Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](O)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+].N1C=CC=CC=1>[O-2].[Cu+2].C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][C:13]([Br:12])=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: Brc1ccc(Br)cc1
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Yield: 49.5 %

Procedure:
To a mixture of Example 1A (505 mg, 3.31 mmol), 1,4-dibromobenzene (2.34 g, 9.92 mmol.), K2CO3 (960 mg, 6.87 mmol) and pyridine (20 mL) at 80° C. was added Cu(II) oxide (650 mg, 8.17 mmol). After the addition, the mixture was refluxed vigorously for 20 h. After cooling, methylene chloride was added and the mixture was filtered through Celite. The filtrate was concentrated to dryness. The residue was dissolved in ether, which was washed with 10% HCl (2×), 1N NaOH (2×), brine (1×), dried over MgSO4, and concentrated to dryness. The residue was purified on silica gel eluting with hexane and ethyl acetate gradient to give the desired product as a white solid (477 mg, 47%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12](OC)=[O:13])[CH2:10][Cl:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[BH4-].C1COCC1.C([O-])(O)=O.[Na+]>C(O)C.C(Cl)Cl.CC(C)=O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:12][OH:13])[CH2:10][Cl:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](CCl)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CO)CCl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of methyl N-(tert-butoxycarbonyl)-3-chloro-L-alaninate (56, 2.13 g, 9.0 mmol) in ethanol (41 ml) stirred at 0° C. under N2 atmosphere was treated with a 2M solution of LiBH4 in THF (5 mL, 10 mmol) (slow addition). The reaction mixture was slowly warmed up to room temperature and further stirred for 4 h, cooled to 0° C., treated with saturated NaHCO3 (5 mL) followed by acetone (5 mL), stirred for 10 minutes, diluted with DCM and washed with brine, dried over MgSO4 filtered and concentrated to afford 1.94 (100% yield) of title compound as a white solid. MS: m/z=232.0 (MNa+).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:33][C:34]1[CH:35]=[C:36]([CH:38]=[CH:39][C:40]=1[N:41]1[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]1)[NH2:37]>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:37][C:36]5[CH:38]=[CH:39][C:40]([N:41]6[CH2:46][CH2:45][N:44]([CH3:47])[CH2:43][CH2:42]6)=[C:34]([F:33])[CH:35]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCN(c2ccc(N)cc2F)CC1
Product: COc1cc(C(=O)Nc2ccc(N3CCN(C)CC3)c(F)c2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was prepared in a manner analogous to the compound 149 from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid and 3-fluoro-4-(4-methylpiperazin-1-yl)aniline with yield 52.4 mg (41%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.60 (br. s., 6 H) 1.99 (s, 2 H) 2.22 (s, 3 H) 2.40-2.51 (m, 4 H) 2.98 (br. s., 4 H) 3.97 (s, 3 H) 4.22 (t, 2 H) 4.79 (m, 1 H) 7.03 (t, J=9.35 Hz, 1 H) 7.45 (dd, J=8.72, 1.64 Hz, 1 H) 7.54-7.78 (m, 3 H) 8.04 (s, 1 H) 8.28 (s, 1 H) 8.36 (d, J=8.34 Hz, 1 H) 10.11 (s, 1 H). [M+H] calc'd for C32H37F2N8O3, 639; found 639.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH2:21][CH2:22][OH:23])[CH2:14][C@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][CH:7]=1.CC1(C)N([O])C(C)(C)CCC1.[Br-].[K+].Cl[O-].[Na+].C([O-])(O)=[O:42].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:12]2[CH2:18][CH2:17][C:16](=[O:19])[N:15]([CH2:20][CH2:21][C:22]([OH:42])=[O:23])[CH2:14][C@H:13]2[CH3:24])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(CCCO)C(=O)CCN1C(=O)/C=C/c1cccc(Cl)c1
Reactant: O=C([O-])O
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: C[C@@H]1CN(CCC(=O)O)C(=O)CCN1C(=O)/C=C/c1cccc(Cl)c1
Temperature: 0 °C
Yield: 92 %

Procedure:
To 0.52 g (1 mmol) of (R)-1-[(E)-3-(3-Chloro-phenyl)-acryloyl]-4-(3-hydroxy-propyl)-2-methyl-[1,4]diazepan-5-one, 0.002 g (0.01 mmol) TEMPO in 5 ml of ice cold CH2Cl2 was added 0.018 g (0.2 mmol) of potassium bromide in a solution of 4.6 ml (6 mmol) of 13% sodium hypochlorite saturated with NaHCO3. The mixture was rapidly stirred for 5 minutes after which time a few drops of MeOH were added and the phases separated. The aqueous was acidified with 1N HCl and repeatedly extracted with CH2Cl2, dried (Na2SO4) and concentrated. This afforded the titled compound in 92% yield as a colorless foam. MS: 365.2 (MH+, Cl).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:42][O:43][C:44]1[CH:45]=[C:46]([CH:49]=[CH:50][C:51]=1[O:52][CH3:53])[CH2:47][NH2:48].C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:48][CH2:47][C:46]2[CH:49]=[CH:50][C:51]([O:52][CH3:53])=[C:44]([O:43][CH3:42])[CH:45]=2)=[O:16])=[CH:17][CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: COc1ccc(CN)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-benzoic acid (1.0 g, 4 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (920 mg, 4.8 mmol), 1-hydroxybenzotriazole hydrate (600 mg, 4.4 mmol), 3,4-dimethoxybenzylamine (730 mg, 4.4 mmol) and N-ethyldiisopropylamine (2.5 ml, 14 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue dissolved in ethyl acetate. This solution was washed with 1N hydrochloric acid (2×), sodium bicarbonate solution (2×) and sodium chloride solution. The solution was dried over magnesium sulphate and evaporated under reduced pressure to afford the title compound as a colourless solid, 1.6 g.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[CH:7]1)(=[O:5])=[O:4].[Li]C(C)(C)C.[Cl-:17].[Zn+2:18].[Cl-]>C1COCC1>[Cl-:17].[CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[Zn+:18])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)n1ccnc1
Reactant: [Zn+2]
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccnc1[Zn+]

Procedure:
N-dimethylsulfamoyl-imidaz-2-yl zinc chloride was prepared in situ by lithiation of N-dimethylsulfamoylimidazole (0.97 g, 5.5 mmol) in THF (20 mL) with t-BuLi (1.7M, 6.7 mL), followed by quenching with zinc chloride (1.87 g, 13.75 mmol).
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=2.[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.O>[CH3:8][C:9]1[N:10]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)[C:11]2[C:16]([C:17]=1[CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: COC(=O)Cc1c(C)[nH]c2ccccc12
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)Cc1c(C)n(Cc2ccc([N+](=O)[O-])cc2)c2ccccc12
Yield: 3.7 %

Procedure:
Into 100 mL toluene were added methyl 2-(2-methyl-1H-indol-3-yl)acetate (4.9 g, 24.1 mmol), p-nitro benzyl bromide (5.18 g, 24.0 mmol), cesium carbonate (9.38 g, 28.8 mmol), and cetyl tributyl phosphonium bromide (1.58 g, 3.1 mmol). Upon completion of addition, it was reacted at 110° C. for 6 hours. Upon completion of the reaction, it was cooled, water was added, and extracted with diethyl ether. The extract was washed with water. The organic phase was rotate evaporated to dryness, and purified by preparative liquid phase to obtain the product 300 mg, at a yield of 3.7%.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)=[CH:7][C:6]=1[F:22])=[N+]=[N-].CO>C(OCC)(=O)C.[C].[Pd]>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)=[CH:7][C:6]=1[F:22]
Reactant: CC(=O)Nc1nc(CCc2ccc(CN=[N+]=[N-])c(F)c2)cs1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(=O)Nc1nc(CCc2ccc(CN)c(F)c2)cs1
Yield: 85.3 %

Procedure:
To a solution of N-(4-{2-[4-(azidomethyl)-3-fluorophenyl]ethyl}-1,3-thiazol-2-yl)acetamide (152.3 mg, 0.477 mmol) in ethyl acetate (21 ml) was added 10% palladium carbon (30.5 mg, containing 50% water), and the mixture was hydrogenated at room temperature under an atmospheric pressure. Ethyl acetate (5 ml) and methanol (5 ml) were added to the reaction mixture, and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure, and the resulting solid was collected by filtration, washed with tert-butyl methyl ether (5 ml) and dried under reduced pressure to give N-(4-{2-[4-(aminomethyl)-3-fluorophenyl]ethyl}-1,3-thiazol-2-yl)acetamide (119.3 mg, 0.407 mmol, yield 85.3%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([OH:28])=O)=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1.[NH2:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[C:15]3[C:21]4[CH:22]=[CH:23][C:24]([C:26]([NH:30][C:31]([CH3:35])([CH3:34])[CH2:32][OH:33])=[O:28])=[CH:25][C:20]=4[O:19][CH2:18][CH2:17][N:16]3[CH:29]=2)=[N:11][CH:10]=[N:9]1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2
Solvent: C1CCOC1
Product: CC(C)(CO)NC(=O)c1ccc2c(c1)OCCn1cc(-c3ncnn3-c3ccccc3Cl)nc1-2

Procedure:
Following the same procedure as for 133, 2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-9-carboxylic acid (20 mg, 0.06 mmol) was reacted with 2-amino-2-methyl-1-propanol (11 mg, 0.12 mmol) in THF to provide 165. LC/MS (ESI+): m/z 480 (M+H). 1H NMR (400 MHz, DMSO) δ 8.19 (s, 1H), 7.93 (s, 1H), 7.78-7.48 (m, 6H), 7.43-7.26 (m, 2H), 4.85 (t, J=6.1, 1H), 4.47 (d, J=9.0, 4H), 3.49 (d, J=6.0, 2H), 1.29 (s, 6H)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][O:7][C:8]1[C:9]([C:14]([NH2:16])=O)=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH3:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.O>C(Cl)Cl>[C:14]([C:9]1[C:8]([O:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:13][CH:12]=[CH:11][N:10]=1)#[N:16]
Reactant: CCOC(=O)COc1cccnc1C(N)=O
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cccnc1C#N
Reaction time: 16 h
Yield: 83 %

Procedure:
To a solution of 3-(ethoxycarbonylmethoxy)picolinamide (5.1 g, 22.8 mmol) and triethylamine (6.68 ml, 47.9 mmol) in 100 ml of dry methylene chloride is added trifluoroacetic anhydride (6.77 ml, 47.9 mmol), dropwise, at ambient temperature under argon. After stirring for 16 hours, 100 ml of water is added. The organic phase is separated and washed with aqueous sodium hydrogen carbonate to neutral pH. After drying over sodium sulfate and evaporation, the residue is purified via flash chromatography on silica gel using a methylene chloride-ethanolic ammonia gradient (99:1 to 95:5) to give 3.90 g of 2-cyano-3-(ethoxycarbonylmethoxy)pyridine (87%).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1)([CH3:3])[CH3:2].[NH2:16][C@H:17]1[CH2:22][N:21]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:20]([CH2:30][CH2:31][OH:32])[CH2:19][CH2:18]1.C(N(CC)C(C)C)(C)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O>[CH2:23]([N:21]1[C@H:20]([CH2:30][CH2:31][OH:32])[CH2:19][CH2:18][C@H:17]([NH:16][C:13]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=2)=[O:15])[CH2:22]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N[C@@H]1CC[C@H](CCO)N(Cc2ccccc2)C1
Reactant: CC(C)n1nc(C(=O)O)c2ccccc21
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)N[C@H]2CC[C@@H](CCO)N(Cc3ccccc3)C2)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.1 %

Procedure:
To a stirred solution of 1-isopropyl-1H-indazole-3-carboxylic acid (235 mg, 1.15 mmol), 2-[cis-5-amino-1-benzylpiperidin-2-yl]ethanol (322 mg, 1.37 mmol, step 8 of Example 1), N,N-diisopropylethylamine (177 mg, 1.37 mmol) in N,N-dimethylformamide (3 mL) was added diethyl cyanophosphonate (223 mg, 1.37 mmol) at room temperature. After stirring at room temperature for 20 h, the mixture was concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol/25% ammonium hydroxide (10:1:0.2) to give 276 mg (52%) of the title compound as a colorless oil.
Reaction SMILES: [N:1]1([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[N:32](C6CCCCO6)[N:31]=[CH:30][C:19]=5[C:20](=[O:29])[N:21]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:22]=4[CH:23]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1(C2C(C3C=CC4C5NN(C6CCCCO6)CC=5C(=O)N(CC(F)(F)F)C=4C=3)=CC=CN=2)CCCNCC1.[ClH:77]>O>[ClH:77].[N:1]1([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][C:17]4[C:18]5[NH:32][N:31]=[CH:30][C:19]=5[C:20](=[O:29])[N:21]([CH2:24][C:25]([F:27])([F:26])[F:28])[C:22]=4[CH:23]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=c1c2cnn(C3CCCCO3)c2c2ccc(-c3cccnc3N3CCCNCC3)cc2n1CC(F)(F)F
Agent: Cl
Agent: O=c1c2c(c3ccc(-c4cccnc4N4CCCNCC4)cc3n1CC(F)(F)F)NN(C1CCCCO1)C2
Solvent: O
Product: O=c1c2cn[nH]c2c2ccc(-c3cccnc3N3CCCNCC3)cc2n1CC(F)(F)F
Yield: 75 %

Procedure:
The product is obtained according to the procedure described in Step 1.7. starting with 7-[2-(1,4-diazepan-1-yl)pyrid-3-yl]-1-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one and 7-[2-(1,4-diazepan-1-yl)pyrid-3-yl]-2-(tetrahydro-2H-pyran-2-yl)-5-(2,2,2-trifluoroethyl)-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one, in the form of a white powder (hydrochloride, 1 H2O; yield 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[C:18]([CH3:19])=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[S:16][CH:15]=2)[N:11]([CH3:27])[N:10]=1.[H-].[Na+].I[CH2:31][CH2:32][CH3:33]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[C:18]([CH3:19])=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:31][CH2:32][CH3:33])=[CH:22][CH:21]=3)[S:16][CH:15]=2)[N:11]([CH3:27])[N:10]=1
Reactant: Cc1c(-c2nc(-c3c(F)cccc3Cl)nn2C)csc1-c1ccc(O)cc1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCOc1ccc(-c2scc(-c3nc(-c4c(F)cccc4Cl)nn3C)c2C)cc1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 114.3 %

Procedure:
A solution of 3-(2-chloro-6-fluorophenyl)-5-[5-(4-hydroxyphenyl)-4-methylthien-3-yl]-1-methyl-1H-1,2,4-triazole (97 mg, 0.2 mmol) in dry THF (2 mL) was cooled to −3° C. and treated with sodium hydride (95% suspension in mineral oil, 9 mg, 0.4 mmol). After stirring for 5 minutes, iodopropane (62 mg, 0.4 mmol) was added and the reaction was allowed to stir at room temperature for 16 hours. An additional batch of sodium hydride (9 mg, 0.4 mmol) and iodopropane (62 mg, 0.4 mmol) was added and the reaction heated to 45° C. After dilution with water (5 mL), the product was extracted with ether (3×5 mL). The combined ethereal extracts were washed with water (2×5 mL) and brine (10 mL), dried over magnesium sulphate and concentrated. Column chromatography gave the product (101 mg, 93%) as a colorless glass: 1H NMR (CDCl3) δ 7.49 (s, 1H), 7.27–7.41 (m, 4H), 7.12 (t, 1H), 6.98 (d, 2H), 4.04 (s, 3H), 3.99 (t, 2H), 2.32 (s, 3H), 1.85 (m, 2H), 1.08 (t, 3H); EI/MS 441 m/e (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Br[C:23]1[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][C:15]1[CH:14]=[C:13]([C:17]([OH:20])([CH3:18])[CH3:19])[CH:12]=[C:11]([F:21])[C:10]=1[C:4]1[S:3][C:2]([NH:1][C:23]2[CH:30]=[CH:29][C:26]([CH:27]=[O:28])=[CH:25][CH:24]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: O=Cc1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3ccc(C=O)cc3)s2)c(F)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A sealed tube was charged with a stir bar and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (750 mg, 2.401 mmol) and 4-bromobenzaldehyde (444 mg, 2.401 mmol), Pd2(dba)3 (220 mg, 0.240 mmol), dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (572 mg, 1.201 mmol), and potassium carbonate (365 mg, 2.64 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed tert-amyl alcohol (8 mL) was added to the mixture via syringe. The solution was sealed and stirred overnight in an oil bath at 100° C. The following day, the reaction was allowed to cool to room temperature and taken up in ethyl acetate. The suspension was washed in aqueous sodium bicarbonate twice and brine twice, and the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification was performed via silica gel chromatography (0-3% methanol in ethyl acetate).
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:14]=[C:13]2[C:9]([CH:10]=[CH:11][NH:12]2)=[CH:8][CH:7]=1)([O-])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([CH2:5][CH2:4][NH2:1])[CH:14]=2)[CH:10]=[CH:11]1
Reactant: O=[N+]([O-])C=Cc1ccc2cc[nH]c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NCCc1ccc2cc[nH]c2c1
Yield: 61.7 %

Procedure:
To a solution of 6-(2-Nitrovinyl)-1H-indole (1.0 g) in tetrahydrofuran (100 mL) was added portionwise lithium aluminum hydride (0.95 g) and the resulting mixture stirred at reflux for 1 hour. The reaction mixture was treated sequentially with water (0.95 mL), 15% sodium hydroxide (0.95 mL), and water (2.85 mL). The resulting suspension was filtered and the filtrate diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate (100 mL), saturated aqueous sodium chloride, dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The residue was subjected to silica gel chromatography. Fractions containing product were combined and concentrated under reduced pressure to provide 0.525 g (62%) of the desired compound.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20](OC(=O)C1C=CC=CC=1)[CH3:21])[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4]>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1C(C)OC(=O)c1ccccc1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: C=Cc1cccc2c(=O)c(C(=O)CCC)c[nH]c12

Procedure:
Ethyl 2-butyryl-3-(2-(1-benzoyloxyethyl)phenylamino)-acrylate (70 g, 0.17 mol) was added dropwise to boiling diphenyl ether (700 ml) keeping the reaction temperature above 240° C. The mixture was heated under reflux for 1 hour then cooled rapidly. The mixture was chromatographed (silica gel, dichloromethane +methanol (2%-4%)) to afford the required compound as a light solid (23.2 g, 56%) m.p. 206° C.-8° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:25]([O:27][CH3:28])=[O:26]>[OH-].[Na+].C1COCC1.CCOC(C)=O>[CH3:28][O:27][C:25](=[O:26])[N:10]([C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc([C@H]2CC[C@H](NCCCc3ccccc3)CC2)cc1
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of trans-4-[4-(3-phenylpropylamino) cyclohexyl]-phenol (0.40 g, 1.3 mmol) in a mixture of 2 N NaOH (5 mL) and THF (5 mL) was added methyl chloroformate (0.12 mL, 1.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. Methyl chloroformate (0.05 mL, 0.65 mmol) was added and stirring continued for another 2 hours. The mixture was diluted with EtOAc (50 mL), washed with H2O, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, 97:3 MeOH/CH2Cl2) gave trans-N-[4-(4-hydroxyphenyl)cyclohexyl]-N-(3-phenylpropyl)carbamic acid methyl ester, as an off-white solid (0.068 g, 14%): mp 128-133° C.; IR (KBr): 3403, 2923, 1673, 1518 cm−1; 1H NMR(300MHz, CD3OD) δ 7.31-7.15 (m, 5H), 7.01 (d, J=8 Hz, 2H), 6.68 (d, J=8 Hz, 2H), 3.91-3.78 (m, 1H), 3.67 (s, 3H), 3.25-3.13 (m, 2H), 2.61 (t, J=8 Hz, 2H), 2.40-2.29 (m, 1H), 1.95-1.45 (m, 10H); CI-MS (methane) (m/z): 368 [M+I]+; HRMS-API (m/z): [M+1]+ Calcd for C23H29NO3, 368.2225. found: 368.2227; HPLC: method A, 13.78 minutes (85.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([CH3:11])=[CH:4][C:3]=1[Cl:12].C1COCC1.[NH4+].[Cl-]>CO.O.[Fe]>[Cl:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([NH2:8])=[C:5]([CH3:11])[CH:4]=1
Reactant: Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(Cl)c(Cl)cc1N
Temperature: 100 °C
Yield: 98.9 %

Procedure:
To a partial suspension of 1,2-dichloro-4-methyl-5-nitrobenzene (2.0 g, 9.71 mmol) in MeOH (25 ml), water (25 ml), and THF (10 ml) was added NH4Cl (5.19 g, 97.1 mmol) followed by iron powder (2.71 g, 48.5 mmol). The heterogeneous reaction mixture was heated at 100° C. for 3 h then cooled to room temperature and filtered over a Buchner funnel, rinsing with MeOH. The filtrate was diluted with water and saturated aqueous NaHCO3 then extracted with CH2Cl2 (3×). The combined organics were dried over MgSO4 and concentrated to afford 1.69 g (99%) of 4,5-dichloro-2-methylaniline as a white solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.10 (s, 1H), 6.75 (s, 1H), 3.74 (br. s., 2H), 2.12 (s, 3H).
Reaction SMILES: [C:1]([NH:5][CH:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[C:13]([Cl:14])=[N:12][C:11](=C(Cl)Cl)[N:10]=1>>[C:1]([NH:5][C:6]([C:11]1[NH:10][C:9]([Cl:8])=[C:13]([Cl:14])[N:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC=O
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Product: CC(C)(C)NC(=O)c1nc(Cl)c(Cl)[nH]1

Procedure:
Using the method described in Example 29b, the reaction of tert.-butylformamide and 4,5-dichloro-2-dichloromethylene-imidazole gave 4,5-dichloro-imidazole-2-carboxylic acid tert.-butylamide as a crystalline product of melting point 218° C.