Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)=[O:7]>CO.Cl.[Pd]>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=1)=[O:7]
Reactant: CC(C)(C)CCNC(=O)Cc1ccc(C#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)CCNC(=O)Cc1ccc(CN)cc1
Yield: 107.4 %

Procedure:
Bubble nitrogen into a solution of 4-[(3,3-dimethylbutyl-carbamoyl)-methyl]-benzonitrile (240 mg, 0.9 mmol) in methanol (20 mL) with 3 drops of concentrated HCl for 10 min. Add 10% Pd/C (Degussa type E101, 48 mg) and submit the mixture to hydrogenation at atmospheric pressure overnight. Filter the catalyst over Celite® and concentrate the filtrate in vacuo. Elute the compound through a SCX column to obtain the title compound (240 mg, 98%). MS (ES+) m/z: 249 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:12]([O-:15])(=O)[CH3:13].[NH4+:16]>CO>[CH2:8]([O:7][C:5]([C:4]1[C:3]([CH:2]([CH3:11])[CH3:1])=[CH:13][C:12](=[O:15])[NH:16][C:1]=1[CH:2]([CH3:11])[CH3:3])=[O:6])[CH3:9]
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Solvent: CO
Product: CCOC(=O)c1c(C(C)C)cc(=O)[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 13.9 %

Procedure:
To a solution of 20.0 g, (126.4 mmol) ethyl 4-methyl-3-oxopentanoate in methanol (100 ml) was added 48.72 g, (632.2 mmol) ammonium acetate. The reaction mixture was stirred at RT for 3 d. Then the mixture was concentrated in vacuo. The residue was taken up with DCM (300 ml) and filtered. The filtrate is water and brine, dried over Na2SO4 and concentrated in vacuo. This residue was dissolved in toluene (100 ml), followed by the addition of HCl (saturated solution in dioxane, 65 ml) at 0° C. The reaction mixture was heated at 120° C. for 20 h and subsequently filtered and the solid is washed with toluene. The filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 3:2) provided 2.2 g (8.76 mmol, 7%) 2,4-diisopropyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethylester.
Reaction SMILES: C[Si]([I:5])(C)C.C[Si](N[Si](C)(C)C)(C)C.[CH2:15]1[N:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1>C(#N)C>[CH2:15]1[N:20]2[CH2:21][CH2:22][N:17]([CH2:18][CH2:19]2)[CH2:16]1.[IH:5]
Reactant: C[Si](C)(C)I
Agent: C1CN2CCN1CC2
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: CC#N
Product: I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The 2-carboxylic acid (8c), as produced in Example 13a, was converted to the carbacephem (9a) through reaction with trimethylsilyl iodide (TMSI). Specifically, the carboxylic acid (8c) (0.726 g, 2 mM), was combined with 5 ml acetonitrile (ACN), HMDS (1.06 ml, 5 mM), and TMSI (0.72 ml, 5 mM), and the mixture was stirred for 4 hours at room temperature. DABCO (0.56 g, 5 mM) in 5 ml ACN was added and the solution stirred overnight at room temperature, yielding a DABCO-HI precipitate. Both reactions appeared normal and the DABCO reaction (elimination) gave an HPLC ratio of product to starting material of 39.1/12.0 for a conversion of about 77%. 5 ml of 1N HCl was added and the mixture stirred for 30 min. at room temperature. The pH was at 3.55. The DABCO-HI precipitate dissolved and the desired carbacephem product (9a) appeared as a precipitate. The product was filtered and washed successively with 10 ml of ACN/H2O (2/1), 5 ml of H2O, and 5 ml of ACN. Vacuum drying at 50° C. yielded 0.275 g of a nearly white solid. Yield was about 63.5%. NMR was excellent in DMSO (d-6) with trifluoroacetic acid (TFA) to dissolve. NMR (DMSO d-6, TFA): δ 1.95 (m, 2), 2.67 (m, 2), 3.94 (m, 1), 4.83 (d, 1), 8.57 (bs, 5).
Reaction SMILES: O[C:2]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[O:7][CH2:6][CH2:5][N:4]([CH3:8])[C:3]1=[O:9].[CH2:18]([Si](C)(C)C)[CH:19]=[CH2:20]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:20]([C:2]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[O:7][CH2:6][CH2:5][N:4]([CH3:8])[C:3]1=[O:9])[CH:19]=[CH2:18]
Reactant: C=CC[Si](C)(C)C
Reactant: COc1cccc(C2(O)OCCN(C)C2=O)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: C=CCC1(c2cccc(OC)c2)OCCN(C)C1=O
Temperature: -23 °C

Procedure:
Following the procedure described by S. Pansare et al., J. Org. Chem. 1998, 63, 4120-4124, 2-hydroxy-2-(3-methoxy-phenyl)-4-methyl-morpholin-3-one, as described in Step C above, (0.133 g, 0.56 mmol) was dissolved in anhydrous CH2Cl2 (10 mL) under Ar, treated with allyltrimethylsilane (0.534 mL, 3.36 mmol), the mixture cooled to −23° C., then treated with TiCl4 (0.37 mL, 3.36 mmol). After 15 min the reaction mixture was quenched slowly with saturated aqueous NH4Cl solution, left to warm to room temperature, and partitioned between CH2Cl2 and H2O. The aqueous layer was washed with CH2Cl2, the organic layers combined, dried (Na2SO4), filtered and concentrated to dryness to give the title compound after chromatography (SiO2, 0-1% MeOH in CH2Cl2).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][CH:19]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:20][C:21](Cl)=O.C([SiH](CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:21][CH2:20][CH:19]([CH3:18])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(-c2ccccc2)cc1
Reactant: CC(C)CCCC(C)CC(=O)Cl
Agent: CC[SiH](CC)CC
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)CCCC(C)CCc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 8 h

Procedure:
A solution of 4-bromo-biphenyl (7.00 g, 0.030 mol), aluminium chloride (4.40 g, 0.033 mol) and 3,7-dimethyloctanoyl chloride (step 2) (6.90 g, 0.036 mol), in dry DCM was prepared at room temperature. The stirring reaction mixture was left to react at room temperature until g.l.c. and t.l.c. analyses revealed a complete reaction, the reaction mixture was then treated with triethylsilane (9.30 g, 0.080 mol) and left stirring overnight. The reaction product was extracted into DCM (2×100 ml) and the combined organic layers were washed with brine, water and dried (MgSO4). The product was adsorbed onto silica gel and purified by column chromatography [DCM] and recrystallised from ethanol to yield a white powder.
Reaction SMILES: [C:1]1([C:7](=[O:11])[C@H:8](O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[NH2:43][C:44]([CH3:48])([CH3:47])[CH2:45][OH:46]>C(Cl)Cl>[C:1]1([C@:7]2([OH:11])[O:46][CH2:45][C:44]([CH3:48])([CH3:47])[NH:43][C@H:8]2[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(N)CO
Reactant: C[C@@H](O)C(=O)c1ccccc1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1NC(C)(C)CO[C@@]1(O)c1ccccc1
Yield: 68.3 %

Procedure:
Compound 4b was synthesized by a procedure similar to that described for (2S,3S)-4a using (R)-1-phenyl-2-hydroxypropan-1-one (10b, 3.49 g, 0.0233 mol), Proton sponge (5.9 g), triflic anhydride (4.2 mL, 26 mmol), and 2-amino-2-methyl-1-propanol (4.6 g, 0.052 mol) in CH2Cl2 (50 mL). After purification by chromatography on silica gel, 3.52 g (68%) of the free base 4b was isolated, and converted to 1.19 g of the hemi-D-tartrate salt, which had >99% ee: mp 112-113° C.; [α]20D +15.8° (c 1.1, CH3OH); 1H NMR (methanol-d4) δ 7.61-7.59 (m, 2H), 7.44-7.36 (m, 3H), 4.32 (s, 1H), 4.24 (d, 1H, J=12.3 Hz), 3.58-3.48 (m, 2H), 1.64 (s, 3H), 1.39 (s, 3H), 1.09 (d, 3H, J=6.6 Hz); 13C NMR (methanol-d4) δ 179.1, 142.4, 130.3, 129.6 (2C), 127.9 (2C), 97.3, 75.4, 67.4, 55.47, 55.27, 24.1, 21.3, 14.3; LCMS (ESI) m/z 222.4 (M-tartrate)+; Anal. (C15H22NO5.0.5H2O) calcd: C, 59.00; H, 7.59; N, 4.59. found: C, 58.77; H, 7.46; N, 4.64.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]([CH3:21])[C:11]3[C:16]([C:17]=2[C:18]#[N:19])=[CH:15][CH:14]=[C:13]([Cl:20])[CH:12]=3)[CH:6]=[N:7][CH:8]=1.[O:22]=[C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25](=[O:32])[N:24]1[CH2:33][CH2:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)CC)C>ClCCl>[Cl:20][C:13]1[CH:12]=[C:11]2[C:16]([C:17]([C:18]#[N:19])=[C:9]([C:5]3[CH:4]=[C:3]([CH2:2][NH:1][S:35]([CH2:34][CH2:33][N:24]4[C:23](=[O:22])[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]4=[O:32])(=[O:36])=[O:37])[CH:8]=[N:7][CH:6]=3)[N:10]2[CH3:21])=[CH:15][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(CN)c2)c(C#N)c2ccc(Cl)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(-c2cncc(CNS(=O)(=O)CCN3C(=O)c4ccccc4C3=O)c2)c(C#N)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A flask is charged with 2-(5-aminomethyl-pyridin-3-yl)-6-chloro-1-methyl-1H-indole-3-carbonitrile (Example 186e, 0.050 g, 0.160 mmol) and dichloromethane (2 mL). 2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethanesulfonyl chloride (0.068 g, 0.239 mmol) and triethylamine (0.045 mL, 0.319 mmol) are added and the reaction is stirred at room temperature for 5 min. The reaction mixture is washed with water and extracted with dichloromethane twice. The combined organic phase is separated, dried over sodium sulfate and concentrated in vacuo to give a residue which is purified by silica gel flash chromatography (dichloromethane-methanol, 19:1) to afford 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethane sulfonic acid [5-(6-chloro-3-cyano-1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-amide as a white solid. MS (ESI) m/z 537.3 (M+H)+.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:16].[CH3:17][O:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:20]=1[C:21](Cl)=[O:22]>ClC(Cl)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:16][C:21](=[O:22])[C:20]1[C:24]([O:28][CH3:29])=[CH:25][CH:26]=[CH:27][C:19]=1[O:18][CH3:17]
Reactant: Nc1ccc2oc3c(c2c1)CCCCCC3
Reactant: COc1cccc(OC)c1C(=O)Cl
Solvent: CC(Cl)Cl
Product: COc1cccc(OC)c1C(=O)Nc1ccc2oc3c(c2c1)CCCCCC3

Procedure:
Following the procedure of Example 1, 6,7,8,9,10,11-Hexahydro-benzo[b]-cycloocta[d]furan-2-ylamine (0.15 g, 0.69 mmol), 2,6-dimethoxybenzoyl chloride (0.15 mL, 0.77 mmol), and poly(vinylpyridine) (0.5 g) in dichloroethane (12 mL) N-(6,7,8,9,10,11-hexahydrobenzo[b]cycloocta[d]furan-2-yl)-2,6-dimethoxybenzamide (0.15 g). MS (ESI) m/z 380 ([M+H]+).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](O)[C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)[C:5]1=[O:21])(=[O:3])[CH3:2].C(Cl)(Cl)(Cl)[Cl:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]([Cl:23])[C:14]2[CH:18]=[C:17]([CH3:19])[O:16][N:15]=2)[C:5]1=[O:21])(=[O:3])[CH3:2]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CC(=O)N1C(=O)C(=C(O)c2cc(C)on2)c2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)C(=C(Cl)c2cc(C)on2)c2ccccc21

Procedure:
3.00 g of 1-acetyl-3-[1-hydroxy-1-(5-methyl-3-isoxazolyl)methylene]-2-indolinone, 5.09 ml carbon tetrachloride and 5.54 g triphenylphosphine are refluxed in 100 ml of THF for 8 hours. The residue obtained after the solvent has been distilled off is purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate=9:1).
Reaction SMILES: [C@@H]1([N:10]2[C:20]3[N:19]=[C:17]([NH2:18])[NH:16][C:14](=[O:15])[C:13]=3[N:12]=[CH:11]2)O[C@H](CO)[C@@H](O)[C@H]1O.[I-].[Na+].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][Cl:30])=[CH:27][CH:26]=1.[ClH:33]>CS(C)=O.CO>[ClH:30].[ClH:33].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][N:12]2[C:13]3[C:14](=[O:15])[NH:16][C:17]([NH2:18])=[N:19][C:20]=3[N:10]=[CH:11]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CS(C)=O
Product: COc1ccc(Cn2cnc3nc(N)[nH]c(=O)c32)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 34.8 %

Procedure:
Guanosine (5.7 g; 20.0 mmol) was dissolved in 13.2 ml of dimethylsulfoxide. To this solution were added sodium iodide (0.6 g; 4 mmol) and 4-methoxybenzyl chloride (6.8 ml; 50.2 mmol), and the mixture was stirred at room temperature for 19 h. Conc. hydrochloric acid (10 ml) was added thereto, and stirred at 45° C. for 1 h. The mixture was cooled down to room temperature. Methanol (50 ml) was added thereto, and the mixture was stirred at room temperature for 3 h. The crystals precipitated were filtered, washed well with methanol (20 ml×3), and then dried at 50° C. under reduced pressure to obtain 2.5 g of 7-(4-methoxybenzyl)guanine dihydrochloride (34.8%).
Reaction SMILES: [C:1]([O:9][CH:10](Cl)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:13].[Na+]>C(#N)C>[C:1]([O:9][CH:10]([I:13])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(Cl)OC(=O)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(I)OC(=O)c1ccccc1
Temperature: 60 °C
Yield: 39 %

Procedure:
1-Chloroethyl benzoate (6.30 g, 34.12 mmol) and sodium iodide (23.0 g, 153.56 mmol) were combined in acetonitrile (150 mL) and heated to 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether and dichloromethane were added to the residue and the solids were filtered off and the filtrate was concentrated under reduced pressure. After silica gel chromatography using ethyl acetate in hexanes the residue was combined with sodium iodide (4.70 g, 31.39 mmol) in acetonitrile (50 mL) and heated to 60° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. Diethyl ether was added, the solids were filtered off and the filtrate was concentrated under reduced pressure. Chromatography on silica gel using ethyl acetate in hexanes provided 1-iodoethyl benzoate as a pale yellow oil (3.67 g, 39% yield).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])=[N:7][CH2:8][C:9](=S)[NH:10][C:4]=2[CH:3]=1.[CH3:22][O:23][CH2:24][C:25]([NH:27][NH2:28])=O>C(O)CCC>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])=[N:7][CH2:8][C:9]3[N:10]([C:25]([CH2:24][O:23][CH3:22])=[N:27][N:28]=3)[C:4]=2[CH:3]=1
Reactant: Fc1cccc(F)c1C1=NCC(=S)Nc2cc(Br)ccc21
Reactant: COCC(=O)NN
Solvent: CCCCO
Product: COCc1nnc2n1-c1cc(Br)ccc1C(c1c(F)cccc1F)=NC2

Procedure:
In the manner given in Example 1, a solution of 1,3-dihydro-8-bromo-5-(2,6-difluorophenyl)-2H-1,4-benzodiazepine-2-thione in n-butyl alcohol was heated to reflux with methoxyacetic acid hydrazide to give 9-bromo-1-(methoxymethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[Mg].[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[CH:23]=[O:24]>O1CCCC1>[CH2:1]([O:3][CH:4]([O:12][CH2:13][CH3:14])[C:5]1[CH:10]=[CH:9][C:8]([CH:23]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:17]=2[CH3:16])[OH:24])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(OCC)c1ccc(Br)cc1
Reactant: Cc1ccncc1C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOC(OCC)c1ccc(C(O)c2cnccc2C)cc1
Reaction time: 0.17 h
Yield: 58.3 %

Procedure:
Under an atmosphere of nitrogen, a solution of 900 mg of 4-bromobenzaldehyde diethylacetal in 1.8 ml of tetrahydrofuran was added dropwise to 83 mg of magnesium at 50° C. to 60° C., and the mixture was stirred at that temperature for 10 minutes, and then diluted with 2 ml of tetrahydrofuran. The solution, thus obtained, was added dropwise to a solution of 280 mg of 4-methyl-3-formylpyridine [prepared as described in J. Org. Chem., 25, 560(1960)]in 7 ml of tetrahydrofuran at 0° C., and the mixture was stirred at the same temperature for one hour. The reaction mixture was quenched with a saturated aqueous solution of ammonium chloride, and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and cyclohexane (7:3) as eluent to give 406 mg of the title compound having the following physical characteristics:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.O[CH2:44][CH2:45][CH2:46][C:47]([O:49]C(C)(C)C)=[O:48]>>[C:47]([CH2:46][CH2:45][CH2:44][O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)([OH:49])=[O:48]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CC(C)(C)OC(=O)CCCO
Product: COc1cc(C(=O)OCCCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 14, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (prepared as described in US20100152190A1) was reacted with tert-butyl 4-hydroxybutanoate to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 3-carboxy-propyl ester after removal of the Boc protection group by trifluoroacetic acid. MS (ES+) m/z calcd. for C35H36Cl2F2N3O6: [(M+H)+]: 702. found: 702.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:27]([NH:22][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([NH:11][CH:9]1[C:10]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])[CH2:7][CH2:8]1)[CH:21]=[CH:20]2)=[O:28])([CH3:25])[CH3:24]
Reactant: CC(C)N=C=O
Reactant: Cc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Product: Cc1cccc2c1C(Nc1ccc3cc(NC(=O)NC(C)C)ccc3n1)CC2

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(7-methyl-indan-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=375.4 (M+H+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[N:9]=[CH:8][NH:7][N:6]=1)(=[O:4])=[O:3].[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14](Cl)=[O:15])[CH:11]=[CH2:12].O1CCCC1>C(N(CC)CC)C>[CH2:10]([N:13]([CH2:17][CH:18]=[CH2:19])[C:14]([N:7]1[CH:8]=[N:9][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[N:6]1)=[O:15])[CH:11]=[CH2:12]
Reactant: CS(=O)(=O)c1nc[nH]n1
Reactant: C=CCN(CC=C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(S(C)(=O)=O)n1

Procedure:
A mixture of 4.1 g. 3-methylsulphonyl-1,2,4-triazole, 4.75 g. diallylcarbamoyl chloride, 20 ml. dry tetrahydrofuran and 5.5 ml. dry triethylamine was refluxed under anhydrous conditions for 1 hour. The reaction mixture was filtered and the filtrate was distilled to dryness under reduced pressure. The solid residue was recrystallized from a mixture of toluene and petroleum ether (b.p. 40° - 60° C.) to give 1-diallylcarbamoyl-3-methylsulphonyl-1,2,4-triazole, m.p. 52° - 54° C. Elemental analysis satisfactory.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH:60]1[CH2:64][CH2:63][CH2:62][CH2:61]1)=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH:60]7[CH2:64][CH2:63][CH2:62][CH2:61]7)[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OC1CCCC1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@H](NC(=O)OC5CCCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
(trans)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsi-lyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (20 mg) and triethylamine (12 μL) are dissolved in dichloromethane (2 mL), treated with cyclopentyl chloroformate (7.3 μL) and stirred for 12 hours at room temperature. Triethylamine (12 μL) and cyclopentyl chloroformate (7.3 μL) are added and the mixture is stirred for 5 hours at room temperature. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound, which is directly used in the next step. LC (method 5): tR=1.30 min.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]([C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[CH2:10][CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C1(C)C=CC=CC=1>[CH3:8][N:9]([CH2:10][CH2:11][N:43]1[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]1)[C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCCN(C)c2ccc([N+](=O)[O-])cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1CCN(CCN(C)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of toluene-4-sulfonic acid 2-[methyl-(4-nitro-phenyl)-amino]-ethyl ester TFA salt (74 mg, 0.21 mmol) in toluene (1 mL) is added triethylamine (50 μL) and N-methylpiperazine (70 μL, 0.63 mmol). The mixture is shaken in 70° C. block shaker overnight. The reaction mixture is concentrated and purified by reverse phase high performance liquid chromatography to give methyl-[2-(4-methyl-piperazin-1-yl)-ethyl]-(4-nitro-phenyl)-amine as a tri-TFA salt (98 mg, 98%).