Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=[O:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)=[O:69]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:36])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[C@@H:14]3[C:25]3[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:66][CH2:67][C:68]([NH:70][C@@H:71]([C:79]([OH:81])=[O:80])[CH2:72][CH:73]4[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]4)=[O:69])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc4c(c3)CCO4)C(=O)N2c2ccc(F)cc2)cc1
Reactant: NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)CCO4)C(=O)N2c2ccc(F)cc2)cc1)NCC(=O)N[C@H](CC1CCCCC1)C(=O)O
Temperature: 30 °C
Reaction time: 0.42 h

Procedure:
To a stirred solution of {4-[(2R,3R)-3-{[2-(2,3-dihydro-1-benzofuran-5-yl)-2-oxoethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetic acid (Method 2) (15.7 mg, 0.031 mmol) in DMF (2 ml, dry) was added N-methylmorpholine (10 μl, 0.091 mmol). TBTU (13.1 mg, 0.041 mmol) and additional DMF (2 ml) were added and the reaction mixture was stirred under at 30° C. for 25 minutes. Glycyl-3-cyclohexyl-D-alanine (7.1 mg, 0.031 mmol) (Method 7) was added and the reaction mixture was stirred for 2 hours. The formation of the ketone of the title compound was confirmed. M/z: 716.57 (M−1). Without further purification, methanol (6 ml) and sodium borohydride (16.1 mg, 0.043 mmol) were added and the reaction mixture was stirred for 20 minutes. Ammonium acetate (85.5 mg) was added. The methanol was removed under reduced pressure and the remaining DMF-solution was purified with preparative HPLC on a C8 column. A gradient from 20 to 55% MeCN in 0.1M NH4OAc was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The residue was extracted between EtOAc and water, the water phase was acidified to pH 2 with KHSO4 (2M). The phases were separated and the organic phase was passed through a phase separator. The solvent was removed under reduced pressure. The residue was dissolved in ACN and water. After lyophilisation, the title compound was obtained. H-NMR (400 MHz, DMSO-d6): 0.69-1.67 (m, 13H), 2.76-2.91 (m, 2H), 2.98-311 (m, 2H), 3.75 (d, 2H), 4.15-4.25 (m, 2H), 4.40-4.47 (m, 2H), 4.49 (s, 2H), 4.55-4.64 (m, 1H), 5.00 (b, 1H), 5.54 (b, 1H), 6.61 (dd, 1H), 6.96 (d, 3H), 7.08-7.16 (m, 3H), 7.18-7.24 (m, 2H), 7.34 (d, 2H), 8.07 (d, 1H), 8.19 (t, 1H), 12.51 (b, 1H). M/z: 718.57 (M−1).
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]1[CH:20]=[CH:19][CH2:18][C:17]2[C:10]=1[CH:11]=[C:12]1[C:16]=2[CH:15]=[N:14][N:13]1[CH2:21][C@@H:22](O)[CH3:23])[CH3:7].C(N(CC)CC)C.[N-:32]=[N+:33]=[N-:34].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:32]([C@H:22]([CH3:23])[CH2:21][N:13]1[C:12]2=[CH:11][C:10]3[C:17]([CH2:18][CH:19]=[CH:20][C:9]=3[O:8][CH2:6][CH3:7])=[C:16]2[CH:15]=[N:14]1)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC1=C2C=c3c(cnn3C[C@H](C)O)=C2CC=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC1=C2C=c3c(cnn3C[C@@H](C)N=[N+]=[N-])=C2CC=C1
Yield: 92.7 %

Procedure:
1.01 ml (13.4 mmol) of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.73 g (6.7 mmol) of (S)-1-(7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 3.72 ml (26.8 mmol) of triethylamine in 50 ml of dichloromethane and the mixture was stirred at this temperature for a further 90 minutes. The reaction mixture was subsequently diluted with 130 ml of dichloromethane, washed twice with 70 ml 70 of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 70 ml of dichloromethane. The combined organic phases were washed with 70 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellowish solid obtained was dissolved in 50 ml of anhydrous dimethylformamide, treated with 0.86 g (13.4 mmol) of sodium azide and the reaction mixture was heated to 90° for 16 hours while stirring. After cooling, the solution was poured into 80 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The yellow oil obtained was purified by column chromatography on silica gel (ethyl acetate). 1.76 g (93%) of (R)-1-(2-azido-propyl)-7-ethoxy-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[CH:19]1([CH2:24][C@H:25]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:36])([F:37])[F:38])[CH:30]=2)[C:26]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]=2)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cl)[C@H](CC1CCCC1)c1cccc(C(F)(F)F)c1
Reactant: COCCn1ccc(N)n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COCCn1ccc(NC(=O)[C@H](CC2CCCC2)c2cccc(C(F)(F)F)c2)n1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
In a round bottom flask was placed 1-(2-methoxy-ethyl)-1H-pyrazol-3-yl-amine (prepared in Example 72, 38 mg, 0.27 mmol), 2,6-lutidine (42 μL, 0.37 mmol) and methylene chloride (5 mL). This solution was then cooled to 0° C. and to it was added dropwise a solution of 3-cyclopentyl-2(R)-(3-trifluoromethyl-phenyl)-propionyl chloride in methylene chloride (prepared in Example 83, 0.12 M solution, 2 mL, 0.24 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction was diluted with methylene chloride (5 mL). The reaction was then washed with a saturated aqueous sodium bicarbonate solution (10 mL) and a 1 N aqueous hydrochloric acid solution (1×10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 20% ethyl acetate/hexanes to 60% ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[1-(2-methoxy-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-trifluoromethyl-phenyl)-propionamide (85 mg, 86%) as a colorless oil: [α]30589=−18.8° (c=0.16, methylene chloride); ES-HRMS m/e calcd for C21H26N3O2F3 (M+H)+ 410.2050, observed 410.2050; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05-1.19 (m, 2H, CH2), 1.35-1.81 (m, 8H, 4×CH2), 2.05-2.19 (m, 1H, CH), 3.19 (s, 3H, OCH3), 3.61 (t, J=5.3 Hz, 2H, OCH2), 3.86-3.94 (m, 1H, ArCH), 4.11 (t, J=5.3 Hz, 2H, NCH2), 6.42 (d, J=2.3 Hz, 1H, Ar), 7.54 (d, J=2.3 Hz, 1H, Ar), 7.55-7.75 (m, 4H, Ar), 10.75 (s, 1H, NH).
Reaction SMILES: [N:1]([O-])=O.[Na+].[Br:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][C:12]=1[F:13])[NH2:9].O.O.[Cl:16][Sn]Cl>Cl>[ClH:16].[Br:5][C:6]1[CH:7]=[C:8]([NH:9][NH2:1])[CH:10]=[CH:11][C:12]=1[F:13]
Reactant: Nc1ccc(F)c(Br)c1
Reactant: Cl[Sn]Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc(F)c(Br)c1
Reaction time: 0.75 h
Yield: 43.6 %

Procedure:
A solution of sodium nitrite (4.2 g, 60 mmol) was added drop-wise to a mixture of 3-bromo-4-fluoroaniline (11.2 g, 58.9 mmol) and concentrated HCl (30 mL, 0.36 M) at 0° C. over 30 min. The resulting clear solution was stirred for 45 min, and a solution of SnCl2.2H2O (27 g, 120 mmol) in concentrated HCl (30 mL) was added drop-wise at 0° C. over 1.5 h. The mixture was stirred for 18 h at room temperature. The resulting precipitate was collected by filtration and crystallized from ethanol to provide the title compound (6.2 g, 42%) as a yellow powder: 1H NMR (300 MHz, DMSO-d6) δ 10.24 (s, 3H), 8.42 (s, 1H), 7.36-7.30 (m, 2H), 7.03-6.98 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:18]1[C:23]([C:24]([OH:26])=[O:25])=[CH:22][C:21]2[C:27]([O:29][C:30](=O)[C:20]=2[CH:19]=1)=[O:28]>>[CH3:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[N:1]1[C:27](=[O:28])[C:21]2[C:20](=[CH:19][CH:18]=[C:23]([C:24]([OH:26])=[O:25])[CH:22]=2)[C:30]1=[O:29]
Reactant: Cc1ccc(-c2nc3ccccc3o2)cc1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 1b), from 2-(3-amino-4-methylphenyl)benzoxazole (250 mg, 1.1 mmol) and 1,2,4-benzenetricarboxylic anhydride (214 mg, 1.1 mmol) the title compound was obtained. 375 mg (84%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.33(d, 2H), 8.23(dd, 1H), 8.12(d, 1H), 7.79(m, 2H), 7.68(d, 1H), 7.44(m, 2H). MS 397 m/z (M−H)−.
Reaction SMILES: Cl.O1CCOCC1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]2[NH:22][C:21]3[CH:23]=[CH:24][C:25]([C:27](O)=[O:28])=[CH:26][C:20]=3[N:19]=2)[N:9]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:54][CH:55]([CH:65]1[CH2:67][CH2:66]1)[CH2:56][C:57]([NH:59][C:60]1[NH:61][CH:62]=[CH:63][N:64]=1)=[O:58]>C(Cl)Cl>[CH:65]1([CH:55]([NH:54][C:27]([C:25]2[CH:24]=[CH:23][C:21]3[NH:22][C:18]([C:10]4[N:9]=[CH:8][C:17]5[C:12]([CH:11]=4)=[CH:13][CH:14]=[CH:15][CH:16]=5)=[N:19][C:20]=3[CH:26]=2)=[O:28])[CH2:56][C:57](=[O:58])[NH:59][C:60]2[NH:61][CH:62]=[CH:63][N:64]=2)[CH2:67][CH2:66]1
Reactant: O=C(O)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1
Reactant: NC(CC(=O)Nc1ncc[nH]1)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(CC(NC(=O)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1)C1CC1)Nc1ncc[nH]1
Yield: 4.3 %

Procedure:
203 mg (1.0 mmol) of 3-tert-butoxycarbonylamino-3-cyclopropyl-propionic acid (0.23 g, 1 mmol) was reacted with 380 mg (1.0 mmol) of HBTU and 130 mg (1.0 mmol) of 2-aminoimidazole sulfate as described in general procedure A. The desired amide product was isolated by column chromatography (EtOAc/silica) and carried on directly to the next step. The BOC compound in DCM (3 mL) was treated with 4.0 M HCl/dioxane (15 mL) for approximately 1 h. The solid 3-Amino-3-cyclopropyl-N-(1H-imidazol-2-yl)-propionamide (180 mg, 100%) was collected by filtration and used directly in the next step 289 mg (1 mmol) of 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid (289 mg, 1 mmol) was reacted with 380 mg (1 mmol) of HBTU and 3-amino-3-cyclopropyl-N-(1H-imidazol-2-yl)-propionamide (230 mg, 1 mmol) as described in general procedure A. A solid precipitated from the solution and was collected by filtration, washed with 1H2O and Et2O, to give 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1-cyclopropyl-2-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide (20 mg, 4%). LCMS: 466 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 9.20 (s, 1H), 8.56 (s, 1H), 8.09-7.34 (m, 9H), 6.39 (s, 2H), 3.71 (t, 1H), 2.44 (m, 2H), 0.81 (m, 1H), 0.10 (m, 4H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](O)=[C:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[CH:6]2.[CH3:19][SH:20]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([S:20][CH3:19])=[C:8]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH:7]=[CH:6]2
Reactant: CS
Reactant: COC(=O)Cc1ccc2cc(OC)ccc2c1O
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1SC

Procedure:
By treating 25 g. of methyl 6-methoxy-1-hydroxy-2-naphthylacetate with 10 ml. of methylmercaptan as described above for the 1,6-dihydroxy compound, methyl 6-methoxy-1-methylthio-2-naphthylacetate is obtained.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[C:38]1([CH2:44][S:45](Cl)(=[O:47])=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:45]([CH2:44][C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)(=[O:47])=[O:46])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1c(C2=NS(=O)(=O)c3c(CNS(=O)(=O)Cc4ccccc4)csc3N2)c(O)c2ccccc2n1NCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
To a solution of the product of Example 353E (16.5 mg, 0.037 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and α-toluene sulfonyl chloride was added (0.008 g, 0.041 mmol). The reaction mixture was warmed to 23° C. and stirred for 0.5 hours. The reaction mixture was then heated to 50° C. and stirred for 1.75 hours. Additional triethylamine (0.010 mL, 0.074 mmol) and α-toluene sulfonyl chloride (0.007 g, 0.037 mmol) were added and the reaction mixture was stirred at 23° C. for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (7.7 mg, 35%). 1H NMR (300 MHz, DMSO-d6) δ 0.15 (d, J=4.04 Hz, 2 H) 0.42 (d, J=7.72 Hz, 2 H) 1.00 (m, 1 H) 2.84 (d, J=7.35 Hz, 2 H) 4.23 (d, J=5.52 Hz, 2 H) 4.44 (s, 2 H) 6.37 (bs, 1 H) 7.32 (s, 1 H) 7.42 (m, 6 H) 7.86 (m, 2 H) 8.07 (d, J=8.46 Hz, 1 H) 8.16 (dd, 1 H) 14.50 (bs, 1 H).
Reaction SMILES: [C:1](=[O:3])=O.[CH3:4]C(C)=O.[OH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15](=[O:17])[CH3:16]>CN(C)C=O>[O:17]=[C:15]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH:4]=[C:16]1[CH:1]=[O:3]
Reactant: CC(C)=O
Reactant: CC(=O)c1ccccc1O
Reactant: O=C=O
Solvent: CN(C)C=O
Product: O=Cc1coc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 13 h

Procedure:
In 80 volume parts of dimethylformamide are dissolved 25 parts of orthohydroxyacetophenone and, while the solution is externally cooled to about -20° C. with dry ice-acetone, 80 volume parts of tetrachloropyrophosphoric acid are added dropwise to the solution. The resulting mixture is stirred at room temperature for 13 hours. Then, the reaction mixture is poured into ice water and the resulting crystals are recovered by filtration, washed with water and ethanol and finally recrystallized from acetone. The procedure yields of 4-oxo-4H-1-benzopyran-3-carboxaldehyde as colorless crystals melting at 152°-153° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH:18]([C@H:31]1[O:36][CH2:35][C@@H:34]([NH2:37])[CH2:33][CH2:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[CH:18]([C@H:31]1[O:36][CH2:35][C@@H:34]([NH:37][C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH2:33][CH2:32]1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reactant: O=C(O)Cc1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccc(F)cc1)N[C@H]1CC[C@@H](C(c2ccccc2)c2ccccc2)OC1
Reaction time: 2 h
Yield: 80 %

Procedure:
Into a solution of 4-fluorophenylacetic acid (0.23 g, 1.46 mmol) in dichloromethane (25 ml) was added oxalyl chloride (0.22 g, 1.76 mmol) dissolved in dichloromethane (5 ml) at 0° C. which was followed by addition of one drop of DMF. The reaction mixture was allowed to reach at room temperature over a period of 2 hours. The solvent was removed in vacuo, and the residue was dissolved in dichloromethane (5 ml) and was added into a solution of cis-N-(6-benzhydryl-tetrahydropyran-3-yl)-amine (0.26 g, 0.96 mmol) and triethylamine (0.31 g, 1.46 mmol) in dichloromethane (25 ml) at 0° C. After 20 minutes the reaction mixture was allowed to come to room temperature. After 3 hours, more dichloromethane was added and the mixture was washed in turn with 1N NaHCO3, H2O and brine, then dried over anhydrous Na2SO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography (hexane/ethyl acetate 7:3) to give cis-N-(6-benzhydryl-tetrahydropyran-3-yl)-2-(4-fluorophenyl)-acetamide 17 (0.31 g, yield 80%) as an oil.
Reaction SMILES: CN(C=O)C.[C:6]([NH:10][S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26]Br)=[CH:22][CH:21]=2)=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7].[CH2:28]([C:32]1[NH:36][C:35]([CH:37]=[O:38])=[C:34]([Cl:39])[N:33]=1)[CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O>[C:6]([NH:10][S:11]([C:14]1[C:15]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][N:36]3[C:35]([CH:37]=[O:38])=[C:34]([Cl:39])[N:33]=[C:32]3[CH2:28][CH2:29][CH2:30][CH3:31])=[CH:22][CH:21]=2)=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:13])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
To a DMF (75 mL) solution of 4′-bromomethylbiphenyl-2-sulfonic acid t-butylamide (4.7 g, 12.2 mmol), was added 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde (2.3 g, 12.2 mmol) and potassium carbonate (1.7 g, 12.2 mmol). The mixture was stirred at room temperature overnight. EtOAc (400 mL) was added and the organic was washed 3 times with a sodium bicarbonate solution (200 mL) followed by saturated aqueous NaCl (200 mL). The solvent was removed and purification was achieved by silica gel chromatography (50/50 hexanes/EtOAc) using an isocratic gradient yielding intermediate (1a) as an off-white solid (5.0 g). Anal. HPLC: retention time=5.2 minutes. Gradient conditions: 10% solvent B/90% solvent A to 90% solvent B/10% solvent B over 6 minutes. MS m/z: [M+H]+ calcd for C25H30ClN3O3S, 488.18; found 488.6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.F[B-](F)(F)F.[O:31]=[N+:32]=[O:33]>O1CCOCC1.ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N+:32]([O-:33])=[O:31])[C:5](=[O:9])[N:6]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:7]=1[CH3:8]
Reactant: Cc1[nH]c(=O)ccc1Br
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1c(Br)cc([N+](=O)[O-])c(=O)n1CC(F)(F)F
Temperature: 66 °C
Reaction time: 16 h

Procedure:
A mixture of 5-bromo-6-methylpyridin-2(1H)-one (10.0 g, 53.2 mmol), cesium carbonate (20.8 g, 63.8 mmol), and 2,2,2-trifluoroethyl methanesulfonate (18.5 g, 80.0 mmol) in dioxane (266 mL) was heated at 66° C. for 1.5 h. The mixture was allowed to cool to 23° C., then diluted with dichloromethane (266 mL). Nitronium tetrafluoroborate (21.2 g, 160 mmol) was added and the resulting mixture was stirred for 16 h. The mixture was then partitioned between half-saturated aqueous sodium chloride solution (500 mL) and ethyl acetate (1 L). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with hexane initially, grading to 50% EtOAc in hexane to provide the title compound. MS: m/z=315.0 (M+1).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C:4](=[O:10])[CH2:3]2.[C-:11]#[N:12].[Na+]>O>[C:11]([C:4]1([OH:10])[CH:5]2[CH2:8][CH2:9][N:2]([CH2:7][CH2:6]2)[CH2:3]1)#[N:12]
Reactant: [C-]#N
Reactant: O=C1CN2CCC1CC2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: N#CC1(O)CN2CCC1CC2
Yield: 96.6 %

Procedure:
1,420 g (8.78 mole) of quinuclidine-3-one-hydrochloride were dissolved in 1800 ml of cold water and at 15° C., 432 g (8.81 mole) of sodium cyanide and 1600 of ml water were added dropwise over one hour followed by stirring for another hour at this temperature. The mixture was filtered, washed with cold water, and dried at 60° C. to obtain 1,290 g (8.48 mole) of 3-cyano-3-hydroxy-quinuclidine (97% yield), in the form of white crystals having a melting point of 157° to 159° C.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([C:26]#[N:27])[C@H:15]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:14]2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([C:26]#[N:27])[C@H:15]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:40])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 88 %

Procedure:
To a solution of rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 342 (95 mg, 0.16 mmol) in tetrahydrofuran (6 mL) was added an aqueous solution (1 N) of NaOH (6 mL, 6 mmol) and methanol (2 mL). The reaction mixture was heated at 80° C. for 2 h, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid as a white solid (80 mg, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:3]=1[CH:4]=[CH:5][N+:6]([O-:8])=[O:7].[CH3:16][N:17]([CH3:21])[C:18](=[S:20])[S-:19].C[NH2+]C>C(=S)=S>[CH3:16][N:17]([CH3:21])[C:18](=[S:19])[S:20][CH:4]([CH2:5][N+:6]([O-:8])=[O:7])[C:3]1[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:2]=1[Cl:1]
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1cc([N+](=O)[O-])ccc1Cl

Procedure:
As in Example 17, reaction of 2-chloro-β,5-dinitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 2-chloro-5-nitro-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 120° - 121° C. after recrystallization without heating from acetone-methanol solution.