O (0.36 g, 8.6 mmol) in THF (15 mL) and H2O (10 mL) was stirred at room temperature for 5 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 7d (0.5 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15](Br)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)CCC.O>CN(C)C=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>[C:1]([O:5][C:6](=[O:30])[NH:7][CH2:8][C:9]1[N:10]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:11](=[O:25])[C:12]2[C:17]([C:18]=1[O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:16][C:15]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3ccccn3)cc12
Yield: 75.1 %

Procedure:
A solution of tert-butyl(6-bromo-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.48 g, 1 mmol), tri-n-butyl(2-pyridyl)tin (0.37 g, 1 mmol) and tetrakis(triphenylphosphine)palladium (58 mg, 0.05 mmol) in N,N-dimethylformamide (10 ml) was stirred at 100° C. for 10 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[4-butoxy-2-isobutyl-1-oxo-6-(2-pyridyl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.36 g, 75.0%) as crystals.
Reaction SMILES: CC1(C)[N:6](C([O-])=O)CCO1.C(S(C[C@@H](CC1C=CC=CC=1)C(N[C@H:23]([C:42]([OH:44])=O)[CH2:24][C:25]1[N:29](C2C=CC([N+]([O-])=O)=CC=2[N+]([O-])=O)[CH:28]=[N:27][CH:26]=1)=O)(=O)=O)(C)(C)C>>[NH:27]1[CH:26]=[C:25]([CH2:24][CH2:23][C:42]([NH2:6])=[O:44])[N:29]=[CH:28]1
Reactant: CC1(C)OCCN1C(=O)[O-]
Reactant: CC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1cncn1-c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(=O)O
Product: NC(=O)CCc1c[nH]cn1

Procedure:
In an analogous manner to that described in Example 16, by reacting t-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R or S)-hydroxy-[(R or S)-tetrahydro-2-furyl]-methyl]-2,2-dimethyl-3-oxazolidinecarboxylate with N-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamoyl]-3-(2,4-dinitrophenyl)-L-histidine there is obtained (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3R or S)-1-(cyclohexylmethyl)-2,3-dihydroxy-3[(R or S)-tetrahydro-2-furyl]propyl]imidazole-4-propionamide in the form of a yellow amorphous powder, MS: 827 (M+H)+. The cleavage of the dinitrophenyl group with thiolactic acid is effected in an analogous manner to Example 13 and yields (S)-α-[(S)-α-[(t-butylsulphonyl)methyl]hydrocinnamamido]-N-[(1S,2R,3R or S)-1-(cyclohexylmethyl -2,3-dihydroxy-3-[(R or S)-tetrahydro-2-furyl]propyl]imidazole-4-propionamide as a pale yellow amorphous solid, MS: 661 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[O:16]=[C:17]1[C:25]2([C:29]3=[CH:30][C:31]4[O:32][CH2:33][CH2:34][O:35][C:36]=4[CH:37]=[C:28]3[O:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]1[CH2:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>ClCCl>[F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:43](=[O:44])[C:42]1[CH:41]=[CH:40][C:39]([CH2:38][N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3([C:29]4[C:28](=[CH:37][C:36]5[O:35][CH2:34][CH2:33][O:32][C:31]=5[CH:30]=4)[O:27][CH2:26]3)[C:17]2=[O:16])=[CH:47][CH:46]=1
Reactant: O=C(Cl)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Reactant: Nc1ccccc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1F)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 42 h
Yield: 50.1 %

Procedure:
To a stirred solution of 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoic acid (0.400 g, 0.93 mmol) in anhydrous chloroform (20 mL) was added thionyl chloride (0.27 mL, 3.7 mmol). The solution was heated at reflux for 2 h and concentrated in vacuo to afford 4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzoyl chloride (0.45 g) as a pale yellow solid. To a solution of 2-fluoroaniline (0.1 mL, 1.0 mmol) and triethylamine (0.43 mL, 3.1 mmol) in anhydrous dichloromethane (10 mL) at 0° C. under nitrogen was added 4-((2′-oxo-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indoline]-1′-yl)methyl)benzoyl chloride (0.46 g, 1.0 mmol). The reaction mixture was stirred at ambient temperature for 42 h and was washed with 10% w/v hydrochloric acid (10 mL), water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography and eluted with hexanes/ethyl acetate (1/1) to afford N-(2-fluorophenyl)-4-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]benzamide (0.262 g, 49%) as a colorless solid: mp 245-251° C.; 1H NMR (300 MHz, CDCl3) δ 8.48-8.43 (m, 1H), 8.11-8.04 (m, 1H), 7.88 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H), 7.24-7.02 (m, 6H), 6.75 (d, J=7.8 Hz, 1H), 6.52 (s, 1H), 6.24 (s, 1H), 5.16 (d, J=15.9 Hz, 1H), 4.95 (d, J=8.7 Hz, 1H), 4.89 (d, J=15.9 Hz, 1H), 4.68 (d, J=9.0 Hz, 1H), 4.21-4.10 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.6, 164.9, 155.3, 152.7 (d, J=241.4 Hz), 144.7, 141.7, 140.0, 138.3, 134.1, 132.2, 128.8, 127.8 (d, J=4.1 Hz), 126.4 (d, J=9.8 Hz), 124.7-124.6 (m), 124.1, 123.7, 121.8, 120.8, 114.8 (d, J=19.1 Hz), 111.4, 109.1, 99.5, 80.1, 64.5, 63.9, 58.0, 43.8; MS (ES+) m/z 523.0 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19])=[O:24]
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(RS)-Amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-one (250 mg, 0.93 mmol) was suspended in methylene chloride (10 ml) and treated with o-chlorobenzoylchloride (0.124 ml, 0.97 mmol) followed by triethylamine (0.143 ml, 0.97 mmol). The solution was stirred at room temperature overnight. The reaction solution was chromatographed on silica gel (chloroform followed by 97/3 chloroform/methanol) and the combined product fractions were evaporated to dryness in vacuo. TLC: Silica gel (90:10:1, CHCl3 :CH3OH:H2O), Rf =0.85.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:5]2=O.O.[NH2:22][NH2:23]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])=[CH:7][NH:23][N:22]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: O=c1c(-c2ccccc2F)coc2cc(O)c(Cl)cc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccccc2F)cc1Cl
Yield: 72.4 %

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-3-(2-fluoro-phenyl)-7-hydroxy-chromen-4-one (0.37 g, 1.27 mmol), hydrazine hydrate (5 ml), ethanol (15 ml). The quenched solution was extracted into ethyl acetate, washed (water), dried (MgSO4), and the solvent removed under vacuum to give a yellow oil which was purified by column chromatography to give 4-chloro-6-[4-(2-fluoro-phenyl)-1H-pyrazol-3-yl]-benzene-1,3-diol as a white solid (0.28 g, 72.4%); Rf 0.8 cf SM 0.9 ethyl acetate/hexane (70/30).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:34][NH2:35]>>[CH3:34][NH:35][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:30]([F:33])([F:32])[F:31])[CH:20]=[C:21]([C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=3[F:29])[C:15]=2[O:14]1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C(F)(F)F)cc(-c4cc(F)ccc4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3cc(F)ccc3F)c2O1

Procedure:
The title compound was prepared (0.045 g, 58%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,5-difluorophenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.10 g, 0.21 mmol) and methylamine (0.12 g, 3.9 mmol). mp 138-140° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:8][CH2:7][CH2:6][S:5][C:4]2[CH:9]=[CH:10][S:11][C:3]1=2.C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26]Cl>C(Cl)Cl>[CH3:21][O:22][CH2:23][CH2:24][O:25][CH2:26][O:1][CH:2]1[CH2:8][CH2:7][CH2:6][S:5][C:4]2[CH:9]=[CH:10][S:11][C:3]1=2
Reactant: COCCOCCl
Reactant: OC1CCCSc2ccsc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCOC1CCCSc2ccsc21
Reaction time: 117 h
Yield: 81.8 %

Procedure:
To a solution of 8-hydroxy-5,6,7,8-tetrahydrothieno[3,2-b]thiepin (16.6 g, 0.089 mole) and diisopropylethylamine (18.1 g, 0.14 mole) in methylene chloride (185 ml) was added β-methoxyethoxymethyl chloride (17.5 g, 0.14 mole) over 10 minutes under nitrogen at ambient temperature. The solution was stirred for 117 hours and then washed with cold 0.5N HCl (2×100 ml), saturated sodium bicarbonate solution, twice with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was chromatographed on silica gel (2.5 kg), eluting with 20% ethyl acetate-hexane (v/v), to yield 19.97 g (82%) of oily product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][NH:14]3)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])[C:26](O)=[O:27])=[O:23].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>C(Cl)Cl>[CH3:20][O:21][C:22](=[O:23])[NH:24][C@H:25]([C:26]([N:14]1[CH2:15][C@@H:16]([CH3:19])[CH2:17][CH2:18][C@H:13]1[C:11]1[NH:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH:9][N:10]=1)=[O:27])[CH:29]([CH3:31])[CH3:30]
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc(Br)cc3)[nH]2)NC1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
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: ClCCl
Product: COC(=O)N[C@H](C(=O)N1C[C@@H](C)CC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A mixture of (2S,5S)-2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-5-methyl-piperidine (400 mg, 1.25 mmol) and (S)-2-methoxycarbonylamino-3-methyl-butyric acid (219 mg, 1.25 mmol), HATU (475 mg, 1.25 mmol), and DIPEA (485 mg, 3.75 mmol) in DCM (20 mL) was stirred at RT overnight. The reaction mixture was concentrated and purified by thin layer chromatography (1:1 petroleum ether:EtOAc) to provide the title intermediate (550 mg, 92% yield). (m/z): [M+H]+ calcd for C22H28BrN4O3 476.13, 478.13. found 478.7.