Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][CH2:5][CH:6]1[O:8][CH2:7]1)([CH3:3])[CH3:2].[CH3:9][C:10]([NH2:21])([CH3:20])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[OH:8][CH:6]([CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[CH2:7][NH:21][C:10]([CH3:20])([CH3:9])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: CC(C)OCC1CO1
Reactant: COc1ccc(CC(C)(C)N)cc1
Product: COc1ccc(CC(C)(C)NCC(O)COC(C)C)cc1
Yield: 17.9 %

Procedure:
Using the method of Example 15, supra, isopropylglycidyl ether (126 μL, 1.0 mmol) and 1,1-dimethyl-2-(4-methoxyphenyl)ethylamine (197 mg, 1.1 mmol) were used to prepare 53 mg of the title compound as a clear, colorless oil; GC/EI-MS, m/z (rel. int.) 296 (M+1, 0.2), 280 (1.4), 222 (1.5), 174 (100), 132 (12), 121(24); 1H-NMR (CDCl3) δ7.03 (2H, d, J=8.4), 6.77 (2H, d, J=8.4), 3.72 (3H, s), 3.70 (1H, m), 3.53 (1H, m), 3.38 (2H, m), 2.80 (1H, broad s), 2.73 (2H, m), 2.58 (4H, m) 1.09 (6H, m), 1.01 (3H, s), 0.99 (3H, s); 13C-NMR (CDCl3) δ157.9, 131.2, 129.9, 113.2, 73.4, 71.2, 69.0, 54.9, 53.1, 46.2, 44.5, 31.5, 26.6, 26.4, 19.1, 13.8.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[NH2:8][C@@H:9]([C:13]([OH:15])=[O:14])[CH:10]([CH3:12])[CH3:11].CN(CCO)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl.C(O)(C(F)(F)F)=O>[Cu]I.O>[CH3:11][CH:10]([CH3:12])[C@@H:9]([NH:8][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)[C:13]([OH:15])=[O:14]
Reactant: Brc1cncnc1
Reactant: CC(C)[C@@H](N)C(=O)O
Agent: [Cu]I
Agent: CN(C)CCO
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)[C@@H](Nc1cncnc1)C(=O)O

Procedure:
5-Bromopyrimidine (407 mg, 2.56 mmol), D-valine (250 mg, 2.13 mmol), copper(I) iodide (40.6 mg, 0.213 mmol), dimethylaminoethanol (400 mg, 4.49 mmol), potassium phosphate tribasic (1359 mg, 6.40 mmol), and water (2 mL) was stirred at 80° C. for several hours. 1 N hydrochloric acid (3 mL) was added to the reaction mixture followed by TFA (3 mL) and the reaction was extracted with EtOAc. The organic portion was dried over sodium sulfate, filtered, concentrated, and the product was isolated as a brown solid using preparative reverse-phase HPLC and used in next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[CH2:12][CH2:11]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:20]>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([O:18][CH3:20])=[O:17])[CH2:14][CH2:15]2)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1
Reactant: N#Cc1cc(Br)cc(N2CCC(C(=O)O)CC2)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C1CCN(c2cc(Br)cc(C#N)c2)CC1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 1-(3-bromo-5-cyanophenyl)piperidine-4-carboxylic acid (1.1 g, 3.6 mmol) in toluene (4 mL) and methanol (2 mL) was added TMSCHN2 (2 M in Et2O, 3.5 mL, 7.0 mmol) dropwise at room temperature. After 1 h, the reaction was quenched with acetic acid (˜0.1 mL), diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic layer was separated, dried (MgSO4), and concentrated to give methyl 1-(3-bromo-5-cyanophenyl)piperidine-4-carboxylate in ˜100% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:20]([CH3:23])[O:21][N:22]=3)[C:6](=[O:19])[N:7]([C@H:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]([NH2:18])[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1.[OH-].[Na+].[C:26]1([N:32]=[C:33]=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:5](=[C:20]([CH3:23])[O:21][N:22]=3)[C:6](=[O:19])[N:7]([C@H:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]([NH:18][C:33]([NH:32][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:34])[CH2:13]3)[C:8]=2[CH:9]=[CH:10][CH:11]=1
Reactant: Cc1onc2c1c(=O)n([C@H]1CCC[C@@H](N)C1)c1cccc(Cl)c21
Reactant: O=C=Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1onc2c1c(=O)n([C@H]1CCC[C@@H](NC(=O)Nc3ccccc3)C1)c1cccc(Cl)c21

Procedure:
To the suspension of cis-1-(9-chloro-3-methyl-4-oxo-5H-isoxazolo[4,3-c]quinolin-5-yl)-3-amino-cyclohexane (0.0446 g, 0.121 mmol) in 1 mL anhydrous THF at RT was added 2N NaOH (0.60 mL, 0.121 mmol). After 5 min. the phenylisocyanate (0.013 mL,0.121 mmol). After 20 min. the reaction was diluted with EtOAc, washed with water and concentrated to near dryness. After sonication and filtration a white solid (0.0412, 75%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7](=[O:19])[CH:6]=[CH:5]2.N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:35][C@H:36]1[C@@H:43]2[N:39]([C:40](=[O:57])N(C3C4CCCCC=4C(C#N)=CC=3)[C:42]2=[O:44])[CH2:38][CH2:37]1>>[OH:35][C@H:36]1[C@@H:43]2[N:39]([C:40](=[O:57])[N:1]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7](=[O:19])[CH:6]=[CH:5]4)[C:42]2=[O:44])[CH2:38][CH2:37]1
Reactant: Nc1ccc2c(ccc(=O)n2Cc2ccccc2)c1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: O=C1[C@@H]2[C@H](O)CCN2C(=O)N1c1ccc2c(ccc(=O)n2Cc2ccccc2)c1

Procedure:
The title compound was prepared from compound 46D by procedures analogous to those described in Experiment 2E and 2F. LC/MS m/z 390 [M+H]+.
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:15][N:16]([C:19]([CH3:29])([CH3:28])[CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[C:17]=2[OH:18])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[CH3:37][O:38][CH2:39]Cl>CN(C)C=O.C(OCC)C>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[N:15][N:16]([C:19]([CH3:28])([CH3:29])[CH2:20][C:21]3[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[C:17]=2[O:18][CH2:37][O:38][CH3:39])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1ccc(-c2c(C(=O)OCC)nn(C(C)(C)Cc3ccc(C)cc3)c2O)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCCCc1ccc(-c2c(C(=O)OCC)nn(C(C)(C)Cc3ccc(C)cc3)c2OCOC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
152 mg (0.329 mol) of ethyl 4-(4-hexylphenyl)-5-hydroxy-1-(2-methyl-1-(p-tolyl)propan-2-yl)-1H-pyrazole-3-carboxylate was dissolved in 1.6 mL of N,N-dimethylformamide, mixed with 26 mg (0.65 mmol) of 60 wt % sodium hydride (suspended in mineral oil) and 0.050 mL (0.66 mmol) of chloromethyl methyl ether under cooling with ice successively and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was diluted with diethyl ether and washed with 1 M hydrochloric acid, with saturated aqueous sodium hydrogen carbonate and with saturated aqueous sodium chloride successively. The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give the desired product (crude yield 174 mg).
Reaction SMILES: [C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]#[N:33]>CN(C=O)C>[C:1]1([C@H:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16]([O:23][CH2:31][C:32]#[N:33])=[CH:17][CH:18]=[CH:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CCOc1cccc2c1c1cccc3c1n2[C@H](c1ccccc1)CO3
Temperature: 25 °C
Reaction time: 20 h
Yield: 89 %

Procedure:
To a mixture of (R)-(−)-1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol (5.9 g 19.6 mmol) in DMF (50 mL) is added potassium carbonate (8.1 g, 58.7 mmol) and brornoacetonitrile (4.1 mL, 58.7 mmol). The mixture is stirred at room temperature for 20 h. The mixture is partitioned between water and Et2O. The organic layer is washed twice with water (200 mL), dried over anhydrous sodium sulfate and concentrated. Column chromatography (800 mL silica) using CH2Cl2 eluent gave 5.94 g (89%) of (R)-(−)-2-[(1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-yl)oxy]acetonitrile.
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH:7]1[CH2:12][CH2:11][C:10](B2OC(C)(C)C(C)(C)O2)=[CH:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][C:26]([C:28]1[C:36]2[C:31](=[CH:32][C:33](Br)=[CH:34][CH:35]=2)[N:30]([CH3:38])[CH:29]=1)=[O:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[CH3:24][O:25][C:26]([C:28]1[C:36]2[C:31](=[CH:32][C:33]([C:10]3[CH2:11][CH2:12][CH:7]([O:6][Si:5]([C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:22])[CH3:23])[CH2:8][CH:9]=3)=[CH:34][CH:35]=2)[N:30]([CH3:38])[CH:29]=1)=[O:27]
Reactant: COC(=O)c1cn(C)c2cc(Br)ccc12
Reactant: CC1(C)OB(C2=CCC(O[Si](C)(C)C(C)(C)C)CC2)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1cn(C)c2cc(C3=CCC(O[Si](C)(C)C(C)(C)C)CC3)ccc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 42.9 %

Procedure:
A flask containing a solution of 2-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohex-1-enyl]-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (1.40 g, 4.14 mmol) and 6-bromo-1-methyl-1H-indole-3-carboxylic acid methyl ester (1.22 g, 4.55 mmol) in toluene (50 mL) is evacuated and filled with N2 three times. Potassium phosphate (1.79 g, 8.27 mmol), Pd(OAc)2 (46 mg), and 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (S-Phos, 50 mg) are added. The mixture is stirred at 100° C. for 16 h and cooled to room temperature. The mixture is filtered through a pad of diatomaceous earth, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with 25% EtOAc/Hexanes to provide the title compound (0.71 g, 43%). MS m/z 400.3 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][C@@H:6]2[CH2:8][C@:5]32[C@H:9]2[C@H:19]([CH2:20][CH2:21][C@:3]13[CH3:4])[C@:17]1([CH3:18])[C:12]3([O:23][CH:13]3[C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]2.S(=O)(=O)(O)O.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[OH:23][C:13]1[C:14](=[O:22])[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12]=1[CH2:11][CH2:10][C@@H:9]1[C@@H:19]2[CH2:20][CH2:21][C@@:3]2([CH3:4])[C@@:5]31[CH2:8][C@H:6]3[CH2:7][C@@H:2]2[OH:1]
Reactant: C[C@]12CCC(=O)C3OC31CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@]12CCC(=O)C(O)=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)C[C@@H]3C[C@]312
Reaction time: 72 h

Procedure:
An epoxide mixture (3.5 g), 17β-hydroxy-4,5-epoxy-14α,15α-methylene-androstan-3-one, (step 1) is dissolved in 50 mL of acetic acid, which contains 2% by volume of concentrated sulfuric acid. The solution is allowed to stand for 3 days at 10° C. After that, it is treated with 200 mL ethyl acetate and neutralized with sodium carbonate solution. The organic phase is dried and concentrated. The residue is dissolved in 100 mL of methanol, treated with 4 g of potassium hydroxide, refluxed for 1 hour and then cooled. After neutralization with 50% acetic acid, it is poured into 1 L of water and the crystals are filtered off with suction, 4,17β-Dihydroxy-14α,15α-methylene-androst-4-ene-3-one being obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH3:14])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][N:10]3[C:11]4[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH3:14])[C:7]=4[N:8]=[CH:9]3)=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: CCn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 24.7 %

Procedure:
In DMF (10 ml) was dissolved 1-ethyl-3-methylxanthine (385 mg), a production process for which is described in Journal of American Chemical Society 75, 114, 1953. To this solution were added potassium carbonate (415 mg) and 4-(4-chlorobenzoyl)benzyl bromide (619 mg) and the mixture was stirred at room temperature for 14 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:4) and recrystallized (ethyl acetate-ether-hexane) to provide the title compound as white powder (207 mg, 25%).
Reaction SMILES: C1COCC1.[C:6](/[C:8](=[CH:13]\[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]2[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[Cl:32])=[CH:16][CH:15]=1)/[C:9]([O:11]C)=[O:10])#[N:7].[OH-].[Na+]>CO>[C:6](/[C:8](=[CH:13]\[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]2[C:25]([Cl:32])=[CH:26][C:27]([CH3:31])=[CH:28][C:29]=2[Cl:30])=[CH:18][CH:19]=1)/[C:9]([OH:11])=[O:10])#[N:7]
Reactant: COC(=O)/C(C#N)=C/c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cl)c(OCCOc2ccc(/C=C(\C#N)C(=O)O)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 2:1 (v/v) THF:MeOH solution (0.1 M) of methyl (2E)-2-cyano-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}acrylate from Example 9, Step 1 (1 eq.) was added sodium hydroxide (1.0 M aq. solution, 3 eq.). The resulting solution was stirred at RT for 18 h before the volatiles were removed in vacuo. Following careful acidification of the resulting mixture to pH ˜1 with 10% aq. HCl, the solution was extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound as a yellow semi-solid.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH2:7][N:8]([CH3:21])[C:9]1[S:10][C:11]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1)[C:3](=[O:5])[CH3:4]>C(O)C.C1COCC1.[Pd]>[NH2:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([N:8]([CH3:21])[CH2:7][CH2:6][N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[S:10][C:11]=2[CH:17]=1
Reactant: CC(=O)N(C)CCN(C)c1nc2ccc([N+](=O)[O-])cc2s1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)N(C)CCN(C)c1nc2ccc(N)cc2s1
Yield: 77.2 %

Procedure:
Shake a mixture of N-methyl-N-{2-[methyl-(6-nitro-benzothiazol-2-yl)-amino]-ethyl}-acetamide (0.30 g, mmol) and Pd/C (5%, 0.1515 g) in absolute ethanol (50 mL) and anhydrous THF (20 mL) under 60 psi H2(g) at room temperature for 18 h. Filter the mixture and concentrate in vacuo. Residue re-subjected to hydrogenation using Pd/C (0.2101 g) in absolute ethanol (50 mL) and THF (10 mL) to yield the desired product (0.209 g). Adsorb onto silica gel and subject to silica gel flash column chromatography (12 g column, eluting with 1-5% MeOH/CH2Cl2). Adsorbed on a Silicycle cartridge (Si-Tosic Acid, 35 mL, 10 g) washing with MeOH and eluted with 2N NH3 in MeOH. The product is 70% pure by LC-MS (0.146 g, %). mass spectrum (m/e): 279.0 (M+1). Used without further purification.
Reaction SMILES: [Cl:1][C:2]1([Cl:17])[CH2:4][CH:3]1[CH2:5][S:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([N+:14]([O-])=O)[CH:8]=1>C(O)C.O=[Pt]=O>[Cl:17][C:2]1([Cl:1])[CH2:4][CH:3]1[CH2:5][S:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[C:9]([NH2:14])[CH:8]=1
Reactant: Nc1ccc(SCC2CC2(Cl)Cl)cc1[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: Nc1ccc(SCC2CC2(Cl)Cl)cc1N

Procedure:
A mixture of 8.8 g (0.03 mole) of 4-[(2,2-dichlorocyclopropyl)methyl]thio-2-nitroaniline and 0.6 g of PtO2 in 200 ml of absolute ethanol is reduced on the Parr hydrogenator at 50 psi until the theoretical amount of H2 is absorbed. The mixture is filtered and the solvent is removed in vacuo to yield a dark oil.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C@H:15]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[C@H:16]([OH:19])[CH2:17][OH:18])(C)(C)C>C(Cl)Cl>[NH2:14][C@H:15]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)[C@H:16]([OH:19])[CH2:17][OH:18]
Reactant: CC(C)(C)OC(=O)N[C@H](c1ccc2ccccc2c1)[C@H](O)CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](c1ccc2ccccc2c1)[C@H](O)CO
Yield: 93.4 %

Procedure:
A solution of TFA (5 mL) and (1R,2S)-(2,3-dihydroxy-1-naphthalen-2-yl-propyl)-carbamic acid tert-butyl ester (1.72 g) in methylene chloride (15 mL) was stirred for 2 h. After concentration, the residue was neutralized with 10 N NaOH and extracted with methylene chloride. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound as a solid (1.1 g).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH:16][CH:17]=O)=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][NH2:30]>CC(O)=O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:29]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[Cl:22])[N:30]=[CH:17][N:16]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: O=CNC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: NNc1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Product: Clc1ccccc1-n1ncnc1-c1cn2c(n1)-c1ccc(Br)cc1OCC2
Temperature: 80 °C
Reaction time: 4 h
Yield: 65.2 %

Procedure:
To a solution of 9-bromo-N-formyl-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (350 mg, 1.04 mmol) in HOAc (10 ml) was added (2-chlorophenyl)hydrazine hydrochloride (557 mg, 3.13 mmol) in one portion. The resulting mixture was stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature and concentrated. The residue was dissolved in MeOH and purified by chromatography on silica gel (Hexanes: EtOAc=10:1-1:1) to give 9-bromo-2-(1-(2-chlorophenyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (300 mg, 65%). LCMS (ESI): m/z 443.7 (M+H+)
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:5][C:6](=O)[C:7]=1[CH3:8])=[O:4].[CH3:10][NH:11][NH2:12]>C(O)C>[CH3:10][NH:11][N:12]1[C:3](=[O:4])[C:2]([CH3:1])=[C:7]([CH3:8])[C:6]1=[O:5]
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: CNN
Solvent: CCO
Product: CNN1C(=O)C(C)=C(C)C1=O
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2,3-Dimethylmaleic acid anhydride (3.5 g, 28 mM) was suspended in 50 ml of ethyl alcohol. To the dispersion was added methylhydrazine (1.28 g, 27.7 mM). After addition, the mixture was stirred at 70° C. for 3 hours. After ethanol was distilled away, the target compound was separated by chromatography from the reaction mixture.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH:16]([CH3:20])[CH2:15]2)[CH:8]=1)=[O:5].C=O.[C:28](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C@H:14]2[CH2:19][CH2:18][N:17]([CH3:28])[C@@H:16]([CH3:20])[CH2:15]2)[CH:8]=1)=[O:5]
Reactant: CC1CC(Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1C[C@@H](Oc2cccc(NC(=O)c3ccc(F)cc3Cl)c2)CCN1C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
Combine 2-chloro-4-fluoro-N-[3-(2-methyl-piperidin-4-yloxy)-phenyl]-benzamide cis isomer 1 (example 57, 0.26 g, 0.72 mmol), dichloromethane (20 mL), and 37% aqueous formaldehyde (0.58 mL, 7.2 mmol) with stirring. After 10 min., add glacial acetic acid (0.08 mL, 1.44 mmol) followed by sodium triacetoxyborohydride (0.23 g, 1.08 mmol). After 3 hr., partition between 1M aqueous sodium hydroxide solution (50 mL) and dichloromethane (50 mL). Separate the organic layer, wash with aqueous NaCl solution, dry over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M ammonia/methanol) in dichloromethane to obtain of the title compound (0.46 g, 85%). Mass spectrum: Obs. m/z 377.1443; Calc. m/z 377.1432; mp: 152° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12]2[C:7](=[C:8]([C:32]([NH:34][CH2:35][C:36]3[C:37](=[O:46])[NH:38][C:39]([CH3:45])=[CH:40][C:41]=3[CH2:42][CH2:43][CH3:44])=[O:33])[CH:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)[CH:11]=2)[CH:6]=[CH:5]1)[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[CH:2]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:18]=[N:17][C:16]([N:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)=[CH:15][CH:14]=3)[CH:9]=[C:8]([C:32]([NH:34][CH2:35][C:36]3[C:37](=[O:46])[NH:38][C:39]([CH3:45])=[CH:40][C:41]=3[CH2:42][CH2:43][CH3:44])=[O:33])[C:7]=2[CH:6]=[CH:5]1)([CH3:1])[CH3:3]
Reactant: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc2c1ccn2C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(-c2ccc(N3CCNCC3)nc2)cc2c1ccn2C(C)C
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a suspension of 1,1-dimethylethyl 4-{5-[1-(1-methylethyl)-4-({[(6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinyl)methyl]amino}carbonyl)-1H-indol-6-yl]-2-pyridinyl}-1-piperazinecarboxylate (70 mg, 0.112 mmol) in dichloromethane (2 mL) was added TFA (0.5 ml, 6.49 mmol), and the mixture was stirred for 1 h. The mixture was concentrated and the residue was treated with saturated aqueous NaHCO3 solution and filtered. The solid was purified using column chromatography (silica gel, 0 to 15% (9:1 MeOH/NH4OH)/CH2Cl2) to give 1-isopropyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-6-(6-(piperazin-1-yl)pyridin-3-yl)-1H-indole-4-carboxamide (51 mg, 84%) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.91 (m, 3H), 1.47 (d, J=4.00 Hz, 6H), 1.53-1.60 (m, 2H), 2.14 (s, 3H), 2.89-2.98 (m, 4H), 3.51-3.59 (m, 4H), 4.40 (d, J=5.05 Hz, 2H), 4.93 (quin, J=6.63 Hz, 1H), 5.92 (s, 1H), 6.87 (d, J=3.03 Hz, 1H), 6.94 (d, J=8.84 Hz, 1H), 7.60 (d, J=3.03 Hz, 1H), 7.66 (d, J=1.26 Hz, 1H), 7.88 (s, 1H), 8.00 (dd, J=8.84, 2.53 Hz, 1H), 8.28 (t, J=5.05 Hz, 1H), 8.58 (d, J=2.27 Hz, 1H). MS: (M+H)+=527.2.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:15]=[C:14]([CH3:16])[S:13][CH:12]=1)[OH:4].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:27][C:22]1[CH:23]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:15]=[C:14]([CH3:16])[S:13][CH:12]=2)[C:2]([F:1])([F:17])[F:18])[N:25]=[C:20]([NH2:19])[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Cc1cc(-c2ccccc2C(O)C(F)(F)F)cs1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2ccccc2C(Oc2cc(Cl)nc(N)n2)C(F)(F)F)cs1
Temperature: 110 °C
Yield: 68.2 %

Procedure:
A mixture of 2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethanol (100 mg, 0.37 mmol), 2-amino-4,6-dichloro-pyrimidine (54 mg, 0.33 mmol), cesium carbonate (481 mg, 1.48 mmol) and 1,4-dioxane (2 ml) was heated at 110° C. overnight. The reaction mixture was cooled to room temperature; 10 ml of ethyl acetate was added. The mixture was then filtered through Celite, the filtrate was concentrated to give 90 mg of 4-chloro-6-{2,2,2-trifluoro-1-[2-(5-methyl-thiophen-3-yl)-phenyl]-ethoxy}-pyrimidin-2-ylamine, yield: 68%