Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCC1.[NH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1.[C:17](=S)=[S:18]>>[N:6]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8]1)=[C:17]=[S:18]
Reactant: CCOC(=O)N1CCC(N)C1
Reactant: S=C=S
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(N=C=S)C1
Temperature: -10 °C
Yield: 99.8 %

Procedure:
a-3) To a stirred and cooled (10° C.) mixture of 37 parts of N,N-methanetetraylbis[cyclohexanamine] and 594 parts of tetrahydrofuran were added 91.2 parts of carbon disulfide. After cooling to -10° C., 27.5 parts of ethyl 3-aminopyrrolidinecarboxylate were added during a period of 5 minutes (exothermic reaction). The reaction mixture was allowed to reach room temperature and evaporated. The residue was purified by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 32 parts (99.8%) of ethyl 3-isothiocyanato-1-pyrrolidinecarboxylate as a residue (interm. 6).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][OH:5].[CH3:6][S:7](Cl)(=[O:9])=[O:8].O>C(Cl)Cl>[F:1][CH2:2][CH2:3][CH2:4][O:5][S:7]([CH3:6])(=[O:9])=[O:8]
Reactant: OCCCF
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCCCF
Temperature: 25 °C
Yield: 91.6 %

Procedure:
A solution of 3-fluoro-propan-1-ol (31.2 g, 400 mmol) in 300 mL of CH2Cl2 was treated with MsCl (55 g, 38 mL, 480 mmol, 1.2 equiv) at 0° C. The resulting reaction mixture was gradually warmed to room temperature and stirred for 1–2 hours. When 1H NMR showed the reaction was complete, the reaction mixture was treated with H2O (100 mL), and the two layers were separated. The aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined organic layers were washed with H2O (3×100 mL) and dried over MgSO4. The solvent was removed in vacuo to afford the desired methanesulfonic acid 3-fluoro-propyl ester (57.2 g, 91% yield) as a yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:21])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:20])[C@H:17]([CH3:19])[NH2:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN1CCOCC1.[C:29]([NH:36][C@H:37]([C:39](O)=[O:40])[CH3:38])([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(ON1C2C(=CC=CC=2)CC(=C=O)C1OCC)C>C(Cl)Cl.O>[CH2:2]([O:9][C:10](=[O:21])[C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:20])[C@H:17]([CH3:19])[NH:18][C:39](=[O:40])[C@H:37]([CH3:38])[NH:36][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: CCOC1C(=C=O)Cc2ccccc2N1OCC
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
L-alanyl-L-proline benzyl ester hydrochloride (13.0 g, 41.6 mmol) was dissolved in methylene chloride (650 ml) under an argon atmosphere in a flask fitted with an over-head stirrer. N-methylmorpholine (4.8 ml, 43.6 mmol) was syringed into the solution and, after 5 minutes, Boc-L-alanine (7.9 g, 41.6 mmol) was added followed by 1-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline (11.8 g, 47.8 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was poured into a separatory funnel containing water (300 ml) and the layers separated. The aqueous layer was extracted with chloroform (200 ml) and the combined organic extracts were washed with0.5 N hydrochloric acid (3×200 ml), water (2×200 ml), saturated sodium bicarbonate (2×200 ml) and brine (200 ml). The organic layer was then dried over magnesium sulfate, filtered and concentrated on a rotary evaporator. Addition of ether-hexane gave crude Boc-L-alanyl-L-alanyl-L-proline benzyl ester which could be recrystallized from ethyl acetate-hexane to give the pure product (15.1 g) mp 124-126° C.
Reaction SMILES: [Na+].[Br-].C([O-])(O)=O.[Na+].[C:8]1([CH2:14][CH:15]([CH3:19])[CH2:16][CH2:17][OH:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1.[O-]Cl.[Na+]>C1(C)C=CC=CC=1.O>[C:8]1([CH2:14][CH:15]([CH3:19])[CH2:16][CH:17]=[O:18])[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]=1
Reactant: CC(CCO)CC1=CCCCC1
Agent: O=C([O-])O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(CC=O)CC1=CCCCC1
Reaction time: 1 h
Yield: 66 %

Procedure:
NaBr (0.6 g, 0.006 mol) and NaHCO3 (6.4 g, 0.076 mol) were mixed together with water (60 ml), toluene (250 g) and 4-(cyclohex-1-en-1-yl)-3-methyl butan-1-ol (96 g (0.573 mol, purity: 99% sum of the isomers) at room temperature with continuous stirring. NaOCl (13% w/w aqueous 426.8 g, 0.745 mol) was added to the reaction mass over 2 h. Stirring was continued for another 1 h. The aqueous phase was removed, organic phase was washed with a solution of NaHCO3 and then with water. The organic phase thus obtained was concentrated and crude product purified by fractional distillation to provide 4-(cyclohex-1-en-1-yl)-3-methylbutanal (62.6 g, yield: 66%, GC purity: 95% sum of the isomers).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][N:12]3[CH:14]=[CH:15][CH:16]=[C:11]3[C:10](=[O:17])[NH:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:9][C:10](=[O:17])[C:11]3[N:12]([CH:14]=[CH:15][CH:16]=3)[CH:13]=2)=[CH:6][CH:7]=1
Reactant: O=C1NC(O)(c2ccc(Br)cc2)Cn2cccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(-c2ccc(Br)cc2)cn2cccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
825 mg (2.69 mmol) 3-(4-bromo-phenyl)-3-hydroxy-3,4-dihydro-2H-pyrrolo[1,2-a]pyrazin-1-one is slurried in 6.6 ml dichloromethane. Then 207 μl (2.69 mmol) trifluoroacetic acid is added. After 10 min stirring at room temperature, the reaction mixture is evaporated. The residue is triturated with saturated sodium carbonate solution. The solids are filtered off, washed with water and dried under vacuum to give 3-(4-bromo-phenyl)-2H-pyrrolo[1,2-a]pyrazin-1-one as white powder; HPLC/MS 2.42 (B), [M+H] 289/291.
Reaction SMILES: [CH2:1]([OH:77])[C@H:2]1[O:7][C@@H:6]2[O:8][C@H:9]3[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]4[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]5[C@H:32]([OH:33])[C@@H:31]([OH:34])[C@@H:30]([O:35][C@H:36]6[C@H:41]([OH:42])[C@@H:40]([OH:43])[C@@H:39]([O:44][C@H:45]7[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]8[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]1[C@H:4]([OH:76])[C@H:5]2[OH:75])[O:56][C@@H:55]8[CH2:63][OH:64])[O:47][C@@H:46]7[CH2:65][OH:66])[O:38][C@@H:37]6[CH2:67][OH:68])[O:29][C@@H:28]5[CH2:69][OH:70])[O:20][C@@H:19]4[CH2:71][OH:72])[O:11][C@@H:10]3[CH2:73][OH:74].[Cu:78](Cl)Cl>>[CH2:67]([OH:68])[C@H:37]1[O:38][C@@H:39]2[O:44][C@H:45]3[C@H:50]([OH:51])[C@@H:49]([OH:52])[C@@H:48]([O:53][C@H:54]4[C@H:60]([OH:61])[C@@H:59]([OH:62])[C@@H:57]([O:58][C@H:3]5[C@H:4]([OH:76])[C@@H:5]([OH:75])[C@@H:6]([O:8][C@H:9]6[C@H:14]([OH:15])[C@@H:13]([OH:16])[C@@H:12]([O:17][C@H:18]7[C@H:23]([OH:24])[C@@H:22]([OH:25])[C@@H:21]([O:26][C@H:27]8[C@H:32]([OH:33])[C@@H:31]([OH:34])[C@@H:30]([O:35][C@H:36]1[C@H:41]([OH:42])[C@H:40]2[OH:43])[O:29][C@@H:28]8[CH2:69][OH:70])[O:20][C@@H:19]7[CH2:71][OH:72])[O:11][C@@H:10]6[CH2:73][OH:74])[O:7][C@@H:2]5[CH2:1][OH:77])[O:56][C@@H:55]4[CH2:63][OH:64])[O:47][C@@H:46]3[CH2:65][OH:66].[Cu:78]
Reactant: Cl[Cu]Cl
Agent: OC[C@H]1O[C@@H]2O[C@H]3[C@H](O)[C@@H](O)[C@@H](O[C@H]4[C@H](O)[C@@H](O)[C@@H](O[C@H]5[C@H](O)[C@@H](O)[C@@H](O[C@H]6[C@H](O)[C@@H](O)[C@@H](O[C@H]7[C@H](O)[C@@H](O)[C@@H](O[C@H]8[C@H](O)[C@@H](O)[C@@H](O[C@H]1[C@H](O)[C@H]2O)O[C@@H]8CO)O[C@@H]7CO)O[C@@H]6CO)O[C@@H]5CO)O[C@@H]4CO)O[C@@H]3CO
Product: [Cu]

Procedure:
The beta-cyclodextrin-copper biaffinity column was prepared by mixing 0.5 ml each of the sulfated beta-cyclodextrin polymer and chelating Sepharose (Pharmacia) that had been saturated with copper (II) chloride. A sample (16 ml) of Chondrosarcoma-derived growth factor partially purified by batchwise adsorption to heparin-Sepharose® was applied directly to this biaffinity column (1×1.3 cm) pre-equilibrated with 2M NaCl, 10 mM Tris, pH 7. The column was rinsed consecutively with 40 ml each of the following four reagents in 10 mM Tris, pH 7: (i) 2M NaCl, (ii) 0.6M NaCl, (iii) 0.6M NaCl plus 10 mM imidazole, and (iv) 0.6M NaCl. Finally, the growth factor was eluted at a flow rate of 20 ml/hour with a linear NaCl/imidazole gradient from 100 mM imidazole in 10 mM Tris, pH 7. Fractions (4 ml) were collected, monitored for conductivity (Radiometer American conductivity meter) and assayed for growth factor activity.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].C(N(CC)CC)C.[CH3:19][C:20]([CH3:25])=[CH:21][C:22](Cl)=[O:23].COC1C=CC(C=O)=CC=1>ClCCl.O>[CH3:25][C:20](=[CH2:19])[CH2:21][C:22]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])=[O:23]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(C)=CC(=O)Cl
Agent: COc1ccc(C=O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=C(C)CC(=O)OC/C=C(\C)CCC=C(C)C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of geraniol (225 ul, 1.29 mmol, 1.0 equivalent) and triethylamine (271 ul, 1.94 mmol, 1.5 equivalent) in dry dichloromethane (I ml) was cooled to −78 C and treated dropwise with 3,3-dimethylacryloyl chloride (159 ul, 1.43 mmol, 1.1 equivalent). After 3 h, the solution was diluted with water (1 ml) and dichloromethane (1 ml), and the cooling hath was removed. The mixture was extracted with dichloromethane (3×20 ml), and the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by radial chromatography (4 mm SiO2 plate; elute, 7% EatOAc-hexanes; product, fractions 4-6; 30 ml/fraction) afforded ##STR3## (301 mg, 1.27 mmol, 99% yield) as a clear oil: Rf starting material, 0.14; product, 0.51 (5:1 hexanes-EtOAc, anisaldehyde); FTIR (film) 2970, 2919, 2858, 1738, 1653, 1445, 1377, 1206, 1153, 987, 896 cm-1; sup. 1H NMR (400 MHz, CDCl3) δ 5.31-5.35 (m, 1H), 5.04-5.08 (m, 1H), 4.88 (bs, 1H), 4.83 (bs, 1H), 4.60 (s, 1H), 4.58 (s, 1H), 3.01 (s, 2H), 2.00-2.09 (m, 4H), 1.79 (s, 3H), 1.69 (s, 3H), 1.66 (s, 3H), 3.01 (s, 2H), 2.00-2.09 (m, 4H), 1.79 (s, 3H), 1.69 (s, 3H), 1.66 (s, 3H), 1.58 (s, 3H); .sup.13 C NMR (101 Mhz, CDCl3) δ 171.2, 142.2, 138.6, 131.7, 123.7, 118.2, 114.5, 61.4, 43.4, 39.4, 26.2, 25.6, 22.3, 17.6, 16.4; HRMS (EI, Pos) m/z calculated for [C15H24O2]+236.1776, found 236.1768.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:23]=[CH:22][C:7]([CH2:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][CH2:13][CH:14]3[C:19]([OH:21])=[O:20])=[CH:6][CH:5]=1.[Mn]([O-])(=O)(=O)=[O:25].[K+].S(=O)(=O)(O)O.S(=O)(O)[O-].[Na+]>O>[C:4]1([CH3:3])[CH:5]=[CH:6][C:7]([C:8]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH2:11][CH2:12][CH2:13][CH:14]3[C:19]([OH:21])=[O:20])=[O:25])=[CH:22][CH:23]=1
Reactant: Cc1ccc(Cc2cccc3c2CCCC3C(=O)O)cc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [K+]
Solvent: O
Product: Cc1ccc(C(=O)c2cccc3c2CCCC3C(=O)O)cc1
Reaction time: 8 h

Procedure:
In 200 ml. of 1N aqueous sodium hydroxide is dissolved 14 g. of 5-(p-methylbenzyl)-1,2,3,4-tetrahydro-1-naphthoic acid, and a solution of 26 g. of potassium permanganate in 800 ml. of water is added dropwise. After stirring overnight, the reaction mixture is rendered acidic by the addition of concentrated sulfuric acid, followed by the addition of sodium bisulfite. The mixture is extracted with chloroform and the chloroform layer is washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the oily residue is purified by column chromatography on silica gel equilibrated with oxalic acid and, then, recrystallized from cyclohexane. The described procedure gives 5-(p-toluoyl)-1,2,3,4-tetrahydro-1-naphthoic acid, melting point: 102°-103°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[C:11](SC)[N:10]=2)=[CH:5][CH:4]=1>[Ni].C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:14]([CH2:15][OH:16])=[CH:13][N:12]=[CH:11][N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(SC)ncc2CO)cc1
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(-c2ncncc2CO)cc1
Yield: 77.3 %

Procedure:
A mixture of [4-(4-methoxyphenyl)-2-(methylsulfanyl)pyrimidin-5-yl]methanol (13.5 g), Raney-nickel (96 g) and ethanol (500 mL) was heated under reflux for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate) to give the title compound (8.6 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6](Br)=[CH:5][C:4]=2[N:3]=1.B1([C:40]2[CH:45]=[CH:44][CH:43]=[N:42][CH:41]=2)OCCCO1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([C:40]3[CH:41]=[N:42][CH:43]=[CH:44][CH:45]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC1CCCCN1C(=O)OC(C)(C)C
Reactant: c1cncc(B2OCCCO2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CC1CCCCN1C(=O)OC(C)(C)C
Yield: 70.8 %

Procedure:
tert-Butyl 2-[(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)methyl]piperidine-1-carboxylate (4.82 g, 9.30 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (1.67 g, 10.2 mmol) were coupled according to the method described in Part F of Example 414. Palladium (II) acetate (0.0103 f, 0.046 mmol) was added as a solid. The reaction was heated for 15 hours. The crude product was purified by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 72:28) to provide 3.4 g of tert-butyl 2-{[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}piperidine-1-carboxylate as an off-white, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[CH2:12][N:11]([CH3:15])[C:10]2=[O:16])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)#[N:18].N1CCCC1.C1COCC1>CCO>[Cl:8][C:6]1[CH:5]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[CH:23]\[C:22]3[CH:25]=[CH:26][C:19]([C:17]#[N:18])=[CH:20][CH:21]=3)/[N:11]([CH3:15])[C:10]2=[O:16])[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CN1CC(=O)N(c2cc(Cl)cc(Cl)c2)C1=O
Reactant: N#Cc1ccc(C=O)cc1
Solvent: CCO
Solvent: C1CCOC1
Solvent: C1CCNC1
Product: CN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)/C1=C\c1ccc(C#N)cc1
Temperature: 65 °C
Yield: 86.3 %

Procedure:
A mixture of 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione (1.00 kg, 3.86 mol), 4-cyanobenzaldehyde (0.70 kg, 5.79 mol), and pyrrolidine (0.27 kg, 3.86 mmol) was refluxed in EtOH (13.00 L) for 20–24 hours at a temperature of 78° C. The completeness of the reaction was followed by HPLC. Upon reaction completion, the suspension was cooled to 65° C. and THF (4.33 L) was added in 5–10 minutes. The suspension was cooled to 20–25° C. in 3–4 hours and was then filtered. The filter cake was washed with EtOH (4×2.00 L) and dried at maximum 40° C. to a constant weight. (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitril (1.24 kg, 86%) was obtained as a fluffy, yellowish crystalline solid. mp=239–241° C. 1H NMR (DMSO-d6): 8.07 (2H, d, J=8.3 Hz), 7.86 (2H, d, J=8.4 Hz), 7.72 (1H, m), 7.59 (2H, m), 6.72 (1H, s), 3.35 (3H, s). 13C NMR (DMSO-d6): 14 Carbons (159.80, 151.48, 137.64, 133.83, 133.70, 131.80, 130.80, 130.68, 127.71, 125.51, 118.83, 114.48, 110.32, 26.72). Anal. Calcd for C18H11Cl2N3O2: C, 58.08; H, 2.97; N, 11.29; Cl, 19.05. Found: C, 58.14; H, 2.72; N, 11.14; Cl, 19.15.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1.[C:11]([O:15][C:16](N=[N+]=[N-])=[O:17])([CH3:14])([CH3:13])[CH3:12].O.O1CCOCC1>C(N(CC)CC)C>[C:11]([O:15][C:16]([NH:2][CH2:3][CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: NCCn1nnnc1S
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCn1nnnc1S
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of 1-(2-aminoethyl)-1H-tetrazole-5-thiol hydrochloride (1.82 g.), t-butoxycarbonylazide (2.86 g.), water (20 ml.) and dioxane (20 ml.) was added triethylamine (6.0 g.), and the mixture was stirred at room temperature for one hour. After dioxane was removed therefrom under reduced pressure, the residue was adjusted to pH 7.5 to 8.0 with 5% aqueous solution of sodium bicarbonate and washed twice with ether. The resultant solution was adjusted to pH 1 with 5% hydrochloric acid and extracted three times with ethyl acetate (each 50 ml.). The extract was washed with an aqueous saturated solution of sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure to give 1-(2-t-butoxycarbonylaminoethyl)-1H-tetrazole-5-thiol (2.05 g.), m.p. 117° to 120° C. (dec.).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[CH:23]=[N:22][C:21]([CH3:24])=[N:20]1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[CH:23]=[N:22][C:21]([CH3:24])=[N:20]2)=[O:11])[C@@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=1
Reactant: Cc1ccc(Br)nc1
Reactant: Cc1ccc(-n2cnc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(NC[C@@H]2[C@H](C)CCCN2C(=O)c2cc(C)ccc2-n2cnc(C)n2)nc1

Procedure:
The title compound was synthesized following the same general protocol as described in Example A44, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanone and 2-bromo-5-methylpyridine. ESI-MS (m/z): 419 [M+1]+.
Reaction SMILES: [C@@H:1]12[NH:8][CH2:7][C@@H:6]1[CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]2.CCN(C(C)C)C(C)C.Cl[C:26]1[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][N:27]=1>C(#N)C.O>[F:33][C:32]([F:35])([F:34])[C:30]1[CH:29]=[CH:28][N:27]=[C:26]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:2]3)[CH2:7]2)[N:31]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2CN[C@H]2C1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H]2CN(c3nccc(C(F)(F)F)n3)[C@H]2C1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
To (1R,6S)-tert-butyl 3,8-diazabicyclo[4.2.0]octane-3-carboxylate (166 mg, 0.8 mmol) and DIPEA (404 μL, 2.3 mmol) in ACN (3.4 mL) was added 2-chloro-4-(trifluoromethyl)pyrimidine (110 μL, 0.9 mmol). The reaction mixture was heated at reflux for 2 h, cooled to rt, diluted with water and extracted with CH2Cl2 (2×). The combined organics were dried (Na2SO4) and concentrated to give 185 mg (66%) of the title compound as a clear oil which was used without further purification. MS (ESI) mass calcd. For C16H21F3N4O2, 358.40; m/z found 359.1 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([CH3:12])=[C:6]([NH:8]C(=O)C)[CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(C)c(NC(C)=O)cc1Br
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c(N)cc1Br
Yield: 83.7 %

Procedure:
To a solution of N-(5-bromo-4-methoxy-2-methylphenyl)acetamide (108 g, 0.42 mol) in MeOH (400 mL) is added concentrated HCl (160 mL, 2 mol). After being heated at reflux overnight, the mixture is neutralized with aqueous NaHCO3, and extracted with EtOAc (1200 mL). The organic phase is dried and concentrated to afford the product (76 g, 84% yield). MS (m/z): 216.0 (M+H).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[CH2:8][C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[NH:5]1.[C:18]([O:22][CH3:23])(=[O:21])[CH:19]=[CH2:20]>>[CH3:1][N:2]([CH2:3][CH:4]1[C:10]2=[CH:11][CH:12]=[CH:13][N:9]2[CH2:8][C:7]2[CH:14]=[CH:15][CH:16]=[CH:17][C:6]=2[NH:5]1)[CH2:20][CH2:19][C:18]([O:22][CH3:23])=[O:21]
Reactant: C=CC(=O)OC
Reactant: CNCC1Nc2ccccc2Cn2cccc21
Product: COC(=O)CCN(C)CC1Nc2ccccc2Cn2cccc21

Procedure:
The solution of 1.5 g of 11-(N-methylaminomethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (Example 1) in 7.5 ml of methyl acrylate is stirred at room temperature for 24 hours and the excess reagent is evaporated to yield the 11-(N-methyl-N-methoxycarbonylethylamino-methyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine as an oil, which is chromatographed on silica gel and eluted with 2% methanol-methylene chloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)[CH3:2].[CH3:17][NH:18][O:19][CH3:20].CN1CCOCC1>C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CCOC(C)=O>[CH3:20][O:19][N:18]([CH3:17])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: CNOC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 73.3 %

Procedure:
2-Ethoxy-4-trifluoromethyl-benzoic acid (1.20 g, 5.12 mmol) was reacted with N,O-dimethylhydroxy amine (609 mg), NMM (0.95 ml) and DMTMM (1.47 mg) as described above to give the title compound (1.04 g, 73%) after column chromatography (Hex/EtOAc=5/1).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Cu][C:26]#[N:27].Cl>O>[C:26]([C:8]1[CH:7]=[C:6]([CH3:11])[C:5]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:14])=[O:15])=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:24])#[N:27]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(Br)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(S(=O)(=O)Nc2c(C)cc(C#N)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.7 %

Procedure:
To a solution of 4.0 g (10 mmol) of the product of Example 10 in 60 mL of pyridi was added 2.0 g (22 mmol) of copper (I) cyanide and the resulting mixture was refluxed for 48 h. The reaction mixture was then cooled to room temperature, poured over cold water, stirred for 16 h and then carefully acidified with concentrated HCl solution. The resulting solid was filtered and washed with water, dissolved in chloroform, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether, filtered and dried to provide 2.0 g (58%) of the desired product as a white solid. m.p. 175° C.; Electrospray Mass Spec 347 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(I)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: Ic1ccc(OCc2ccccc2)cc1
Yield: 88.1 %

Procedure:
4-iodoanisole (10.12 g, 0.046 mole), benzyl bromide (8.00 g, 0.046 mole), and potassium carbonate (6.31 g, 0.046 mole) in acetone (20 ml) were refluxed for 24 hours. Water was added and the aqueous layer extracted with ether (3×100 ml). The combined organic layers were washed with 2M NAOH (2×150 ml) and dried over anhydrous potassium carbonate. Evaporation of the solvent followed by crystallisation from methanol yielded 12.57 g (88%) benzyl 4-iodophenyl ether.