Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][CH2:8][CH2:7]2.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:23]=[CH:24][C:25]([CH2:28]Cl)=[N:26][CH:27]=2)=[CH:18][CH:17]=1>CN(C=O)C>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[N:9]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)=[CH:27][N:26]=1)[CH2:8][CH2:7]2
Reactant: O=C1NCCc2cc(Br)ccc21
Reactant: Fc1ccc(-c2ccc(CCl)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccc(Br)cc2CCN1Cc1ccc(-c2ccc(F)cc2)cn1
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) suspension of NaH (0.084 g. 3.5 mmol) and Kl (0.1 g, 0.6 mmol) in DMF (10 mL) is added dropwise a solution of 6-bromo-1-oxo-1,2,3,4-tetrahydroisoquinoline (0.65 g, 2.9 mmol) in DMF (10 mL). After 15 minutes, a solution of 5-(4-fluorophenyl)-2-(chloromethyl)pyridine (1.27 g, 5.8 mmol) in DMF (10 mL) is added dropwise and the resulting solution stirred for 12 hours. The reaction mixture is then partitioned between water (200 mL) and EtOAc (200 mL). The aqueous layer is extracted with EtOAc (1×200 mL). The combined organic extracts are then washed with H2O (4×200 mL), saturated NaCl solution (2×200 mL), and dried over MgSO4 and concentrated in vacuo. The resulting material is chromatographed (silica gel. 1:4 EtOAc-hexanes) to afford 6-bromo-2-{[5-(4-fluorophenyl)-2-pyridyl]methyl}-1-oxo-1,2,3,4 -tetrahydroisoquinoline as pale yellow oil.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[S:12][CH:13]=2)O1.Br[C:20]1[CH:21]=[N:22][N:23]2[CH:28]=[C:27](C3C=NC=CC=3)[CH:26]=[N:25][C:24]=12.C(=O)(O)[O-].[Na+].O1[CH2:45][CH2:44]OCC1>>[N:22]1[CH:45]=[CH:44][CH:24]=[C:20]([N:25]2[CH:26]=[CH:27][C:28]3=[C:20]([C:9]4[CH:10]=[C:11]([C:14]([O:16][CH3:17])=[O:15])[S:12][CH:13]=4)[CH:21]=[N:22][N:23]3[CH2:24]2)[CH:21]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cs1
Reactant: Brc1cnn2cc(-c3cccnc3)cnc12
Reactant: C1COCCO1
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)c1cc(-c2cnn3c2C=CN(c2cccnc2)C3)cs1
Temperature: 85 °C

Procedure:
A solution of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiophene-2-carboxylate (1.09 g, 4.1 mmol) and 3-bromo-6-pyridin-3-ylpyrazolo[1,5-a]pyrimidine (1.1 g, 4.1 mmol) in dioxane (20 mL) and 1M aqueous sodium bicarbonate (12.2 mL, 12.2 mmol) was degassed with nitrogen and treated with palladium tetrakistriphenylphosphine (0.24 g, 0.20 mmol) and heated to 85° C. for 16 hours. The reaction was cooled to room temperature and partitioned between water/methylene chloride. The organics were washed with water and brine, dried over sodium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (1-5% methanol/methylene chloride) gave methyl 4-(6-pyridin-3-ylpyrazolo[1,5-c]pyrimidin-3-yl)thiophene-2-carboxylate. LC-MS SIMS: m/z 337.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Si:11]([O:28][CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH2:33])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>S(Cl)(Cl)=O.C(Cl)Cl>[Si:11]([O:28][CH2:29][CH2:30][C:31]1[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=1[NH:33][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[N:10][C:2]=1[F:1])([C:24]([CH3:27])([CH3:25])[CH3:26])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(C)(C)[Si](OCCc1ccccc1N)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cccnc1F
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](OCCc1ccccc1NC(=O)c1cccnc1F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A mixture of 2-fluoronicotinic acid (Aldrich, 0.42 g, 2.9 mmol) in thionyl chloride (15 mL) was refluxed for two hours before being concentrated in vacuo to a residue which was used without further purification. The residue was dissolved in anhydrous DCM (5 mL) then added dropwise to a 0° C. solution of 2-(2-(tert-butyldiphenylsilyloxy)ethyl)aniline (1.10 g, 2.9 mmol) and TEA (0.43 mL, 3.1 mmol) in anhydrous DCM (15 mL). The reaction was then stirred at ambient temperature for 16 hours before being quenched with water then stirred for an additional thirty minutes. The layers were separated and the aqueous layer extracted with DCM. The combined organic layers were washed sequentially with water, saturated aqueous NaHCO3, and brine before being dried over anhydrous MgSO4, and then concentrated in vacuo. The resultant residue was purified by silica gel flash chromatography, eluting with 4:1 hexane/EtOAc, to afford the desired compound as a white solid (1.1 g, 72%). 1H NMR (DMSO-d6) δ 9.93 (s, 1H), 8.41 (d, 1H, J=4.4 Hz), 8.22 (t, 1H, J=7.6 Hz), 7.27-7.60 (m, 15H), 3.84 (t, 2H, J=6.7 Hz), 2.98 (t, 2H, J=6.7 Hz), 0.92 (s, 9H); HRMS(ESI+), 499.2217 (M+H)+ calc, 499.2230 (M+H)+ found.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=O)[C:6]=1[CH:16]=[CH2:17])=[O:4].BrBr.NC(N)=[S:22].[OH-].[NH4+]>C(Cl)(Cl)Cl.C(O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]2[S:22][CH:17]=[CH:16][C:6]=12)=[O:4]
Reactant: C=Cc1c(C(=O)OC)c2ccccc2[nH]c1=O
Reactant: NC(N)=S
Agent: BrBr
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c2ccccc2nc2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.8 g (7.2 mmol) Methyl-2-oxo-3-vinyl-1,2-dihydroquinoline-4-carboxylate 5 in 40 mL chloroform was added slowly over a dropping funnel a solution of 1.15 g (7.2 mmol) bromine in 40 mL chloroform and the reaction mixture was stirred for 1 hour at ambient temperature. After evaporation of the solvent the residue was mixed with 40 mL ethanol and 1.7 g (18 mmol) thiourea and refluxed for 2.5 h. After cooling the mixture was poured on ice, the pH-value was adjusted with ammonium hydroxide at pH=7-8 and the solution was extracted with 100 mL chloroform. The organic layer was separated, dried over sodium sulfate and filtered. Then the solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel, eluting with methylene chloride/acetone 9:1, to give 1.0 of the desired product 14.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([CH:60]=[CH:61][CH:62]=1)[CH2:45][N:46]1[CH2:50][CH2:49][N:48]([C@@H:51]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:52](O)=[O:53])[C:47]1=[O:59].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:52](=[O:53])[C@@H:51]([N:48]1[CH2:49][CH2:50][N:46]([CH2:45][C:44]2[CH:60]=[CH:61][CH:62]=[C:42]([O:41][CH3:40])[CH:43]=2)[C:47]1=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: COc1cccc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)c1
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N1CCN(Cc2cccc(OC)c2)C1=O)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.7 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 71A (0.018 g, 0.056 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.033 mL, 0.189 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between ethyl acetate and saturated NaHCO3 solution. The organic phase was washed brine, dried over MgSO4, filtered and concentrated to give the title compound (0.018 g, 54% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.80 (s, 9 H), 0.87 (s, 9 H), 1.25 (m, 1 H), 1.39 (m, 1 H), 1.54 (m, 1 H), 2.42 (m, 1 H), 2.64 (m, 3 H), 2.89 (m, 2 H), 3.21 (m, 1 H), 3.54 (m, 4 H), 3.72 (s, 3 H), 3.84 (d, J=9.56 Hz, 1 H), 3.96 (m, 1 H), 4.04 (s, 1 H), 4.18 (m, 1 H), 4.27 (s, 2 H), 4.44 (d, J=6.99 Hz, 1 H), 6.85 (m, 4 H), 7.06 (m, 5 H), 7.29 (m, 4 H), 7.54 (d, J=9.56 Hz, 1 H), 7.89 (m, 5 H), 8.65 (d, J=4.41 Hz, 1 H).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][SH:3].Cl.[OH-].[K+].Cl[C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:23])[C:11]=2[CH:10]=1.CN1C(=O)N(C)CCC1.Cl>C1(C)C=CC=CC=1.O>[NH2:4][CH2:1][CH2:2][S:3][C:15]1[CH:16]=[CH:17][C:18]2[S:19][C:20]3[C:11](=[CH:10][CH:9]=[CH:22][CH:21]=3)[C:12](=[O:23])[C:13]=2[CH:14]=1
Reactant: O=c1c2ccccc2sc2ccc(Cl)cc12
Reactant: NCCS
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCN(C)C1=O
Solvent: Cc1ccccc1
Product: NCCSc1ccc2sc3ccccc3c(=O)c2c1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
17.0 g (0.15 mol) of cysteaminium chloride and 19.8 g (0.3 mol) of potassium hydroxide are boiled for 3 hours on a water separator in 180 ml of toluene. 24.6 g (0.1 mol) of 2-chlorothioxanthone and 180 mol of dimethylpropyleneurea are added to the evaporated residue, and the mixtureis stirred for 20 hours at 100° C. The reaction mixture is poured into 1 l of 2N hydrochloric acid and the aqueous phase is extracted with ethyl acetate. The aqueous phase is then adjusted to pH 10 and extracted with ethyl acetate. Work-up of the organic phase gives 24.0 g of the analytically pure compound IIIb.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:13]1[O:15][CH2:14]1.[C:16](O)(=[O:18])[CH3:17]>>[OH:18][CH2:16][CH2:17][N:1]([C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)[CH2:14][CH2:13][OH:15]
Reactant: CC(=O)O
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: C1CO1
Product: COC(=O)Cc1ccc(N(CCO)CCO)cc1

Procedure:
Methyl 4-aminophenylacetate (5.5 g; 33 mmol) was reacted with 45 g (341 mmol, 10 equivalents) of ethylene oxide in 33 ml of 30% acetic acid, followed by post treatments. The crude product so obtained was purified by chromatography on a silica gel column (n-hexane/ethyl acetate=1/2→1/4) and washed with n-hexane, whereby 6.07 g (24.0 mmol) of the title compound were obtained as white crystals (yield: 72.6%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[N:17][C:18]=3[NH:28][NH2:29])[N:13]=2)=[CH:8][CH:7]=1.O.[C:31]1(C)C(S(O)(=O)=O)=CC=C[CH:36]=1.C1(C)C=CC=CC=1.C(OC)(OC)(OC)C>CO>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:20][C:19]3[C:18]4=[N:28][N:29]=[C:31]([CH3:36])[N:17]4[CH:16]=[CH:15][C:14]=3[N:13]=2)=[CH:8][CH:7]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: NNc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Agent: COC(C)(OC)OC
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nnc2c3cc(-c4ccccc4)c(-c4ccc(C5OCCO5)cc4)nc3ccn12
Temperature: 100 °C

Procedure:
To a solution of [2-(4-[1,3]dioxolan-2-yl-phenyl)-3-phenyl-[1,6]naphthyridin-5-yl]-hydrazine (3-4, 0.35 g, 0.91 mmol) and toluenesulfonic acid monohydrate (17 mg, 0.09 mmol) in 3:1 toluene:MeOH (4 mL) was added trimethyl orthoacetate (0.157 mL, 1.23 mmol). The mixture was heated to 100° C. in a microwave reactor for 75 min. The reaction mixture was then concentrated in vacuo. The solid was collected and dried with toluene azeotropically to give the title compound which was used for next step without further purification. LRMS m/z (M+1) Calcd: 409.2. Found 409.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[NH2:30][CH2:31][CH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:35]1[CH2:36][CH2:37][CH:32]([CH2:31][NH:30][C:27]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:12]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24])[NH:10]2)=[O:28])[CH2:33][CH2:34]1
Reactant: NCC1CCOCC1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC2CCOCC2)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.2 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 4-aminomethyl tetrahydropyran (34.5 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (tetrahydro-pyran-4-ylmethyl)-amide (10.8 mg, 10.2%) as an off-white powder. HRMS (ES+) m/z Calcd for C29H35Cl2N3O2S+H [(M+H)+]: 528.2179. found: 528.2180.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4].[Cl:22][C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:30](Cl)Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:29][C:28]1[C:23]([Cl:22])=[CH:24][CH:25]=[CH:26][C:27]=1[CH3:30])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH2:18][CH2:19][S:20][CH3:21])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: ClCCl
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Cl
Reactant: Nc1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1c(C)cccc1Cl
Temperature: 90 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
A mixture of 3-butyryl-4-chloro-8-(2-methylthioethoxy)quinoline (0.8 g, 2.5 mmol) and 2-methyl, 6-chloroaniline (0.52 g, 3.7 mmol) in toluene (12 ml) was heated to 90° C. and stirred 3.0 h. After cooling to room temperature, methylene chloride and water were added. The mixture was neutralized with a saturated solution of sodium bicarbonate. The organic layer was dried over sodium sulfate and evaporated. Chromatography (SiO2 ; EtOAc) gave 0.77 g (72%) of the title compound.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4].[OH2:12].O.O.O.O.O.O.O.O.[S-2:21].[Na+].[Na+]>CC(C)=O.O>[S:21]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:12])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: O
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: [S-2]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(CSCC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Yield: 86.4 %

Procedure:
A solution of 2-bromo-1-(4-bromophenyl)ethanone (27.8 g, 100 mmol) was dissolved in acetone, the solution was cooled in an ice bath then sodium sulfide nonahydrate (12.01 g, 50 mmol) dissolved in water (100 mL) was added dropwise over 45 minutes time. The resultant solution was stirred an additional 2 hours at room temperature, the solid formed in the reaction was collected and then washed with water then ethanol and dried in a vacuum oven to provide 18.5 g (43%) of the title compound.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[Cl:5][C:6]1[C:11]2[C:12](=[O:24])[N:13]3[CH2:23][CH2:22][C@H:14]3[C:15]3[N:16]([CH:17]=[N:18][C:19]=3[C:20]#[N:21])[C:10]=2[CH:9]=[CH:8][C:7]=1[F:25]>CO>[Cl:5][C:6]1[C:11]2[C:12](=[O:24])[N:13]3[CH2:23][CH2:22][C@H:14]3[C:15]3[N:16]([CH:17]=[N:18][C:19]=3[C:20](=[N:3][OH:4])[NH2:21])[C:10]=2[CH:9]=[CH:8][C:7]=1[F:25]
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: NC(=NO)c1ncn2c1[C@@H]1CCN1C(=O)c1c-2ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
3.1 g (134.8 mmol) of sodium were dissolved in 140 ml of methanol. 10 g (145 mmol) of hydroxylamine hydrochloride and 28.6 g (94.5 mmol) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile were added in succession at room temperature. The suspension was stirred at room temperature overnight, cooled to 0° during 30 min., the crystals were filtered off, suspended in 50 ml of water and filtered off. The methanol solution was concentrated, whereupon the residue was suspended in 30 ml of water and the crystals were filtered off. By drying the combined crystallizate there were obtained 30.94 g (97%) of (S)-8-chloro-7-fluoro-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxamidoxime of m.p. 236°-238°.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][CH:13]=[C:14]([Cl:15])[C:8]2=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Cl:15][C:14]1[C:8]2[C:9](=[N:10][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[N:7]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(N)(C#N)Cn1nc2cccc(Cl)c2n1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Product: CC(C#N)(Cn1nc2cccc(Cl)c2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4-chloro-2H-benzotriazol-2-yl)-2-methylpropionitrile (100 mg, described in Example 35) and 4-trifluoromethylthiobenzoyl chloride (0.1 mL), the title compound was isolated as a white solid (130 mg, 70%). Rf=0.6 (1:1 EA/heptane). MS (ES): M/Z [M+H]=440. NMR: (400 MHz, DMSO-d6): 1.75 (s, 3H), 5.43 (d, J=13.3 Hz, 1H), 5.55 (d, J=13.4 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.59 (d, J=6.7 Hz, 1H), 7.75-7.95 (m, 5H) and 8.97 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.98 (s, 3F).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][Br:15]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc([N+](=O)[O-])c1CBr

Procedure:
2-Methyl-3-nitrobenzoic acid methyl ester (commercially available) is treated in a solvent such as carbon tetrachloride with N-bromosuccinimide under light to produce 2-bromomethyl-3-nitrobenzoic acid methyl ester. This benzylic bromide is treated in a solvent such as dimethylformamide with [2-(3-amino-2,6-dioxo-piperidin-1-yl)-ethyl]-phosphonic acid diethyl ester (for the preparation of this compound, see below) in the presence of a base such as triethylamine. The coupled product is then reduced by hydrogenation (Bioorg. Med. Chem. Lett., 1999, 9, 1625) to afford the desired analog.
Reaction SMILES: Br[C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][NH2:25].O>C(OCC)(=O)C>[Cl:18][C:8]1[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:12]([Cl:13])[C:7]=1[N:6]1[C:2]([NH:25][CH3:24])=[C:3]([N+:21]([O-:23])=[O:22])[C:4]([C:19]#[N:20])=[N:5]1
Reactant: CN
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(Br)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CNc1c([N+](=O)[O-])c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 55 °C
Yield: 92.1 %

Procedure:
A mixture of 5-bromo-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-nitro-1H-pyrazole-3-carbonitrile (EP 295118 A1, 50 mg, 0.12 mmol) and methylamine (2M in tetrahydrofuran, 1.0 mmol, 2.0 mmol) was heated at 55° C. for 2.5 h. To the reaction mixture was added water (5 ml), followed by ethyl acetate (5 ml). The two layers were separated and the aqueous layer was extracted with ethyl acetate (3×5 ml). The combined organic phases were dried (MgSO4) and concentrated in vacuo to give the titled compound (42 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[CH2:27][NH:26][CH2:25][CH2:24][C:19]=5[N:20]([CH3:23])[C:21]=4[CH:22]=3)[C:10](=[O:28])[CH:9]=2)=[C:4]([O:29][CH3:30])[CH:3]=1.[C:31]1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:43].Cl>>[ClH:43].[CH3:31][N:26]1[CH2:25][CH2:24][C:19]2[N:20]([CH3:23])[C:21]3[CH:22]=[C:14]([N:11]4[CH:12]=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=5[O:29][CH3:30])=[CH:9][C:10]4=[O:28])[CH:15]=[CH:16][C:17]=3[C:18]=2[CH2:27]1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: COc1cc(F)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CCNC4)c(=O)c1
Agent: Cl
Product: COc1cc(F)ccc1-c1ccn(-c2ccc3c4c(n(C)c3c2)CCN(C)C4)c(=O)c1
Yield: 52 %

Procedure:
4-(4-Fluoro-2-methoxyphenyl)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (37 mg, 0.092 mmol) was reacted according to the procedure of Example 47 to provide the free-base. Conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound (21 mg, 52%) as a yellow solid: mp 294-298° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.83 (br s, 1H), 7.65 (d, J=7.1 Hz, 1H), 7.61 (d, J=1.4 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.46 (dd, J=8.4, 6.9 Hz, 1H), 7.12-7.10 (m, 1H), 7.08 (d, J=1.4 Hz, 1H), 6.91 (overlapping ddd, J=8.4, 2.4 Hz, 1H), 6.55 (d, J=1.6 Hz, 1H), 6.48 (dd, J=7.1, 1.6 Hz, 1H), 4.62 (d, J=12.2 Hz, 1H), 4.30 (dd, J=14.2, 7.5 Hz, 1H), 3.86 (s, 3H), 3.80-3.76 (m, 1H), 3.75 (s, 3H), 3.52-3.42 (m, 1H), 3.24-3.15 (m, 2H), 2.79 (d, J=4.6 Hz, 3H); ESI MS m/z 418 [M+H]+; HPLC (Method B)>99% (AUC), tR=12.6 min.
Reaction SMILES: C([C@@H]1CO[C:10](=O)[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16]C=O)C1C=CC=CC=1.N[C@H:38]1[CH2:43][CH2:42][C@H:41]([OH:44])[CH2:40][CH2:39]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([Cl:35])[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:10][N:9]([C@H:38]3[CH2:43][CH2:42][C@H:41]([OH:44])[CH2:40][CH2:39]3)[C:14]2=[O:36])=[C:25]([Cl:26])[CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Mix (R)-4-((R)-4-benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde (Preparation 10) (3.054 g, 5.8 mmol), trans-4-amino-cyclohexanol (1.35, 11.6 mmol), NaBH(OAc)3 (5.18 g, 23.21 mmol) and acetic acid (0.63 mL, 11.2 mmol) in 50 mL of 1,2-dichloroethane. Stir for 12 hours at room temperature. Quench with saturated solution of NaHCO3 and extract with ethyl acetate. Wash the extract with brine. Dry over magnesium sulfate, filter, and concentrate. After flash column chromatography receive 1.39 g (54%) of the title compound: Mass spectrum (apci) m/z=448 (M+H).