Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[C:9]3[CH:10]=[N:11][C:12]4[C:17]([C:18]=3[C:4]=2[CH:3]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4.[CH3:30][I:31]>C1(C)C=CC=CC=1.CCOCC>[I-:31].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[C:9]3[CH:10]=[N+:11]([CH3:30])[C:12]4[C:17]([C:18]=3[C:4]=2[CH:3]=1)=[CH:16][CH:15]=[CH:14][CH:13]=4
Reactant: CI
Reactant: Clc1ccc2c(c1)c1c3ccccc3ncc1n2CCCCCC1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: C[n+]1cc2c(c3cc(Cl)ccc3n2CCCCCC2CCCCC2)c2ccccc21
Product: [I-]
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of 10-chloro-7-(5-cyclohexyl-pentyl)-7H-indolo[2,3-c]-quinoline (65 mg) in toluene (3 ml) and CH3I (0.3 mL) was stirred in a sealed pressure tube at 110° C. for 24 hours. The reaction mixture was allowed to cool to room temperature, diluted with Et2O (15 ml) and the resulting precipitate was filtered and washed with Et2O (3×20 ml) to yield the pure angular product as an orange solid (50 mg). Mp 246-248° C.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH2:7][CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])(=[O:5])=[O:4].CCN(C(C)C)C(C)C.[NH:41]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[C@@H:42]([C:51](O)=[O:52])[CH2:43][C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[O:19]=[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:17](=[O:18])[N:9]1[CH2:8][CH2:7][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:26]1[CH2:31][CH2:30][N:29]([C:51](=[O:52])[C@H:42]([NH:41][C:54]([O:56][C:57]([CH3:59])([CH3:58])[CH3:60])=[O:55])[CH2:43][C:44]2[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=2)[CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CS(=O)(=O)N(CCN1C(=O)c2ccccc2C1=O)c1ccccc1C1CCNCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)N1CCC(c2ccccc2N(CCN2C(=O)c3ccccc3C2=O)S(C)(=O)=O)CC1
Yield: 92.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, (Step f) from 2-(2-[(methylsulfonyl)(2-(4-piperidyl)phenyl)amino]ethyl) isoindoline-1,3-dione hydrochloride (Step b) (1.28 g, 2.8 mmol), DIEA (0.54 mL, 3.0 mmol), Boc-p-Cl-D-PheOH (PepTech Corporation) (1.36 g, 4.5 mmol), HOAT (Aldrich) (0.615 g, 4.5 mmol) and EDC (Aldrich) (0.864 g, 4.5 mmol) in DMF (15 mL). Purification by silica gel chromatography (1:1 hexane:EtOAc) provided the title compound as a white foam (1.83 g %). MS (ESI, pos. ion) m/z: 709 (M+1); MS (ESI, neg. ion) m/z: 707 (M−1). Calc'd for C36H41ClN4O7S: 708.24.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:22])[C:4]1[CH:21]=[CH:20][C:7]2[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=2[CH:5]=1.[H-].[Na+].[C:25]([C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[C:30](OC)=O)#[N:26]>C1COCC1.O.C(OC(=O)C)C>[C:25]([C:27]1[CH:28]=[C:29]([C:30]2[O:1][N:2]=[C:3]([C:4]3[CH:21]=[CH:20][C:7]4[CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:11][CH2:12][C:6]=4[CH:5]=3)[N:22]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])#[N:26]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(C(=N)NO)cc2CC1
Reactant: COC(=O)c1ccc(OC)c(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(-c3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)no2)cc1C#N
Temperature: 75 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
1,1-Dimethylethyl 7-[(hydroxyamino)(imino)methyl]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (Preparation 41) (240 mg, 0.785 mmol) was added to a suspension of sodium hydride (60% dispersion in mineral oil) (23.01 mg, 0.575 mmol) in THF (5 ml) at room temperature (note slight effervescence). The resultant mixture was stirred at room temperature for 30 mins, methyl 3-cyano-4-(methyloxy)benzoate (100 mg, 0.523 mmol) was then added and the reaction mixture was heated to reflux (75° C.) for 45 mins. The reaction mixture was diluted with water and ethylacetate and the layers partitioned, solid was present in the bi-phasic mixture so this was transferred to a conical flask and stirred at room temperature for 2 h at room temperature. The mixture was then partitioned and the organic layer concentrated in vacuo. to yield the title compound (280 mg, 0.502 mmol, 96% yield) as a yellow oil. MS (ES): C25H26N4O4 requires 447; no mass ion present. 1H NMR (400 MHz, CDCl3) δ 1H, d (8.44), 1H, dd (8.38), 2H, m (7.89-7.95), 1H, m (7.35-7.42), 1H, m (7.13-7.17), 3H, s (4.06), 4H, m (3.50-3.66), 4H, m (2.87-3.06), 9H, s (1.50).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]([C:15](=[O:28])[CH:16]=[CH:17][C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]([CH3:27])=[O:26])=[CH:20][CH:19]=2)[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.ClC1C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.C(O)(=O)C>CN(C)C=O.C1C=CC=CC=1>[NH:24]([C:21]1[CH:22]=[CH:23][C:18]([C:17]2[N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[CH:9]=[C:10]([C:15](=[O:28])[CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:19][CH:20]=1)[C:25]([CH3:27])=[O:26]
Reactant: COC(=O)C(=CNc1ccc(F)cc1)C(=O)C=Cc1ccc(NC(C)=O)cc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: c1ccccc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
In 25 ml of N,N-dimethylformamide was dissolved 2.9 g of methyl 2-(4-fluorophenylaminomethylene)-5-(4-acetaminophenyl)-3-oxo-4-pentenoate, and they are reacted at 140° C. for 2 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform) to obtain an oily substance. This oily sugstance was dissolved in 30 ml of benzene, followed by dropwise addition thereto of a solution of 2.06 g of 2,3,5,6-tetrachloro-p-benzoquinone in 18 ml of benzene at 80° C. After completion of this dropwise addition, the reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and washed with 30 ml of benzene. These crystals were then dissolved in a mixed solution of 20 ml of methanol and 20 ml of a 1N aqueous sodium hydroxide solution, and they were reacted at room temperature for 30 minutes. The reaction solution was adjusted to a pH of 6.0 with acetic acid and the precipitated crystals were collected by filtration, washed with water and dried to obtain 2.3 g of 6-(4-acetaminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 249°-250° C.
Reaction SMILES: [CH2:1]=O.[CH:3](=[O:7])[CH:4]([CH3:6])[CH3:5].[CH:8]1([CH2:14][NH2:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>>[CH3:5][C:4]([CH3:1])([CH2:6][NH:15][CH2:14][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[CH:3]=[O:7]
Reactant: C=O
Reactant: NCC1CCCCC1
Reactant: CC(C)C=O
Product: CC(C)(C=O)CNCC1CCCCC1

Procedure:
Under the same conditions as for the preparation of 2,2-dimethyl-3-(N-morpholino)propanal, 36.8 g (0.44 mol) of 36% aqueous formaldehyde were reacted with 33.4 g (0.46 mol) of isobutyraldehyde and 50.0 g (0.44 mol) of N-cyclohexylmethylamine, and worked up. The product distilled at a top temperature of 69° C. and a pressure of 4·10−2 mbar. Yield: 65.8 g (76% of theory) as a colorless, clear liquid smelling of amine, which had an amine content of 4.94 mmol N/g.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]1COC[CH2:16]1.C([Mg]Br)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]([OH:14])[CH2:15][CH3:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CCOC1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Agent: CC[Mg]Br
Product: CCC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C

Procedure:
(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (1 g, 5 mmol) and THF (10 mL, 100 mmol) were combined under nitrogen, and the resulting solution cooled to −78° C. 1.0 M of Ethyl magnesium bromide in THF (7.5 mL, 7.5 mmol) was added dropwise over 10 minutes. The mixture was allowed to warm to room temperature slowly overnight. The reaction was then quenched by the dropwise addition of saturated aqueous NH4Cl (30 mL). The resulting mixture was extracted with EtOAc (2×30 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 (1×30 mL) and saturated aqueous NaCl (1×30 mL), then dried over anhydrous MgSO4, filtered, and concentrated in vacuo to yield (S)-3-(1-hydroxypropyl)pyrrolidine-1-carboxylic acid t-butyl ester.
Reaction SMILES: [C:1]1([S:7][C:8]2[C:9]([NH:24][C:25]3[S:29][N:28]=[C:27]([CH:30]4[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[N:26]=3)=[N:10][CH:11]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[ClH:45]>C(Cl)Cl.O1CCOCC1>[ClH:45].[ClH:45].[C:1]1([S:7][C:8]2[C:9]([NH:24][C:25]3[S:29][N:28]=[C:27]([CH:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:26]=3)=[N:10][CH:11]=[C:12]([S:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[CH:22][S:23][C:16]=34)[CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nsc(Nc3ncc(Sc4ccnc5ccsc45)cc3Sc3ccccc3)n2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: c1ccc(Sc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(C3CCNCC3)ns2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
Tert-butyl 4-(5-(3-(phenylthio)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidine-1-carboxylate was dissolved in 1:1 CH2Cl2:methanol (4 mL) and 4N HCl in dioxane added (2 mL) and stirred at ambient temperature for 1 hour. The solvent was removed and placed on high vacuum to afford the title compound (100 mg, 89.6% yield) as a yellow solid. 1H NMR (d6-DMSO) δ 8.70 (m, 2H), 8.20 (m, 3H), 7.95 (m, 1H), 7.40 (m, 5H), 3.80-3.05 (m, 9H). Mass spectrum (apci) m/z=535.2 (M+H-3HCl).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][C@H:12]([NH:15][S:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=4)[CH:20]=3)(=[O:18])=[O:17])[C:11]2=[O:31])[CH:6]=[CH:5][N:4]=1)#[N:2].Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>>[C:37]([O:36][C:34](=[O:35])[CH2:33][N:15]([C@H:12]1[CH2:13][CH2:14][N:10]([CH2:9][C:7]2[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[CH:8]=2)[C:11]1=[O:31])[S:16]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][C:23]([O:29][CH3:30])=[CH:24][CH:25]=2)[CH:20]=1)(=[O:18])=[O:17])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1
Product: COc1ccc2ccc(S(=O)(=O)N(CC(=O)OC(C)(C)C)[C@H]3CCN(Cc4ccnc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared from 7-methoxynaphthalene-2-sulfonic acid-[1-(2-cyano-pyridin-4-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]amide as described in EXAMPLE 141, Part D using tert-butyl bromoacetate in place of benzyl bromide. The crude product is purified by column chromatography eluting with gradient of 10% EtOAc/CH2Cl2 to 25% EtOAc/CH2Cl2 to afford the title compound as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H][H].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([O:23][CH2:22]1)[C@@H:17]([CH3:21])[C:18]([OH:20])=[O:19].[NH4+].[Cl-]>CN(C=O)C.CCCCCC>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@@:16]([OH:23])([CH2:22][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C@@H:17]([CH3:21])[C:18]([OH:20])=[O:19]
Reactant: [H][H]
Reactant: C[C@@H](C(=O)O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: C[C@@H](C(=O)O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 60 °C

Procedure:
To a cooled (0° C.) suspension of Nail (55% mineral oil dispersion, 288 mg, 6.6 mmol, washed with hexane) in DMF (25 mL) was added 1,2,4-triazole (0.5 g, 7.2 mmol) and the mixture was stirred at 0° C. until hydrogen gas ceased to evolve. Then, a solution of unpurified (2R,3R)-3-(2,4-difluorophenyl)-3,4-epoxy-2-methylbutanoic acid (0.5 g) (obtained in reference example 29) in DMF (3 mL) was slowly added and the mixture was heated to 60° C. during 2 h. A saturated NH4Cl aqueous solution was then added and the solvents were removed in vacuo. The mixture was then partitioned between brine containing AcOH and EtOAc. The organic layer was separated and the aqueous phase was extracted with more EtOAc (3x). The collected organic fractions were then dried over anhydrous Na2SO4, the drying agent was filtered and the filtrate was concentrated under reduced pressure to a white solid. Recrystallization from EtOAc afforded the title product as a white solid.
Reaction SMILES: [OH:1][C@H:2]1[C:11]2[CH:10]=[CH:9][N:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@H:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@H:3]1[OH:22].[C:23]1(C)C=CC(S(O)(=O)=O)=CC=1.CC(C)=O>COC(OC)(C)C>[OH:22][C@H:3]1[C@@H:2]([O:1][CH3:23])[C:11]2[CH:10]=[CH:9][N:8]3[CH:12]=[C:13]([CH3:15])[N:14]=[C:7]3[C:6]=2[NH:5][C@@H:4]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Cc1cn2ccc3c(c2n1)N[C@H](c1ccccc1)[C@@H](O)[C@H]3O
Solvent: CC(C)=O
Solvent: COC(C)(C)OC
Product: CO[C@H]1c2ccn3cc(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a suspension of 0.62 g (2.10 mmol) (7S,8R,9R)-7,8-dihydroxy-2-methyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine in dimethoxypropane is added 0.51 g (26.2 mmol) p-toluenesulphonic acid and acetone (4.0 ml). The mixture is stirred for 6 h at 60° C. and 96 h at 25° C. The reaction is quenched by adding of saturated aqueous sodium hydrogen carbonate solution. Subsequently the mixture is extracted twice with dichloromethane. The combined organic layers are washed with brine, dried over sodium sulphate and evaporated in vacuo. The crude product is purified by column chromatography (dichloromethane/methanol: 100/3) to give 0.18 g (0.52 mmol/25%) of the title compound as an amorphous solid. 1H-NMR (200 MHz,[D6] DMSO): δ=2.28 (s, 3H), 3.30 (s, 1H), 3.09-4.03 (m, 1H), 4.06 (d, 1H), 4.49 (dd, 1H), 6.67 (d, 1H), 7.22-7.44 (m, 5H), 7.54 (d, 1H), 7.69 (d, 1H).
Reaction SMILES: [CH:1]([CH:4]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[C:5](O)=[O:6])([CH3:3])[CH3:2].S(Cl)(Cl)=O.C(N(CC)CC)C.Cl.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]([CH:1]([CH3:3])[CH3:2])=[C:5]=[O:6])=[CH:13][CH:12]=1
Reactant: CC(C)C(C(=O)O)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)C(=C=O)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 60.4 %

Procedure:
A sample of 53.2 g of isopropyl(4-chlorophenyl)acetic acid was treated with 21.5 ml of thionyl chloride in a 500 ml flask and heated slowly to 80° C. and maintained at 80° C. for 20 minutes. The reaction mixture was allowed to stand at room temperature for 2 days. The volatiles were stripped to 75° C. at 0.5 mm Hg. The resulting yellow liquid was diluted with 250 ml of methylene chloride followed by addition of 38.0 g of triethylamine. The mixture was stirred until triethylamine hydrochloride began to precipitate after 30 minutes. After 16 hours, the reaction mixture was filtered and solid triethylamine hydrochloride was washed with heptane. Most of the solvent was stripped from the filtrate by rotary evaporation at 50° C. The residue was diluted with 75 ml of heptane and additional triethylamine hydrochloride was removed by filtration as above. The filtrate was restripped and rediluted with 75 ml heptane and refiltered with the aid of 25 ml of heptane. The filtrate was cooled in dry ice, seeded and crystallized. The resulting crystals were filtered with a filter stick and washed with chilled heptane. The filtered solids were melted, diluted with one-half volume heptane, crystallized at -80° C. and the collected solid was melted and stored at -80° C. The filtrate solution was warmed, stripped of most solvent, then distilled through a Bantam were short path head at 0.05 to 0.06 mm Hg from an oil bath at 90°-120° C. Total distillate was 14.5 g collected as a bright yellow-orange liquid at a head temperature of 60°-85° C. The distillate was crystallized from an equal volume of pentane at -80° C., filtered and washed twice with heptane as above to give, on warming, a second melt. The stripped filtrates totalling 5.79 g were crystallized as above in a 6-inch test tube and the melt was recrystallized immediately as described above to give a third melt. The three melts were combined and stripped to 50° C. at 5 mm Hg to give 29.4 g of the desired ketene as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]([NH:20][NH2:21])=[O:19])[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:5][CH:4]=1.[OH-].[K+].[C:24](=S)=[S:25]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13]3[CH:14]=[C:15]([C:18]4[O:19][C:24]([SH:25])=[N:21][N:20]=4)[CH:16]=[CH:17][C:12]=3[N:11]=[CH:10]2)=[CH:7][CH:8]=1
Reactant: S=C=S
Reactant: COc1ccc(-n2cnc3ccc(C(=O)NN)cc32)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-n2cnc3ccc(-c4nnc(S)o4)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A mixture of 1-(4-methoxyphenyl)-1H-benzimidazole-6-carbohydrazide (1.09 g, 3.86 mmol), potassium hydroxide (0.32 g, 5.79 mmol), carbon disulfide (2.31 mL, 38.6 mmol) and ethanol (20 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, N,N-dimethylformamide (15 ml) was added to the residue, and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was acidified with 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with water to give the title compound (0.66 g, yield 53%) as colorless crystals.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][CH:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13](=[O:32])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[CH:17][CH:16]=2)[CH:9]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:8]1=[O:37])[CH3:6]>[OH-].[Na+].C(O)(C)(C)C>[CH2:33]([CH:9]1[N:10]([C:13](=[O:32])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:31])=[O:23])=[CH:19][CH:20]=2)[CH2:11][CH2:12][N:7]([CH:5]([CH3:6])[CH2:4][C:3]([OH:38])=[O:2])[C:8]1=[O:37])[CH:34]([CH3:36])[CH3:35]
Reactant: COC(=O)CC(C)N1CCN(C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)cc2)C(CC(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)N2CCN(C(C)CC(=O)O)C(=O)C2CC(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A solution of 3-(3-isobutyl-2-oxo-4-{[4-(3-o-tolyl-ureido)-phenyl]-acetyl}-piperazin-1-yl)-butyric acid methyl ester (20 mg, 0.038 mmol) in a mixture of 1 ml of 0.1 N NaOH and 1 ml of tert-butanol was stirred for 16 hrs at room temperature. The reaction mixture was then concentrated under reduced pressure, dissolved in water (5 ml) and extracted with ether (5 ml×2). The aqueous portion was then acidified to pH<3 with 1N HCl and extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 16 mg of the title compound as a yellow sticky oil. MS [M+1]+509.3; 1H nmr (400 MHz, CD3OD) δ0.88-1.70 (m, 12H), 2.25 (s, 3H), 2.34-4.96 (m, 10H), 6.98 (t, J=7.4 Hz, 1H), 7.11-7.40 (m, 6H), 7.59 (d, J=7.5 Hz, 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1.C(OCC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][C:11]([C:20]2[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=2)([OH:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)CC1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a cold (0° C.) stirred solution of 1-t-butoxycarbonyl-4-oxohomopiperidine (1.42 g, 6.07 mmol) in anhydrous THF (50 mL) under argon was added dropwise 1.0 M 4-chlorophenylmagnesium bromide in diethyl ether (10 mL, 10 mmol). The reaction was warmed to RT for 2 hrs then quenched with sat'd aqueous NH4Cl (5 mL). The reaction mixture was extracted with EtOAc (2×50 mL), the organic layers combined and dried over Na2SO4. Pure 1-t-butoxycarbonyl-4-(4-chlorophenyl)-4-hydroxyhomopiperidine (2.1 g, 96%) was isolated via silica gel flash chromatography eluting with 50% EtOAc/hexane. 1H-NMR CDCl3 6: 1.43 (9H, s), 1.61-2.22 (6H, m), 3.21-3031 (2H, m), 3.48-3.82 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C@H:16]([O:18]C1CCCCO1)[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.FC(F)(F)C(O)=O>C(O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: C[C@@H](OC1CCCCO1)C(O)(Cn1ccnc1)c1ccc(F)cc1F
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)C(O)(Cn1ccnc1)c1ccc(F)cc1F
Reaction time: 0.17 h
Yield: 131.4 %

Procedure:
In ethanol (8.5 ml) was dissolved (3R)-2-(2,4-difluorophenyl)-1-(1-imidazolyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-2-butanol (1.7 g) followed by addition of trifluoroacetic acid (8.5 ml) at 0° C. After 10 minutes, the temperature was adjusted to 20° C. and the mixture was allowed to stand for 1 hour. The reaction mixture was then concentrated under reduced pressure and the residue was subjected to silica gel chromatography (2 cm×10 cm) using methanol-methylene chloride (1:9) as the eluent. The desired fraction was concentrated to give (3R)-2-(2,4-difluorophenyl)-1-(1-imidazolyl)-2,3-butanediol (1.7 g).