Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:17]2[C:16]3[C:11]4=[C:12]([O:18][CH2:19][CH:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:10]4[C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH:13]=[CH:14][CH:15]=3.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:21]1([CH:20]2[N:10]3[C:11]4[C:16]([C:17]5[C:5]([O:4][CH2:3][CH2:2][N:31]6[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]6)=[CH:6][CH:7]=[CH:8][C:9]=53)=[CH:15][CH:14]=[CH:13][C:12]=4[O:18][CH2:19]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN1CCNCC1
Reactant: ClCCOc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CCN(CCOc2cccc3c2c2cccc4c2n3C(c2ccccc2)CO4)CC1
Temperature: 85 °C
Yield: 32.3 %

Procedure:
To a mixture of 7-(2-chloroethoxy)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazole (0.412 g, 1.13 mmol) in dry DMF (10 mL) is added N-methyl piperazine (0.125 mL, 1.13 mmol), sodium iodide (0.17 g, 1.13 mmol), and potassium carbonate (0.312 g, 2.26 mmol). The mixture is heated at 85° C. for 20 h. The mixture is then cooled and partitioned between water and CH2Cl2. The organic layer is separated and washed twice with water (200 mL), dried over anhydrous sodium sulfate and concentrated. Column chromatography (50 mL silica) using CH3OH/CH2Cl2 (8/92) with 2 drops per 100 mL of NH4OH gave 0.156 g (32%) of 2-(4-methyl-1-piperazinyl)ethyl 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl ether; mp 57° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:16]=[C:15]([CH3:23])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])C.C1O[C@@H]1CO>>[OH:12][CH2:11][C:10]([NH:9][CH2:8][C@H:7]([OH:14])[CH2:6][O:5][C:4]1[C:3]([CH3:1])=[CH:18][C:17]([C:19](=[NH:22])[NH:20][OH:21])=[CH:16][C:15]=1[CH3:23])=[O:13]
Reactant: CCc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO
Agent: OC[C@@H]1CO1
Product: Cc1cc(C(=N)NO)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
The title compound is obtained as a white solid (0.90 g) in analogy to N—((S)-3-[2-ethyl-4-(N-hydroxycarbamimidoyl)-6-methyl-phenoxy]-2-hydroxy-propyl)-2-hydroxy-acetamide starting from 4-hydroxy-3,5-methyl-benzonitrile and (R)-glycidol; LC-MS: tR=0.47 min, [M+H]+=311.98.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=3)[CH2:11][C:12](O)([C:14]([F:17])([F:16])[F:15])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([C:19]3[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:21][CH:20]=3)[CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:13]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-c2nc(C(F)(F)F)cn2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 93.6 %

Procedure:
A mixture of 2-(3-chloro-4-methylphenyl)-4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazole from Step 2 (725 mg, 1.7 mmol) and p-toluenesulfonic acid monohydrate (150 mg) in toluene (40 mL) was heated to reflux for 48 hours. The reaction mixture was cooled and the solvent removed under reduced pressure. The crude residue was redissolved in methylene chloride and washed with water, aqueous sodium bicarbonate and brine. After drying (Na2SO4), filtration and concentration in vacuo, the crude mixture (860 mg) was purified by chromatography on silica gel using toluene/ethyl acetate 1/1 to give pure 2-(3-chloro-4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole (660 mg, 95%) as a white solid: mp(DSC) 206° C. Anal. Calc'd. for C18H14N2SO2F3Cl: C, 52.12; H, 3.40; N, 6.75; S, 7.73. Found: C, 52.24; H, 3.45; N, 6.64; S, 7.83.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:20])[CH:8]=2)[N:3]=1.O.[NH2:22][NH2:23]>>[Cl:20][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:22][NH2:23])[CH:11]=[C:10]2[C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[F:19]
Reactant: Fc1cccc(F)c1-c1cc(Cl)nc2ccc(Cl)cc12
Reactant: NN
Solvent: O
Product: NNc1cc(-c2c(F)cccc2F)c2cc(Cl)ccc2n1

Procedure:
In the manner given in Example 1, 2,6-dichloro-4-(2,6-difluorophenyl)quinoline is reacted at reflux with hydrazine hydrate to give 6-chloro-4-(2,6-difluorophenyl)-2-hydrazinoquinoline.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH:18]=[O:19])=[C:11]([CH:15]([CH3:17])[CH3:16])[NH:12]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].Cl[CH2:23][C:24]1[O:25][CH:26]=[CH:27][N:28]=1>CN(C=O)C.CCOC(C)=O>[CH:18]([C:10]1[C:9]2[C:13](=[CH:14][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)[N:12]([CH2:23][C:24]2[O:25][CH:26]=[CH:27][N:28]=2)[C:11]=1[CH:15]([CH3:16])[CH3:17])=[O:19]
Reactant: ClCc1ncco1
Reactant: CCOC(=O)c1ccc2c(C=O)c(C(C)C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2c(C=O)c(C(C)C)n(Cc3ncco3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl3-formyl-2-isopropyl-1H-indole-6-carboxylate (Compound 34, 1.22 g, 4.72 mmol) in DMF (10 ml) was added NaH (170 mg, 7.08 mmol) and 2-(chloromethyl)oxazole (1.10 g, 9.44 mmol). The reaction was stirred at 25° C. for 12 h, diluted with EtOAc, washed with H2O, brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][O:8][CH2:9][C:4]=2[CH:3]=1.[C:12]1([C:18]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:19]2[CH:23]=[C:22]([CH:24]=[O:25])[N:21]=[CH:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:6]1[C:5]2[CH:10]=[CH:11][C:2]([CH:24]([C:22]3[N:21]=[CH:20][N:19]([C:18]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:23]=3)[OH:25])=[CH:3][C:4]=2[CH2:9][O:8][CH2:7]1
Reactant: Brc1ccc2c(c1)COCO2
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: OC(c1ccc2c(c1)COCO2)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 53 %

Procedure:
This compound is prepared like the preceding compound but starting from 6-bromo-4H-1,3-benzodioxin and 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. After decomposing the reaction mixture, the reaction product is extracted with dichloromethane and recrystallized from isopropyl alcohol. By chromatography of the residue obtained after evaporation of the mother liquors, there is obtained a second crop of product. Yield: 53% of theory; M.P.: 165°-167° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[N:8]=[C:9]([CH:12]3[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[NH:10][CH:11]=2)[CH2:3][CH2:2]1.[I-].[Na+].[OH-].[K+].CC(C)([O-])C.[K+].[ClH:35].[Cl:36][CH2:37][CH2:38][N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1.C.Cl.CO>CS(C)=O.C(OC)(C)(C)C>[ClH:36].[ClH:35].[ClH:36].[N:39]1([CH2:38][CH2:37][N:10]2[CH:11]=[C:7]([CH:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)[N:8]=[C:9]2[CH:12]2[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C3CCOCC3)c[nH]2)CC1
Reactant: ClCCN1CCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [I-]
Solvent: COC(C)(C)C
Solvent: CS(C)=O
Solvent: CO
Product: c1c(C2CCOCC2)nc(C2CCNCC2)n1CCN1CCCC1
Temperature: 32.5 °C
Reaction time: 2.5 h

Procedure:
Charge degassed dimethylsulfoxide (750 mL) to a flask, followed by tert-butyl 4-(4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine-1-carboxylate (150 g, 1.0 equiv), sodium iodide (87.2 g, 1.3 equiv), potassium hydroxide (15 g, 0.6 equiv) and potassium tert-butoxide (95.3 g, 1.9 equiv) while maintaining the temperature between 20° and 35° C. Heat the mixture to 30-35° C. In a separate reactor, dissolve 1-(2-chloroethyl)pyrrolidine hydrochloride (83.7 g, 1.1 equiv) in dimethylsulfoxide (750 mL) and transfer to the first reactor at 30°-35° C. Adjust the temperature to 40°-45° C. and stir for 2-3 h. Cool the mixture to 20°-30° C. and add methyl tert-butyl ether (3 L). Wash the organic phase with water (1.5 L), and back-extract the aqueous layer with methyl tert-butyl ether (3 L). Combine the organic layers, wash with water (1.5 L), separate and treat the organic layer with activated charcoal (7.5 g, 0.05 equiv)) for 1-2 h at 40°-45° C. Filter off the charcoal and wash with methyl tert-butyl ether (150 mL). Concentrate to 3-v volumes in vacuo and add methanol (1.05 L). Concentrate again to 3-4 volumes. Add a solution of 2 N hydrochloric acid in methanol (1.1 L, 5.0 equiv), and heat at 50° C.-60° C. for 2 h. Concentrate to 3-4 volumes in vacuo and add ethyl acetate (1.35 L) drop wise with the temperature at 50° C.-60° C., and stir at that temperature for 1-2 h. Cool the reaction mixture to 20° C.-30° C. and stir at that temperature for 1-2 h. Filter and rinse the cake with 3:1 ethyl acetate:MeOH (300 mL) to give 4-(1-(2-(pyrrolidin-1-yl)ethyl)-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-2-yl)piperidine trihydrochloride as a single regioisomer (130 g, 58%). MS (ES) m/z=333 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](B(O)O)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Br[C:21]1[C:22]([NH2:27])=[N:23][CH:24]=[N:25][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCO.COCCOC.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([C:21]4[C:22]([NH2:27])=[N:23][CH:24]=[N:25][CH:26]=4)=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccnc2c1cnn2-c1ccc(F)cc1
Reactant: Nc1ncncc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Solvent: O
Product: Nc1ncncc1-c1ccnc2c1cnn2-c1ccc(F)cc1
Temperature: 105 °C
Yield: 33.5 %

Procedure:
Example 8 was prepared according to the general procedure of Example 1, except that the reaction mixture was heated at 105° C. for 2.25 h, and using the following materials: Intermediate 5A (38.0 mg, 0.148 mmol), 5-bromopyrimidin-4-amine (55.2 mg, 0.317 mmol), sodium carbonate (59.2 mg, 0.559 mmol), degassed EtOH:DME:H2O (1.2:2.5:1.0 ratio) (1.5 mL) and tetrakis(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol). Example 8 was isolated as a white solid (15.2 mg, 33.0%). Purification was done by preparative HPLC (Condition A) using a Phenomenex Luna Axia 30×100 mm S10 column from 10% Solvent B to 90% Solvent B over 12 min, ret. T=7.4 min. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.65-8.85 (1 H, m), 8.44-8.60 (1 H, m), 8.21-8.39 (4 H, m), 7.36-7.52 (3 H, m), 6.95 (2 H, br. s.). LC/MS (Condition B): ret. T=2.22 min, (M+H)+ 307.05. Analytical HPLC: (Condition A): >98%, ret. T=18.63 min, (Condition B): >99%, ret. T=19.30 min, (Condition C): >99%, ret. T=7.15 min, (Condition D): >99%, ret. T=7.56 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.I[CH:17]([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>CC(C)=O.C(OCC)(=O)C>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH:17]([CH3:19])[CH3:18])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: CC(C)I
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC(C)C)cc(C(=O)OC)c1
Temperature: 25 °C

Procedure:
Stir 5-hydroxy-isophthalic acid dimethyl ester (4 g, 19.0 mmol), 2-iodopropane (10.2 mL, 101 mmol), and potassium carbonate (4 g, 28.9 mmol) in acetone (20 mL) at 60° C. overnight. Cool to room temperature and pour into ethyl acetate (100 mL) and 5% aqueous ammonium chloride solution (100 mL). Separate the organic layer and wash it with water, saturated aqueous sodium chloride, dry (sodium sulfate), and concentrate to give the title compound and which is used directly in the next step without further purification.
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][CH:12]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N:14]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[C:5]([O:4][C:3]([N:2]([CH3:1])[CH2:10][CH2:11][CH2:12][N:17]1[CH2:16][CH2:15][N:14]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH2:19][CH2:18]1)=[O:9])([CH3:6])([CH3:7])[CH3:8]
Reactant: CN(CCC=O)C(=O)OC(C)(C)C
Reactant: O=C(OCc1cc(Cl)cc(Cl)c1)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCCN1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl methyl(3-oxopropyl)carbamate (step 3) (1.528 g, 8.16 mmol) was solubilised in DCM (50 ml) and added to 3,5-dichlorobenzyl piperazine-1-carboxylate (step 2) (3.09 g, 9.82 mmol). The resulting mixture was treated with acetic acid (56 μl, 0.982 mmol) and after stirring for 1 hr at RT, sodium triacetoxyborohydride (4.16 g, 19.64 mmol) was added. The reaction mixture was stirred at RT overnight and then quenched by addition of 2M NaOH (aq.). The aqueous layer was basified to pH 14 with conc NaOH solution. The organic layer was separated and the aqueous layer was extracted with more DCM. The organic portions were combined, dried over MgSO4 (anh), filtered and evaporated under reduced pressure, yielding a yellow oil. The crude product was purified by chromatography on silica eluting with 0-10% MeOH (with ammonia) in DCM to afford the title compound;
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6][NH:7]2.C(=O)([O-])[O-].[K+].[K+].[CH2:27](I)[CH3:28]>CN(C)C=O>[CH2:27]([N:7]1[C:8]2[C:3](=[C:2]([F:1])[C:11]([F:12])=[C:10]([F:13])[C:9]=2[F:14])[C:4](=[O:20])[C:5]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:6]1)[CH3:28]
Reactant: CCI
Reactant: CCOC(=O)c1c[nH]c2c(F)c(F)c(F)c(F)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2c(F)c(F)c(F)c(F)c2c1=O
Reaction time: 8 h

Procedure:
To 38.5 g (134 mmol) of 5,6,7,8-tetrafluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, ethyl ester in 700 ml of N,N-dimethylformamide was added 37.15 g (two equivalents) of potassium carbonate and 50 ml (five equivalents) of ethyl iodide. The mixture was brought to 50° C. and stirred vigorously overnight. The solvents were removed and the residue partioned between water and dichloromethane. The dichloromethane was dried (magnesium sulfate) and concentrated. The residue was triturated with diethyl ether to give 30.5 g of material which was recrystallized from ethanol. Filtration gave 23.5 g of the title compound, mp 217°-220° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.[Cl:12][C:13]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:14]=1[CH:15]=[C:16]([C:19]#[N:20])[C:17]#[N:18]>>[NH2:20][C:19]1[N:3]2[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[C:15]([C:14]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:13]=2[Cl:12])[C:16]=1[C:17]#[N:18]
Reactant: N#CC(C#N)=Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1c[nH]nc1N
Product: CCOC(=O)c1cnn2c(N)c(C#N)c(-c3ccc(Cl)cc3Cl)nc12

Procedure:
Commercial 3-amino-4-carbethoxypyrazole and (2,4-dichlorobenzylidene)malononitrile (Intermediate 1) were reacted according to the procedure of Example 1, Step A, and the crude product was purified by preparative HPLC(C18 reverse phase column, gradient elution with 30-80% acetonitrile in water containing 0.05% trifluoroacetic acid) to give the title compound as a reddish-orange solid. LC-MS 376 (M+1).
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:18]C(OC(C)(C)C)=O)[CH:4]([F:17])[CH2:5][N:6]1C(=O)C2=CC=CC=C2C1=O.[ClH:26]>>[ClH:26].[ClH:26].[F:1][CH2:2][CH:3]([NH2:18])[CH:4]([F:17])[CH2:5][NH2:6]
Reactant: CC(C)(C)OC(=O)NC(CF)C(F)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Product: NCC(F)C(N)CF

Procedure:
A mixture of 1,3-difluoro-2-tert.butoxycarbonylamino-4-phthalimidobutane (0.1 g, 0.27 mmol) obtained as in Step C above and concentrated hydrochloric acid is heated at 100° C. for 48 hours. The solvent is evaporated in vacuo and the residue is taken up in water. Insoluble phthalic acid is filtered off and the filtrate concentrated to yield 1,3-difluoro-2,4-diaminobutane, dihydrochloride (0.03 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)C.[F:29][C:30]([F:45])([F:44])[C:31]1[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=1)[C:34]([NH:36][CH2:37][C:38](O)=[O:39])=[O:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:38](=[O:39])[CH2:37][NH:36][C:34](=[O:35])[C:33]2[CH:41]=[CH:42][CH:43]=[C:31]([C:30]([F:29])([F:45])[F:44])[CH:32]=2)[C@H:10]([CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: CC(C)CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CCN(CC)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 35.7 %

Procedure:
A sample of [(1R,3R,4S)-4-amino-3-(3-methyl-butyl)-cyclohexyl]-carbamic acid tert-butyl ester (50 mg, 0.18 mmol) was dissolved in 1:1 CH2Cl2/DMF (2 mL). The resultant solution was charged successively with N,N-diethylisopropylamine (0.16 mL, 0.9 mmol), (3-trifluoromethyl-benzoylamino)-acetic acid (47 mg, 0.19 mmol, prepared as described in WO PCT 0250019), and BOP (116 mg, 0.26 mmol). The reaction was stirred for 12 h at RT and then partitioned between EtOAc and sat. NaHCO3; the aqueous phase was back extracted with EtOAc (1×). The organic phases were combined, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography afforded {(1R, 3R,4S)-3-(3-methyl-butyl)-4-[2-(3-trifluoromethyl-benzoylamino)-acetylamino]-cyclohexyl}-carbamic acid tert-butyl ester (33 mg). MS found: (M+H)+=514.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.Br[C:12]1[S:16][C:15]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=2[C:13]=1[CH3:22].C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:12]3[S:16][C:15]4[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:14]=4[C:13]=3[CH3:22])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cc1c(Br)sc2ccc(Cl)cc12
Reactant: Clc1ccc2nccn2n1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cnc3ccc(Cl)nn23)sc2ccc(Cl)cc12
Yield: 37.9 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine (606 mg, 3.95 mmol, 1.0 equiv) in toluene (10.00 mL) was added 2-bromo-5-chloro-3-methylbenzo[b]thiophene (1.03 g, 3.95 mmol, 1.0 equiv), potassium carbonate (1.09 g, 7.90 mmol, 2.0 equiv), triphenyl phosphine (207 mg, 0.790 mmol, 0.20 equiv) and potassium acetate (89 mg, 0.395 mmol, 0.1 equiv). The reaction mixture was heated to reflux for 24 h. Purification by column chromatography using 50% ethyl acetate in hexanes elution gave 500 mg of the white solid, 38%.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.C1COCC1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1cc(Br)ccc1CO
Yield: 71.5 %

Procedure:
To a solution of 4-bromo-2-methansulfonyl-benzaldehyde (1.0 g, 3.88 mmol) in EtOH (11 mL)/THF (2.5 mL) was added NaBH4 (1.29 g, 34.2 mmol) in three portions. The reaction was carefully quenched with water and the product was extracted with EtOAc, dried (Na2SO4), and purified by silica gel chromatography to give 735 mg of (4-bromo-2-methansulfonyl-phenyl)-methanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[C:15]([F:32])=[CH:16][C:17]3[O:22][CH2:21][C:20](=O)[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([O:13][C:14]2[C:15]([F:32])=[CH:16][C:17]3[O:22][CH2:21][C:20](=[S:42])[N:19]([CH:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:25])[C:18]=3[CH:31]=2)([CH3:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2cc(F)c(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Solvent: Cc1ccccc1
Solvent: COCCOC
Product: CCOC(=O)C(C)N1C(=S)COc2cc(F)c(OC3(C)CN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Yield: 58.9 %

Procedure:
To a solution of 3-[4-(1-ethoxycarbonyl-ethyl)-7-fluoro-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.164 g, 0.362 mmol) in toluene (3 mL) and DME (3 mL) was added Lawesson's reagent (0.117 g, 0.290 mmol) and the mixture was heated to reflux for 4 h. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 5% to 10% EtOAc in petroleum ether) to give 3-[4-(1-ethoxycarbonyl-ethyl)-7-fluoro-3-thioxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-yloxy]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.080 g, 47%) as a pale yellow solid. 1H NMR (CDCl3, 400 MHz): δ 6.82 (d, J=10.0 Hz, 1H), 6.72 (brs, 1H), 6.47 (d, J=6.8 Hz, 1H), 4.89 (d, J=13.2 Hz, 2H), 4.16 (m, 4H), 3.85 (m, 2H), 1.64 (d, J=7.2 Hz, 3H), 1.56 (s, 3H), 1.43 (s, 9H), 1.16 (t, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15].CC(O)=O>C(OCC)(=O)C.[Fe]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:11][CH2:12][CH2:13][C:14]([NH:16][CH3:17])=[O:15])=[C:2]([F:1])[CH:7]=1
Reactant: CNC(=O)CCCc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CNC(=O)CCCc1ccc(N)cc1F
Temperature: 21 °C
Yield: 95.1 %

Procedure:
A solution of compound 4-(2-Fluoro-4-nitrophenyl)-N-methylbutanamide (81) (18 mg, 0.07 mmol), Fe (30 mg, 0.52 mmol) and AcOH (1 mL) in ethyl acetate (3 mL) was heated under reflux for 2 h. The reaction mixture was allowed to cool to 21° C. and then filtered. The organic layer was concentrated and the residue was purified with silica gel column chromatography (dichloromethane:acetone, 9:1) to give desired 4-(4-Amino-2-fluorophenyl)-N-methylbutanamide (80) (14 mg, 86%): 1H NMR δ 6.92 (dd, 1H, J=8.3, 8.2 Hz), 6.39 (dd, 1H, J=8.3, 2.0 Hz), 6.33 (dd, 1H, J=13.3, 2.0 Hz), 5.48 (br s, 1H), 3.69 (br s, 2H), 2.79 (d, 3H, J=4.8 Hz), 2.55 (t, 2H, J=7.4 Hz) 2.16 (t, 2H, J=7.5 Hz) 1.85-1.94 (m, 2H).