Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH3:33])[CH2:30][C:31]=4[N:32]=3)=[O:23])[CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[OH-:34].[Na+].OO>CC(C)=O>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:22]([C:24]3[S:25][C:26]4[CH2:27][NH:28][CH:29]([CH3:33])[CH2:30][C:31]=4[N+:32]=3[O-:34])=[O:23])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: [OH-]
Reactant: CC1Cc2nc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)sc2CN1
Agent: Cl
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1Cc2c(sc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)[n+]2[O-])CN1
Temperature: 25 °C
Reaction time: 192 h

Procedure:
In acetone (10 ml), 1-[(6-chloronaphthalen-2-yl)sulfonyl]-4-[(6-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]piperazine hydrochloride (400 mg) was suspended, followed by the addition of a 1N aqueous solution of sodium hydroxide (0.38 ml) and 30% aqueous hydrogen peroxide (3.50 ml). The resulting mixture was stirred at room temperature for 8 days. After the reaction mixture was concentrated under reduced pressure, the residue was purified by the chromatography through a synthetic adsorbent (“Diaion HP-20”, water˜water:acetonitrile=2:5), whereby the title compound (84 mg, 39%) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@@H:27]4[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:39])[CH2:35][C:36](O)=[O:37].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([C@@H:27]4[CH2:32][CH2:31][CH2:30][N:29]([C:36](=[O:37])[CH2:35][N:34]([CH3:39])[CH3:33])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CC(=O)O
Reactant: Nc1ncnn2c([C@@H]3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC[C@@H](c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
A mixture of 5-(2-benzyl-2H-indazol-6-yl)-7-[(3R)-piperidin-3-yl]pyrrolo[2,1-f][1,2,4]triazin-4-amine (107 mg, 0.25 mmol), N,N-dimethylglycine (31 mg, 0.30 mmol), EDCl (53 mg, 0.28 mmol), HOBt (38 mg, 0.28 mmol), and N,N-diisopropylethylamine (132 μL, 0.76 mmol) in DMF (2.3 mL) was stirred at rt for 16 h. The crude reaction mixture was purified via preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 35 mg (27%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.92 (d, 1 H), 7.80 (d, 1 H), 7.59 (s, 1 H), 7.27-7.39 (m, 5 H), 7.14 (d, 1 H), 6.64 (d, 1 H), 5.65 (s, 2 H), 3.95-4.97(m, 2 H), 2.62-3.32 (m, 5 H), 2.03-2.23 (m, 7 H), 1.68-1.91 (m, 2 H), 1.37-1.64 (m, 1 H); ES-MS m/z 509.15 [M+H]+, HPLC RT (min) 2.22.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[NH:8][CH:9]=1)[CH2:2][CH3:3].C[Si](Cl)(C)C.C1C=CC=CC=1.ClC1C=CC(C([C@@:30]2([OH:47])[C@@H:34]([CH:35](C(=O)C3C=CC(Cl)=CC=3)[OH:36])[O:33][CH:32](Cl)[CH2:31]2)=O)=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[CH2:1]([C:4]1[C:5](=[O:11])[NH:6][C:7](=[O:10])[N:8]([CH:9]=1)[C@@H:32]1[O:33][C@H:34]([CH2:35][OH:36])[C@@H:30]([OH:47])[CH2:31]1)[CH2:2][CH3:3]
Reactant: CCCc1c[nH]c(=O)[nH]c1=O
Reactant: O=C(c1ccc(Cl)cc1)C(O)[C@H]1OC(Cl)C[C@@]1(O)C(=O)c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)Cl
Agent: [Hg+2]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 24 h
Yield: 166.5 %

Procedure:
To a solution of 15,4 g 5-propyluracil (0.1 mole) and 21,7 g trimethylsilyl chloride (0,2 mole) in 250 ml anhydrous benzene 20.2 g dry triethylamine (0,2 mole) are added dropwise under stirring and exclusion of humidity within a time span of 15 minutes. After further stirring for about 12 hours the unreacted 5-propyl-uracil and the precipitated dry ethylamine hydrochloride are separated and the filtrate is concentrated under vacuum. The residue is dissolved in 150 ml of absolute toluene and under stirring a solution of 43 g 3,5-di-(p-chlorobenzoyl)-2-desoxy-D-ribofuranosyl chloride (0,1 mole) in 500 ml toluene and thereafter 31,8 g mercury (II)-acetate are added and the stirring is continued another 24 hours. After filtration the filtrate is extracted with a 30% aqueous potassium iodide solution and thereafter washed with water. After drying over sodium sulfate the toluene solution is concentrated to approximately 100 ml. Upon standing the protected nucleoside crystallizes. 45 g of a product with melting point 140°-165° C. are obtained.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([NH:11][C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.C(OCC)C>C(Cl)Cl>[CH3:4][C:2]([C:1](=[O:5])[N:11]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:12](=[O:16])[C:13]([CH3:15])=[CH2:14])=[CH2:3]
Reactant: C=C(C)C(=O)NC(C)(C)C
Reactant: C=C(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(C)C(=O)N(C(=O)C(=C)C)C(C)(C)C
Reaction time: 0.5 h

Procedure:
A solution of 52.7 g of methacrylyl chloride in 570 ml of methylene chloride is added dropwise to a stirred solution, cooled to 0°-5° C., of 71 g of N-tert-butyl-methacrylamide, 50.8 g of triethylamine and 570 ml of methylene chloride. After the addition, the mixture is stirred for 2 1/2 hours and the reaction solution is left to stand for 4 days. The concentrated reaction material is taken up in 0.5 1 of diethyl ether, the mixture is filtered and the solution is concentrated. The red oil obtained is filtered with hexane-diethyl ether (4:1) on silica gel to give the title compound as a white crystalline product (m.p. 47°-48° C).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH3:24])=[O:9])=[C:4]([O:27][C:28]#[N:29])[CH:3]=1.[N-:30]=[N+:31]=[N-:32].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][CH2:7][C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH2:12][C@H:11]2[CH3:24])=[O:9])=[C:4]([O:27][C:28]2[N:30]=[N:31][NH:32][N:29]=2)[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1OC#N
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1Oc1nn[nH]n1
Temperature: 25 °C

Procedure:
To a solution of 2-(4-chloro-2-cyanato-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.17 g, 0.427 mmol) in acetone (2 mL) was added sodium azide (0.061 g, 0.94 mmol) and the reaction was stirred at reflux for 3 hours, then cooled to ambient temperature and stirred 18 hours. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The product was purified by anion exchange chromatography to give the title compound as its acetic acid addition salt (0.073 g, LRMS: 461.2, 463.3).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][N:14]([CH3:51])[C:15]1[N:16]([C:40]2[CH:41]=[CH:42][C:43]3[O:47][C:46]([CH3:49])([CH3:48])[CH2:45][C:44]=3[CH:50]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32]([C:37]#[N:38])=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:27][CH:26]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1>O>[CH3:51][N:14]([CH3:13])[C:15]1[N:16]([C:40]2[CH:41]=[CH:42][C:43]3[O:47][C:46]([CH3:49])([CH3:48])[CH2:45][C:44]=3[CH:50]=2)[C:17](=[O:39])[C:18]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]3[NH:3][C:4](=[O:7])[O:5][N:38]=3)=[CH:29][CH:30]=2)=[C:19]([CH2:21][CH2:22][CH3:23])[N:20]=1
Reactant: CCCc1nc(N(C)C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCc1nc(N(C)C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogen carbonate (1.01 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-{[2-(dimethylamino)-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.31 g) was added, and the mixture was stirred at 90° C. for 16 hr. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.13 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.1 g, 33%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=4)[C:11]=3[CH:22]=2)=[N:4][N:3]=1.[H-].[Na+].[CH3:25][S:26][CH2:27]Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[O:14][CH:13]=[C:12]([C:15]4[CH:16]=[CH:17][C:18]([O:21][CH2:25][S:26][CH3:27])=[CH:19][CH:20]=4)[C:11]=3[CH:22]=2)=[N:4][N:3]=1
Reactant: CSCCl
Reactant: Cc1nnc(-c2ccc3occ(-c4ccc(O)cc4)c3c2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCOc1ccc(-c2coc3ccc(-c4nnc(C)o4)cc23)cc1
Reaction time: 1 h
Yield: 86.5 %

Procedure:
To a solution of 4-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1-benzofuran-3-yl]phenol (1.17 g, 4.00 mmol) in N,N-dimethylformamide (15 mL) was added sodium hydride (60% in oil, 0.320 g, 8.00 mmol) at room temperature, and the resulting mixture was stirred for 15 min. (Chloromethyl) methyl sulfide (90%, 0.744 mL, 8.00 mmol) was added to the reaction mixture, and the resulting mixture was further stirred for 1 hr. The reaction mixture was diluted with ethyl acetate, washed twice with water and once with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=2/1) and recrystallized from methanol to give the title compound (1.22 g, yield 87%) as colorless crystals.
Reaction SMILES: C([Li])(CC)C.Br[C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1.[C:17]([C:19]([CH3:24])([N:21]([CH3:23])[CH3:22])[CH3:20])#N.C1C[O:28]CC1>>[CH3:22][N:21]([CH3:23])[C:19]([CH3:24])([CH3:20])[C:17]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1)=[O:28]
Reactant: CC(=O)Nc1ccc(Br)cc1
Reactant: CN(C)C(C)(C)C#N
Reactant: C1CCOC1
Agent: [Li]C(C)CC
Product: CC(=O)Nc1ccc(C(=O)C(C)(C)N(C)C)cc1
Temperature: -70 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
Sec butyllithium (298 ml: 1.3 M) was added dropwise at −60° C. under N2 flow to a solution of N-(4-bromophenyl)acetamide (0.1892 mol) in THF (400 ml) and the mixture was stirred at −70° C. for 2 hours. A solution of 1-cyano-1-methyl-N,N-dimethylethanamine (0.075 mol) in THF (60 ml) was added dropwise, the mixture was brought to RT and then stirred at RT for 12 hours. The mixture was poured into ice and extracted with EtOAc. The solvent was evaporated the residue was taken up in HCl (3 N) and EtOAc, extracted with EtOAc, basified with K2CO3 (10%) and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was recrystallized from (C2H5)2O and DIPE. The precipitate was filtered off and dried, yielding 6.8 g (36%) of N-[4-[2-(dimethylamino)-2-methyl-1-oxopropyl]phenyl]acetamide (interm. 3).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH:36]=[C:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:33][CH:34]=[C:35]([C:38]([OH:40])=[O:39])[CH2:36][CH2:37]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: O=C(O)C1=CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C(O)C1=CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
1-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-1,2,3,6-tetrahydropyridine-4-carboxylic acid was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 1,2,3,6-Tetrahydro-pyridine-4-carboxylic acid following general procedure C.
Reaction SMILES: C([NH:11][C@H:12]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:34])[NH2:33])=[O:25])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(OCC1C=CC=CC=1)=O.[C:38]([NH:48][CH2:49][C:50]([OH:52])=O)([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39]>>[C:38]([NH:48][CH2:49][C:50]([NH:11][C@H:12]([C:20]([NH:22][CH2:23][C:24]([NH:26][C@H:27]([C:35]([OH:37])=[O:36])[CH2:28][CH2:29][CH2:30][NH:31][C:32](=[NH:33])[NH2:34])=[O:25])=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:52])([O:40][CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:39]
Reactant: N=C(N)NCCC[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Product: N=C(N)NCCC[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1)C(=O)O

Procedure:
Carbobenzoxy-glycyl-phenylalanyl-glycyl-arginine is prepared by the method similar to that described for the preparation of carbobenzoxy-phenylalanyl-glycyl-arginine on the basis of 2.71 g (5.28 mM) of the latter and 1.93 g (5.83 mM) of p-nitrophenyl ester of carbobenzoxy-glycin.
Reaction SMILES: [CH:1]1([CH:7]([O:35][CH3:36])[C:8]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:9]=2[CH2:10][NH:11][CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:47]([O:49][CH3:50])=[O:48]>ClCCl>[CH3:50][O:49][C:47](=[O:48])[N:11]([CH2:12][C:13]1[CH:14]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:16]=[C:17]([C:19]([F:20])([F:21])[F:22])[CH:18]=1)[CH2:10][C:9]1[CH:27]=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:29]=[CH:30][C:8]=1[CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[O:35][CH3:36]
Reactant: COC(c1ccc(C(F)(F)F)cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCCC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1C(OC)C1CCCCC1
Reaction time: 8 h
Yield: 28.5 %

Procedure:
To a solution of (3,5-bis-trifluoromethyl-benzyl)-[2-(cyclohexyl-methoxy-methyl)-5-trifluoromethyl-benzyl]-amine (Example 41, STEP E, 22 mg, 0.042 mmol) in dichloromethane (1 ml) was added diisopropylethyl amine (8.09 mg, 0.063 mmol) followed by methyl chloroformate (3.94 mg, 0.042 mmol) at room temperature and stirred for overnight. Reaction mixture was then concentrated in vacuo and the product was purified on Biotage column (12+S), eluting with 2% ethyl acetate in heptane (1 CV), 2-20% (10CV), 20% (2CV) to yield the title compound (7 mg, 30%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (m, 6H) 1.4(m, 1H) 1.5(m, 2H) 1.7(s, 1H) 1.9 (d, J=11.2 Hz, 1H) 3.0 (s, 3H) 3.8(s, 3H) 4.0 (d, J=17.9 Hz, 1H) 4.6 (m, 4H) 7.25 (d, J=10.4 Hz, 1H) 7.45 (d, J=7.5 Hz, 1H) 7.53 (m, 3H) 7.7 (s, 1H) 7.8 (s, 1H). MS (ES+) Calc: 585.2, Found: 630.3 (M+45).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]#N)=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.OS(O)(=O)=O.[O-:30]S([O-])(=O)=O.[Mg+2].[C:36]([O-])([O-])=[O:37].[K+].[K+]>O.C(Cl)Cl.CO>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][C:23]([O:37][CH3:36])=[O:30])=[N:20][CH:21]=3)=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)([O-])[O-]
Reactant: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Mg+2]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)Cc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Temperature: 115 °C
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
A 2 L single-necked round-bottomed flask was charged with 6 (64.00 g, 0.198 mol) and MeOH (360 g) followed by the slow, careful, and dropwise addition of H2SO4 (240 g) and the resulting homogeneous solution stirred at reflux (115° C. oil bath) until the reaction was complete (25 h with 0.8% unreacted starting material) with 3.5% ArCH2CO2H. After brief cooling, MgSO4 (75 g) was added and the mixture swirled and allowed to stand an additional 45 min (composition now 96.3% product, 0.8% unreacted starting material, and 2.5% ArCH2CO2H). The reaction mixture was then added slowly to a rapidly stirred and cooled (ice-water bath) mixture of DCM (2 L) and a solution of K2CO3 (450 g) in H2O (600 mL). The resulting emulsion was allowed to stand overnight. The clear portions of organic solution were siphoned off and the remainder portions were treated iteratively with water and DCM, the clear organics being combined with the original portion that was siphoned off. The combined organics were dried (Na2SO4), filtered, and concentrated to a volume of ˜1.2 L followed by the addition of 300 mL of 5% EtOAc (in heptane) and then heptane (300 mL) and the mixture concentrated (rotovap with heat) again to remove the DCM. At this point 15 mL EtOAc was added and the hot mixture swirled until crystallization had begun, swirling continued until crystallization was near complete, and then allowed to stand and cool to room temperature for complete crystallization. The solid was then filtered, washed with 300 mL 5% EtOAc (in heptane) and heptane (100 mL) and then fully air dried to give 57.74 g (yield of 82%) of 7 as a light yellow solid (98.9% AUC). Another 3.94 g of clean product (97.9% AUC) was obtained from the filtrate (total yield of 87%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[N:19]#[C:20]Br.[OH-].[K+]>C(O)(C)C>[N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:17]=[C:20]2[NH2:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccccc1NCCCN1CCCCC1
Reactant: N#CBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: Nc1nc2ccccc2n1CCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 20.0 g. (0.086 mole) of N-[3-(1-piperidinyl)propyl]-o-phenylenediamine in 80 ml. water, 20 ml. of isopropanol was added to obtain a homogenous solution. With continued stirring, 21.2 g. (0.200 mole) of cyanogen bromide was added in portions over a one hour period. Room temperature was maintained throughout the addition. After stirring for an additional 2 hours the reaction mixture was allowed to stand overnight. The mixture was then poured into ice-water, made strongly alkaline with KOH and extracted with methylene chloride. The extracts were evaporated to a red oil which crystallized from ether, 7.9 g. (36% yield), m.p. 176°-178° C. An analytical sample of 1-[3-(1-piperidinyl)propyl]-2-amino benzimidazole was obtained by crystallization from benzene-cyclohexane, m.p. 179°-181° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:16]([O-])=O)[C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1>CO.O1CCCC1.[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1NCC1CCOCC1
Agent: [Pt]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1cc(Br)cnc1NCC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.4 %

Procedure:
A mixture of 5-bromo-3-nitro-N-(tetrahydro-2H-pyran-4-ylmethyl)pyridin-2-amine (Step C, 792 mg, 2.51 mmol) and 3% platinum on sulfide carbon (N.E.CHEMCAT, 125 mg) in methanol (9 mL) and tetrahydrofuran (9 mL) was stirred at room temperature for 3 h under hydrogen. The mixture was filtered through a pad of celite and the filtrate was concentrated to afford the crude title compound (764 mg) as red viscous oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)[CH:2]=[CH2:3].[C:25](=[O:28])([O-])O.[Na+].BrC(Br)=[N:32][OH:33]>C(OCC)(=O)C>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([C:13]2[CH:12]=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[C:5]([NH:4][CH2:1][CH:2]3[O:33][NH:32][C:25](=[O:28])[CH2:3]3)[N:14]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: O=C([O-])O
Reactant: ON=C(Br)Br
Reactant: C=CCNc1nc(-c2ccc(OC)c(OC)c2)cc2ncccc12
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3ncccc3c(NCC3CC(=O)NO3)n2)cc1OC
Temperature: 25 °C
Reaction time: 21 h

Procedure:
0.233 g Allyl-[7-(3,4,dimethoxy-phenyl)-[1,6]-naphthyridin-5-yl]-amine (I.35) were placed in 2.9 mL ethyl acetate at ambient temperature, then 0.265 g sodium hydrogen carbonate and 0.220 g dibromoformaldoxime were added. The reaction was stirred at ambient temperature for 21 h. After this time the reaction was poured onto water and extracted with ethyl acetate (×2). The combined organic fractions were dried with sodium sulfate and the solvent was removed from the filtrate under reduced pressure to provide 1.36 as a mixture of enantiomers which was used without further purification. The crude material was placed in 6 mL tetrahydrofuran at ambient temperature, then 23.9 mL of 1M sodium hydroxide and 23.8 mg tetrabutylammonium hydrogensulfate were added. The reaction was heated to 80° C. where it was maintained for 22 h. After this time, reaction mixture was cooled to ambient temperature and washed with diethyl ether (×2). The aqueous phase was acidified to pH ˜6 using 4M hydrochloric acid and extracted with dichloromethane (×4). The combined organic fractions were dried with sodium sulfate, filtered and the solvent was removed from the filtrate under reduced pressure. Purification by silica gel chromatography (methanol/dichloromethane: 2-5%) gave the title compound as a mixture of enantiomers.