Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=4)[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH:9]3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1.[CH2:25](O)[CH2:26][OH:27].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:8]12[CH2:16][CH2:15][C:14]3([O:27][CH2:26][CH2:25][O:17]3)[CH2:13][CH:9]1[CH2:10][CH2:11][CH2:12][C:4]1[CH:3]=[C:2]([OH:1])[N:7]=[CH:6][C:5]=12
Reactant: OCCO
Reactant: O=C1CCC2(Cc3ccccn3)c3cnc(O)cc3CCCC2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1cc2c(cn1)C1(Cc3ccccn3)CCC3(CC1CCC2)OCCO3
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.8 %

Procedure:
A flask fitted with a Dean-Stark apparatus was charged with rac-(7aR,11aS)-3-hydroxy-11a-(pyridin-2-ylmethyl)-6,7,7a,8,11,11a-hexahydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridin-9(10H)-one (132, R2=Pyridin-2-ylmethyl) (6.8 g, 21.09 mmol), toluene (250 mL), ethane-1,2-diol (4.76 mL, 85 mmol) and pTSA (0.401 g, 2.109 mmol). The mixture was heated to reflux for about 2 h, cooled to rt then concentrated on under reduced pressure. The material was treated with sat. aq. NaHCO3 (50 mL), water (50 mL) and EtOAc (˜100 mL). The mixture was stirred for about 10 min then the solids were collected by filtration and washed with EtOAc (˜15 mL). The material was dried under vacuum. The filtrate layers were separated then the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic solutions were dried over MgSO4, filtered then combined with solids from the first filtration and concentrated under reduced pressure to yield rac-(7aR,11aS)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolan]-3-ol (143, R2=Pyridin-2-ylmethyl) (7.25 g, 94%); LC/MS, method 3, Rt=1.49 min, MS m/z 367 (M+H)+. 1H NMR (400 MHz, DMSO) δ 10.95 (s, 1H), 8.37-8.36 (m, 1H), 7.51-7.46 (m, 1H), 7.10-7.07 (m, 1H), 6.54 (s, 1H), 6.51 (d, J=7.8 Hz, 1H), 6.14 (s, 1H), 3.92-3.81 (m, 4H), 3.33 (d, J=13.3 Hz, 1H), 3.20-3.13 (m, 1H), 3.04 (d, J=13.3 Hz, 1H), 2.69-2.64 (m, 1H), 2.14-2.06 (m, 1H), 2.04-1.96 (m, 1H), 1.91-1.77 (m, 1H), 1.75-1.47 (m, 7H), 1.41-1.23 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13]O.S(Cl)([Cl:17])=O>ClCCl.O>[Cl:17][CH2:13][C:3]1[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][O:6][C:2]=1[CH3:1]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1CCl
Temperature: 0 °C
Reaction time: 2 h
Yield: 9.4 %

Procedure:
To a solution of (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (4.5 g, 236 mmol) in dichloromethane (50 mL) was added at 0° C. thionyl chloride (3.6 g, 2.7 mL, 306 mmol) dropwise over 3 min and the solution stirred at 0° C. for 2 h. After this time, the mixture was diluted with water (50 mL) and the organic phase separated and washed with brine. The aqueous phase was extracted with dichloromethane and the combined extracts dried over sodium sulfate, filtered and evaporated to afford the title compound (4.6 g, 93%) which was obtained as a light brown liquid. MS: m/e=208.1 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][C:5]([O:15][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCCBr)OCc1ccccc1
Reaction time: 2 h
Yield: 83.3 %

Procedure:
To a solution of 4-bromobutyryl chloride (Aldrich Chemical Company, Wisconsin), (10.27 g, 55.4 mmol) in 100 mL of dichloromethane was added benzyl alcohol (Aldrich Chemical Company, Wisconsin), (6.29 g, 58.1 mmol), followed by potassium carbonate (8.3 g, 60 mmol) in four portions. After 2 hours, water was added, and the layers were separated. The organic layer was washed with water, brine, and dried over magnesium sulfate. Evaporation of the solvent gave the title compound (11.87 g, 83% yield) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.36 (m, 5H), 5.14 (s, 2H), 3.46 (t, J=6.4 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 2.20 (quin, J=6.6 Hz, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:26]([F:29])([F:28])[F:27])=[C:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:19]4[CH2:25][NH:24][CH2:23][C:20]=4[NH:21][N:22]=3)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9].Cl[C:31]([N:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1)=[O:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:2][C:3]1[C:4]([C:26]([F:27])([F:28])[F:29])=[C:5]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([C:18]3[C:19]4[CH2:25][N:24]([C:31]([N:33]5[CH2:34][CH2:35][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:37][CH2:38]5)=[O:32])[CH2:23][C:20]=4[NH:21][N:22]=3)=[O:17])[CH2:12][CH2:11]2)[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: O=C(c1n[nH]c2c1CNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)N2Cc3[nH]nc(C(=O)N4CCC(c5ccc(F)c(F)c5C(F)(F)F)CC4)c3C2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
A solution of (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl) methanone hydrochloride salt (50 mg, 0.11 mmol), N,N,N-diisopropylethylamine (0.05 mL, 0.3 mmol) and DMAP (0.5 mg, 0.004 mmol) in anhydrous CH2Cl2 (1 mL) was cooled to 0° C. under an atmosphere of N2, treated with tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (30 mg, 0.12 mmol) and stirred at 0° C. for 1 h. The cooling bath was then removed and the reaction stirred at room temperature for a further 4 h. After this time, the mixture was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep gold column, 0% to 10% CH3OH in CH2Cl2) to provide tert-butyl 4-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole-5-carbonyl)piperazine-1-carboxylate as a white solid (48 mg, 71%): 1H NMR (500 MHz, CDCl3) δ 10.76 (br s, 1H), 7.33 (dd, J=17.0, 9.0 Hz, 1H), 7.11 (dd, J=9.0, 4.0 Hz, 1H), 4.88-4.52 (m, 2H), 4.69 (br s, 2H), 4.62 (s, 2H), 3.49 (apparent t, J=4.5 Hz, 4H), 3.32 (apparent t, J=4.5 Hz, 4H), 3.25 (apparent t, J=12.5 Hz, 1H), 3.14-2.88 (m, 2H), 1.94 (d, J=12.5 Hz, 2H), 1.72-1.66 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [C:1]([O:14][C@H:15]([CH2:54][O:55][C:56](=[O:68])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[CH2:16][S:17][CH2:18][C@H:19]([NH:36]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:20](=[O:35])[NH:21][C@@H:22]([CH2:33][CH3:34])[CH2:23][O:24][CH2:25][C:26](=[O:32])[O:27]C(C)(C)C)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:36][C@@H:19]([CH2:18][S:17][CH2:16][C@H:15]([O:14][C:1](=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:54][O:55][C:56](=[O:68])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])[C:20](=[O:35])[NH:21][C@@H:22]([CH2:33][CH3:34])[CH2:23][O:24][CH2:25][C:26]([OH:32])=[O:27]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC)COCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)N[C@@H](CC)COCC(=O)O)OC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (8S,11R,15R)-11-(((9H-fluoren-9-yl)methoxy)carbonylamino)-8-ethyl-2,2-dimethyl-4,10-dioxo-3,6-dioxa-13-thia-9-azahexadecane-15,16-diyl didodecanoate (1 eq, from the previous step) in 50% TFA in DCM (0.05 M) was stirred in open air at 40° C. for 1.5 hours. The mixture was dried under a stream of air and briefly evaporated under high vacuum. The resulting oil was dissolved in 20% piperidine in THF (0.1 mL) and stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate. The reaction mixture was concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% methanol in DCM to give the product as a solid. 1H NMR (DMSO-d6): δ 8.30 (d, 1H), 5.11 (m, 1H), 4.27 (dd, 1H), 4.09 (dd, 1H), 3.96 (s, 2H), 3.67-3.76 (m, 2H), 3.37-3.48 (m, 2H), 2.71-2.95 (m, 4H), 2.25-2.28 (m, 4H), 1.23-1.62 (m, 41H), 0.83-0.88 (m, 6H). LRMS [M+H]=689.4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:11]([CH3:21])([CH3:20])[C:12]([NH:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.ClS([N:32]=[C:33]=O)(=O)=O.CN(C=O)C>C(#N)C>[C:33]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:11]([CH3:21])([CH3:20])[C:12]([NH:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)=[O:13])[CH:5]=2)[NH:1][CH:2]=1)#[N:32]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2[nH]ccc2c1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2[nH]cc(C#N)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
To a stirred solution of 3-(1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 101, 25 mg, 0.067 mmol) in anhydrous acetonitrile (1 mL) was added chlorosulfonyl isocyanate (0.007 mL, 0.074 mmol) at 0° C. under argon. The reaction mixture was stirred at 0° C. for 30 min before anhydrous DMF (0.006 mL, 0.074 mmol) was added. After the reaction mixture was stirred at 0° C. for 30 min and at rt for 1 hr, it was concentrated, mixed with saturated aqueous sodium bicarbonate solution (5 mL), and extracted with dichloromethane (10 mL). The dichloromethane extract was dried (Na2SO4) and concentrated. Silica gel flash chromatography gave 3-(3-cyano-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 108, 11 mg, 0.027 mmol, 41% yield) as a white solid. MS found: (M+H)+=401. 1H-NMR (400 MHz, Acetone-d6): δ ppm 11.15 (1 H, s) 10.48 (1H, s) 8.06 (1H, d, J=2.40 Hz) 7.78 (1H, s) 7.46-7.53 (3H, m) 7.39 (1 H, d, J=8.65 Hz) 7.35 (1H, d, J=3.56 Hz) 7.28 (2H, t, J=7.38 Hz) 7.18 (1H, t, J=7.38 Hz) 7.04 (1H, d, J=3.56 Hz) 5.04 (1H, s) 1.51 (6H, d, J=2.54 Hz).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:11]1([CH3:20])[CH:16]=[CH:15][CH:14]=[C:13]([C:17](Cl)=[O:18])[CH:12]=1>O1CCCC1>[CH3:20][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[C:17]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18]
Reactant: CC(C)(C)O
Reactant: Cc1cccc(C(=O)Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)OC(C)(C)C)c1

Procedure:
To a solution of tert-butanol (12.2 ml) in tetrahydrofuran (300 ml) at 0° C. was added n-butyllithium (52 ml) dropwise over 10 minutes. m-Toluoyl chloride (20 g) was added and the mixture heated at reflux for 1 hours. The mixture was partitioned between ethyl acetate and water and the organic phase dried (MgSO4) and evaporated. Purified by chromatography eluting with 20% dichloromethane in isohexane. Yield 14.78 g. Used directly in the next step.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=2)=[C:13]([CH3:24])[S:12][C:11]=1[N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35])=[O:9])C.Cl>O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:25]3[C:33](=[O:34])[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:26]3=[O:35])[S:12][C:13]=2[CH3:24])=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1c(N2C(=O)c3ccccc3C2=O)sc(C)c1CCc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1sc(N2C(=O)c3ccccc3C2=O)c(C(=O)O)c1CCc1ccc(Br)cc1

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-[2-(4-bromophenyl)ethyl]-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-5-methy-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 30, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [C:1]1([N:7]2[CH2:13][C:11](=[O:12])[NH:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([O:16][CH2:17][CH2:18]Cl)=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]1([N:7]2[CH2:13][C:11](=[O:12])[N:10]([CH2:18][CH2:17][O:16][CH:14]=[CH2:15])[C:8]2=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CN(c2ccccc2)C(=O)N1
Reactant: C=COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=COCCN1C(=O)CN(c2ccccc2)C1=O

Procedure:
16.12 g (0.1 mol) of 1-phenylhydantoin, 12.25 g (0.1 mol+15% excess) of 2-chloroethyl vinyl ether, 7.25 g (0.05 mol+5% excess) of potassium carbonate and 50 ml of dimethylformamide are reacted for 1 hour at 120°-125° C. The reaction mixture is worked up analogously to Example 1 to 20.3 g (82.4% of theory) of a brownish, crystalline crude product melting at 119°-120° C. are obtained. 5 g of crude product are recrystallised from 25 ml of chloroform and 3.9 g of the pure compound are isolated. The melting point is 120°-121° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]([NH:12][NH:13][C:14](=[S:17])[NH:15][CH3:16])=O.[OH-].[Na+]>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:15]([CH3:16])[C:14]([SH:17])=[N:13][N:12]=1
Reactant: CNC(=S)NNC(=O)c1cc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(S)nnc1-c1cc2ccccc2s1
Yield: 58.1 %

Procedure:
2-(1-Benzothien-2-ylcarbonyl)-N-methylhydrazine-carbothioamide (15.30 mmol, 4.06 g) and 50 ml of 2N sodium hydroxide solution were heated to reflux for 8 h. The reaction mixture was diluted with water and extracted three times with ethyl acetate. The aqueous phase was acidified with 2N hydrochloric acid and extracted with dichloromethane. The crude product obtained after drying and concentration of the organic phase was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 6:4), resulting in 2.2 g of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=2[F:37])=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1ccc(F)cc1F
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccc(F)cc2F)=CC1=O
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 34.6 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.90 g, 4.96 mmol) in acetonitrile (12.4 mL) was treated with N,N-diisopropylethylamine (0.80 mL, 4.87 mmol). After addition was complete, the mixture was stirred at 60° C. for 45 min. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.80 mL, 4.87 mmol) and acetonitrile (12.4 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(2,4-difluoro-phenoxy)-but-2-enoic acid ethyl ester (1.45 g, 4.51 mmol) in acetonitrile (11.3 mL). After the addition was complete, the reaction mixture was heated to 80° C. where it stirred overnight. At this time, the reaction mixture was cooled to 25° C. and was concentrated in vacuo. The residue was diluted with dichloromethane (75 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-2-[4-(2,4-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.53 g, 35%) as a yellow oil: HR-ES-MS m/z calculated for C17H19NO4F2 [M+Na]+ 362.1174, observed 362.1174; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.85 (d, J=6.5 Hz, 3H), 0.91 (d, J=6.5 Hz, 3H), 1.34-1.51 (m, 1H), 1.59 (ddd, J=13.8, 9.4, 4.4 Hz, 1H), 1.71-1.87 (m, 1H), 3.64 (s, 3H), 4.11-4.31 (m, 2H), 4.71 (dd, J=11.3, 4.4 Hz, 1H), 4.94 (s, 1H), 7.07-7.27 (m, 1H), 7.42-7.70 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH2:14].C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[C:10](=[S:14])[NH2:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: S
Reactant: CC(C)(C#N)NC(=O)OC(C)(C)C
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Reaction time: 19 h

Procedure:
2-tert-Butyloxycarbonylamino-2-methylpropiononitrile (80.00 g) in Benzene (700 ml) was stirred at 0° C., and saturated with hydrogen sulfide. To the reaction mixture was dropped triethyl amine (1000 ml) and bubbled hydrogen sulfide at ambient temperature for 9 hours, and left at the same temperature for 19 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate, water and brine, and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. The residue was washed with n-hexane, to give 2-tert-butyloxycarbonylamino-2-methylpropanethioamide (80.14 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])/[C:4](/[CH2:10]Br)=[CH:5]/[C:6]([O:8][CH3:9])=[O:7].[CH3:13][Mg]Br.Cl.[Cl-].[NH4+]>C(OCC)C.CN(C)P(=O)(N(C)C)N(C)C>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH3:10])[C:5](=[CH2:13])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C[Mg]Br
Reactant: COC(=O)/C=C(\CBr)C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: C=C(C(=O)OC)C(C)C(=O)OC
Reaction time: 1 h

Procedure:
To a solution of (Z)-2-bromomethyl-2-butenedioic acid dimethyl ester (19.3 g) and hexamethylphosphoric acid triamide (70 ml) in diethyl ether (200 ml) was added dropwise methyl magnesium bromide (1.12 M solution in tetrahydrofuran, 100 ml) over 1 hour at −20° C. and stirred for additional 1 hour. To this reaction mixture were added a 6M aqueous solution of hydrochloric acid (18 ml) and a saturated aqueous solution of ammonium chloride (100 ml), and then the mixture was warmed to room temperature and extracted with diethyl ether (200 ml). The resulting organic layer was washed with water twice, followed by a saturated aqueous solution of sodium chloride once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/chloroform=1/1 to 0/1) to give the titled compound (9.92 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].[OH:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH:13]2[CH2:15][CH2:14]2)[CH:9]=1)[C:5]#[N:6]
Reactant: OCC1CC1
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: N#Cc1cc(Br)cc(OCC2CC2)c1
Yield: 84 %

Procedure:
In analogy to the procedure described in WO2007060448, the reaction of 3-bromo-5-fluorobenzonitrile with hydroxymethylcyclopropane using sodium bis(trimethylsilyl)amide as the base yielded the title compound as a white solid (yield: 84% of theory). TLC: Rf: 0.55 (silica gel:heptane:ethyl acetate=6:1, UV, 254 nm).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].[C:16]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH2:19].N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>O>[ClH:1].[CH2:26]([O:25][C:16]([C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:13]([C@H:10]1[CH2:9][CH2:8][C@H:7]([CH2:6][NH:2][C:3]([NH2:5])=[NH:4])[CH2:12][CH2:11]1)=[O:15])=[O:24])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Nc1ccccc1C(=O)OCc1ccccc1
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Nc2ccccc2C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride (3.0 g, 0.013 mole) (which is prepared by the method as disclosed in Japanese Patent First Publication No. 19694/1977, C.A., 87, 53269x) and benzyl anthranilate (3.4 g, 0.015 mole) are added to pyridine (25 ml), and thereto is added dicyclohexylcarbodiimide (3.1 g, 0.015 mole), and the mixture is stirred at room temperature for 72 hours. After the completion of the reaction, water (10 ml) is added to the reaction mixture, and the mixture is stirred for 30 minutes, and the undissolved materials are filtered off. The filtrate is concentrated to driness. The resulting residue is washed with ethyl acetate (100 ml) and recrystallized from water to give N-(o-benzyloxycarbonylphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride (3.2 g) as white crystals. m.p. 93°-95° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.S([O-])(O)(=O)=O.Cl[O-].[Na+].O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[C:9]([F:11])([F:12])[F:10])=[CH:4][N:3]=1
Reactant: OC(c1ccc(Cl)nc1)C(F)(F)F
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccc(Cl)nc1)C(F)(F)F

Procedure:
2.11 g (0.01 mol) of 2-chloro-5-(2,2,2-trifluoro-1-hydroxyethyl)pyridine and 0.18 g (0.0005 mol) of tetrabutylammnonium hydrogen sulfate are dissolved in 25 ml of toluene at room temperature. 6.1 ml (0.012 mol) of an approximately 12% strength sodium hypochlorite solution are metered in within 5 minutes with vigorous stirring and the mixture is stirred for a further 2.5 hours during which the reaction temperature rises to 27° C. The reaction mixture is added to 50 ml of water, the phases are separated, the aqueous phase is extracted several times with toluene and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phases with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.4 mbar, 100°-115° C. bath temperature), 1.78 g (85% of theory) of 2-chloro-5-trifluoroacetylpyridine are obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH:16]=O)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31]([CH:33]3[CH2:35][CH2:34]3)=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>CC(O)=O>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([CH2:16][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:30][C:31]([CH:33]5[CH2:34][CH2:35]5)=[O:32])[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: O=C(Nc1cccc(C2CCNCC2)c1)C1CC1
Reactant: CCn1c2ccccc2c2cc(C=O)ccc21
Solvent: CC(=O)O
Product: CCn1c2ccccc2c2cc(CN3CCC(c4cccc(NC(=O)C5CC5)c4)CC3)ccc21

Procedure:
Prepared by Procedure F and Scheme R, without HOAc, using 9-ethyl-9H-carbazole-3-carbaldehyde and N-[3-(4-piperidinyl)phenyl]cyclopropanecarboxamide: ESMS m/e: 452.6 (M+H)+.