Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:44])[CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][C@H:21]1[C@H:26]([NH:27][C:28](=[O:30])[CH3:29])[C@@H:25]([O:31][C:32](=[O:34])[CH3:33])[C@@H:24]([O:35][C:36](=[O:38])[CH3:37])[C@@H:23]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[O:22]1)C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:32]([O:31][C@H:25]1[C@@H:24]([O:35][C:36](=[O:38])[CH3:37])[C@@H:23]([CH2:39][O:40][C:41](=[O:43])[CH3:42])[O:22][C@@H:21]([O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][C:9]([OH:44])=[O:8])[C@@H:26]1[NH:27][C:28](=[O:30])[CH3:29])(=[O:34])[CH3:33]
Reactant: CC(=O)N[C@H]1[C@H](OCCOCCOCCOCC(=O)OCc2ccccc2)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)N[C@H]1[C@H](OCCOCCOCCOCC(=O)O)O[C@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 45.2 %

Procedure:
The above prepared (2-{2-[2-((2R,3R,4R,5R,6R)-4,5-diacetoxy-6-acetoxymethyl-3-acetylamino-tetrahydro-pyran-2-yloxy)-ethoxy]-ethoxy}-ethoxy)-acetic acid benzyl ester (15.7 g, 25 mmol) was dissolved in 525 mL of ethyl acetate and hydrogenated over 1.6 g of Pd/C (10%) under 1 atm. of H2 at ambient temperature for 3 h. Filtration over Celite and evaporation of the solvent, followed by flash chromatography (SiO2, CH2Cl2/MeOH=80/20) gave 6.07 g of the title compound as a brownish gum. MS (ISP): 536.5 [M−H]−.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].[H][H]>C(O)C.[Pd]>[CH2:1]([C@H:6]1[CH2:7][CH2:8][C@H:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:11]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC[C@H]1CC[C@H](C=CC(=O)OCC)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCCC[C@H]1CC[C@H](CCC(=O)OCC)CC1
Yield: 91.6 %

Procedure:
41.6 g of ethyl β-(trans-4-pentylcyclohexyl)acrylate were dissolved in 368 ml of ethanol, treated with 7.4 g of palladium/carbon (5%) and hydrogenated at room temperature and under normal pressure until the hydrogen uptake came to a standstill (hydrogen uptake 0.167 mol). The mixture was gassed with nitrogen and filtered (rinsing with ethanol and methylene chloride). Concentration of the filtrate in vacuo gave 38.4 g of ethyl β-(trans-4-pentylcyclohexyl)propionate as a colourless oil which was distilled in a high vacuum; b.p. 113°-121° C./0.05-0.06 mmHg.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[CH:5][C:6]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[C:7]([CH:11]=1)[C:8]([OH:10])=O.[F:18][C:19]1[CH:20]=[C:21]([C:31](=[O:33])[CH3:32])[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[F:18][C:19]1[CH:20]=[C:21]([C:31](=[O:33])[CH3:32])[CH:22]=[CH:23][C:24]=1[N:25]1[CH2:30][CH2:29][N:28]([C:8](=[O:10])[C:7]2[CH:11]=[C:3]([S:2][CH3:1])[CH:4]=[CH:5][C:6]=2[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH2:27][CH2:26]1
Reactant: CC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: CSc1ccc(N2CCOCC2)c(C(=O)O)c1
Product: CSc1ccc(N2CCOCC2)c(C(=O)N2CCN(c3ccc(C(C)=O)cc3F)CC2)c1

Procedure:
The title compound was prepared according to the procedure described for example K step 2 from 5-Methylsulfanyl-2-morpholin-4-yl-benzoic acid and 1-(3-Fluoro-4-piperazin-1-yl-phenyl)-ethanone (8%, white solid), MS (m/e): 458.2 (M+, 100%)
Reaction SMILES: [Br:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([CH2:15][O:16]C)=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1.ClCCl.O.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:12])[CH3:13])[C:5]([CH:15]=[O:16])=[C:4]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:3]=1
Reactant: CCOC(=O)c1cc(Br)n(COCC[Si](C)(C)C)c1COC
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Br)n(COCC[Si](C)(C)C)c1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To 450 g (1.15 mol) of ethyl 5-bromo-2-methoxymethyl-1-(2-trimethylsilylethoxymethyl)-1H-pyrrol-3-carboxylate obtained in Reference example 15-(e) were added 5.4 L of dichloromethane and 540 ml of water, and then, 363 g (1.60 mol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added to the mixture by dividing it into several portions at room temperature. The mixture was stirred at room temperature for 30 minutes, and then, refluxed for 6 hours. After completion of the reaction, 450 g of Celite and 2.5 L of toluene were added to the reaction suspension, the mixture was stirred at room temperature for 30 minutes, and insoluble material was removed by filtration. The organic layer obtained by separating the filtrate was washed successively with a saturated aqueous solution of sodium hydrogencarbonate, and with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 430 g of the title compound as a pale brownish oil substantially quantitatively.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[O:16][CH:15]([CH2:18][NH2:19])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[NH:19][CH2:18][CH:15]1[CH2:14][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:17]=2[O:16]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1cccc(-c2cccc3c2OC(CN)C3)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)c1
Yield: 93.4 %

Procedure:
Treatment of (±)-1-[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (2.4 g, 9.4 mmol) with diisopropylethylamine (1.82 g, 14.10 mmol) and benzyl chloroformate (1.92 g, 11.28 mmol) generally according to the reaction conditions described for Intermediate 12 afforded 3.42 g (93%) of (±)-benzyl[7-(3-methoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methylcarbamate as a colorless oil. Rf=0.78 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C24H23NO4′: C, 74.02; H, 5.95; N, 3.6. Found: C, 73.52; H, 6.06; N, 3.28.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[N-]=[N+]=[N-].[Li+]>C(#N)C>[N:20]([C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1)=[N+:21]=[N-:22]
Reactant: Clc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Solvent: CC#N
Product: [N-]=[N+]=Nc1nc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 264 h
Yield: 22.5 %

Procedure:
A suspension of 2-chloro-4,6-diphenyl-s-triazine (30 g, 0.112 mol), sodium azide (12.86 g, 0.199 mol) and lithium azide (1.24 g, 0.025 mol) in acetonitrile (550 ml) was stirred at room temperature for 11 days. After filtration, the filtrate on evaporation yielded 6.9 g of 2-azido-4,6-diphenyl-s-triazine, mp 115°-117° C. The residue on extraction with hot heptane, followed by crystallization from heptane, gave an additional 20 g quantity having a mp of 114°-116° C bringing the total yield of 2-azido-4,6-diphenyl-s-triazine to 26.9 g (88% yield). The melting point and infrared spectrum were identical with that of an authentic sample.
Reaction SMILES: O[CH:2]([C:4]1[CH:8]=[N:7][N:6]([CH2:9][C@@H:10]2[C@H:13]([NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12](=[O:25])[NH:11]2)[N:5]=1)[CH3:3].[C:26]([O:30][C:31](/[N:33]=[C:34](\[NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])/[N:35]1[CH:39]=[CH:38][CH:37]=[N:36]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:17]([O:16][C:15]([NH:14][C@@H:13]1[C:12](=[O:25])[NH:11][C@@H:10]1[CH2:9][N:6]1[N:5]=[C:4]([CH:2]([N:40](/[C:34](=[N:33]/[C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])/[N:35]2[CH:39]=[CH:38][CH:37]=[N:36]2)[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[CH3:3])[CH:8]=[N:7]1)=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)/N=C(\NC(=O)OC(C)(C)C)n1cccn1
Reactant: CC(O)c1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1)N(C(=O)OC(C)(C)C)/C(=N/C(=O)OC(C)(C)C)n1cccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.4 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(1-hydroxyethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate (460 mg, 1.33 mmol), (E)-tert-butyl (((tert-butoxycarbonyl)imino)(1H-pyrazol-1-yl)methyl)carbamate (455 mg, 1.465 mmol), and triphenylphosphine (419 mg, 1.60 mmol) in THF (7 ml) at 0° C. was added DIAD (0.311 ml, 1.598 mmol) dropwise. The reaction was stirred at room temperature overnight and concentrated to dryness. Purification of the crude residue via silica gel chromatography (EtOAc-Heptane, 30-60%) afforded the title compound (190 mg, 22%) as a light yellow solid. LCMS: Rt=0.99 min, m/z=638.4 (M+1) Method 2m_acidic.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[CH2:20][C@@H:19]2[CH2:21][C@H:16]1[CH2:17][N:18]2[S:22]([CH3:25])(=[O:24])=[O:23])=O)(C)(C)C>C(Cl)Cl>[CH3:25][S:22]([N:18]1[CH2:17][C@@H:16]2[CH2:21][C@H:19]1[CH2:20][NH:15]2)(=[O:23])=[O:24]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2S(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1C[C@@H]2C[C@H]1CN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Methanesulfonyl chloride (120 μL, 1.55 mmol) and DIPEA (187 μL, 1.07 mmol) were added to a solution of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (200 mg, 1.01 mmol) in DCM (20 mL) and the reaction mixture stirred at ambient temperature for 17 h, then partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo to give (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]-heptane-2-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of (1S,4S)-5-methanesulfonyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 30 min. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g); the cartridge was washed with MeOH before the desired product was eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo to afford the title compound as a white solid (170 mg, 96%). 1H NMR (CDCl3, 400 MHz) δ 4.37 (d, J=2.0 Hz, 1 H); 3.83 (d, J=2.0 Hz, 1 H); 3.41 (dd, J=9.2, 2.19 Hz, 1 H); 3.25 (d, J=9.2 Hz, 1 H); 3.20 (d, J=10.3 Hz, 1 H); 3.01 (dd, J=10.3, 2.14 Hz, 1 H); 2.89 (s, 3 H); and 1.79 (bs, 2 H)
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]([NH:22][NH:23][C:24]([C@@H:26]1[CH2:30][CH2:29][CH2:28][N:27]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=O)=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1(C)C=CC=CC=1>[Si:1]([O:18][CH2:19][C:20]1[O:21][C:24]([C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:23][N:22]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NNC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)o1
Yield: 73.2 %

Procedure:
To a toluene (112 mL) solution of the compound (5.87 g) obtained in Example 9-(1), Burgess reagent (5.322 g) was added and the mixture was heated under reflux for 2.5 hours. The reaction mixture was concentrated to give a crude product, which was further purified by silica gel chromatography (AcOEt/hexane) to give the titled compound (4.151 g, colorless amorphous.)
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Li]CCCC.C(NC(C)C)(C)C.[NH2:21]/[C:22](/[C:33]([F:36])([F:35])[F:34])=[C:23](/[C:29](=[O:32])[CH2:30][CH3:31])\[C:24]([O:26][CH2:27][CH3:28])=[O:25].[F:37][C:38]([F:48])([F:47])[C:39]([F:46])([F:45])[C:40](OCC)=O>CCOCC.O>[OH:32][C:29]1[C:30]([CH3:31])=[C:40]([C:39]([F:45])([F:46])[C:38]([F:37])([F:47])[F:48])[N:21]=[C:22]([C:33]([F:34])([F:35])[F:36])[C:23]=1[C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)/C(C(=O)CC)=C(\N)C(F)(F)F
Reactant: CCOC(=O)C(F)(F)C(F)(F)F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)C(F)(F)F)c(C)c1O
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 30.7 %

Procedure:
To a -78° C. solution of LDA (0.10 mol), prepared from 0.10 mol of n-BuLi and 14 ml (0.10 mol) of diisopropylamine in 70 ml ether was added a solution of 10.0 g (0.042 mol) of product of Example 34 in 20 ml of ether slowly to maintain a temperature below -60° C. After stirring for 30 minutes, the reaction mixture was treated with 21 ml (0.042 mol) of ethyl pentafluoropropionate. After stirring at -78° C. for 15 minutes, the reaction mixture was warmed to 10° C. in 0.5 hour and poured into 100 ml of water, and extracted with ether. The ether extract was extracted with 10% K2CO3. The combined aqueous layer and K2CO3 extract was acidified with concentrated HCl to give 4.73 g (29.5%) of beige solid; mp 115°-117° C. (dec). A 2.73 g (0.00709 mol) of the solid was heated in a kugelrohr pot at 130° C. for 0.5 hour. The distillate and residue were combined and dissolved in ether. The ether solution was dried (CaSO4) and concentrated to give 2.0 g (76.9%) of product as a solid; mp 36°-38° C.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:36]([O:37]C(=O)C)[C@H:35]([O:41]C(=O)C)[C@@H:34]([CH2:45][O:46]C(=O)C)[O:33][CH:6]1[O:7][CH2:8][CH2:9][O:10][C:11]1[C:16]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=[CH:13][C:12]=1[C:25]#[C:26][C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1)(=O)C.C[O-].[Na+].C(=O)([O-])O.[Na+]>CO>[O:7]([CH2:8][CH2:9][O:10][C:11]1[C:12]([C:25]#[C:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)=[CH:13][CH:14]=[CH:15][C:16]=1[C:17]#[C:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[CH:6]1[O:33][C@H:34]([CH2:45][OH:46])[C@@H:35]([OH:41])[C@H:36]([OH:37])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1OC(OCCOc2c(C#Cc3ccncc3)cccc2C#Cc2ccncc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: OC[C@H]1OC(OCCOc2c(C#Cc3ccncc3)cccc2C#Cc2ccncc2)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 86.9 %

Procedure:
2-[2,6-Bis(4-pyridylethynyl)phenoxy]ethyl 2,3,4,6-tetra-O-acetyl-D-glucopyranoside (600 mg, 0.895 mmol) and a methanol (90 ml) solution of sodium methoxide (242 mg, 4.47 mmol) were stirred at room temperature for 12 hours. The reaction mixture was neutralized with a sodium hydrogen carbonate aqueous solution, and concentrated under reduced pressure. The residue was washed with water, and dried to obtain 391 mg of the target product as a white solid (yield: 87%).
Reaction SMILES: [C:1]([C:4]1[C:9](=O)[NH:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=1)(=O)[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=1.C(N(CC)CC)C.[OH-].[NH4+]>C(OC(=O)C)(=O)C>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[C:29](=[O:31])[O:30][C:9]3=[N:8][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=[C:4]3[C:1]=2[CH3:2])=[CH:26][CH:27]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cc(C(C)=O)c(=O)[nH]c1C(=O)OCC
Agent: [NH4+]
Agent: [OH-]
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc2c(C)c(-c3ccc(Cl)cc3)c(=O)oc2nc1C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Diethyl 5-acetyl-1,6-dihydro-6-oxo-2,3-pyridinedicarboxylate, (6.0 g, 0.0213 mol), 4-chlorophenyl acetic acid (3.64 g, 0.0213 mol) and triethylamine (3.0 g,.1.5 eq) are refluxed in 50 mL of acetic anhydride for three and one-half hours and then stirred at room temperature overnight. The reaction mixture is poured into 100 mL of ice cold water and the pH is adjusted to 8 with an ammonium hydroxide solution. The crystalline solid is filtered, washed with water, dried and dissolved in 100 mL of methylene chloride. The solution is dried over anhydrous sodium sulfate and the solvent removed under reduced pressure to give the desired product (8.8 g, 99%), which is crystallized from ethyl acetate to give the pure product having a melting point 179°-181° C.
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[Cs].[N+:11]([C:14]1[CH:19]=[CH:18][C:17](Cl)=[CH:16][CH:15]=1)([O-:13])=[O:12].C(NC1C=CC=CC=1)=O>C1(C)C(C)=CC=CC=1>[CH:7]1[CH:8]=[CH:9][C:4]([NH:3][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:5][CH:6]=1
Reactant: O=CNc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [Cs]
Solvent: Cc1ccccc1C
Product: O=[N+]([O-])c1ccc(Nc2ccccc2)cc1
Temperature: 140 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To the resulting slurry of cesium formanilide is added 63 parts by weight (0.4 mole) of p-nitrochlorobenzene, 7.9 parts by weight (0.065 mole) of formanilide and 200 parts by weight of xylene. The reaction mixture is heated to about 140° C. over a period of about an hour and heating continued at 140°-146° for about 3 hours. Gas evolution increases rapidly at about 121° C. and continues throughout most of the heating period. During the heating, the major proportion of the hydrocarbon solvent is removed as distillate. The reaction mixture is washed with water and then xylene is added at 90° C. The organic layer is separated and dried. From the organic layer 54.6 parts by weight (0.255 mole) of 4-nitrodiphenylamine is isolated by crystallization. From the brown mother liquor another 0.041 moles is obtained. The yield is 74.1% and conversion 80.3%.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)#[N:2].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18]3=[C:19]([CH2:21][S:22][CH2:23][CH2:24][N:17]3[C@H:16]3[CH2:25][CH2:26][N:27](C(OC(C)(C)C)=O)[CH2:28][C@@H:15]23)[CH:20]=1>>[CH2:24]1[N:17]2[C:18]3[C:14]([C@@H:15]4[CH2:28][NH:27][CH2:26][CH2:25][C@@H:16]42)=[CH:13][C:12]([NH:11][CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[C:1]#[N:2])=[CH:20][C:19]=3[CH2:21][S:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Reactant: N#Cc1ccccc1C=O
Product: N#Cc1ccccc1CNc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2

Procedure:
Using 2-cyanobenzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 162. 1H NMR(CDCl3) δ: 8.14 (d, 1H, J=7.7 Hz) 7.63-7.50 (m, 3H), 6.88-6.80 (m, 2H), 7.13 (s, 1H), 6.95 (s, 1H), 4.90 (broad s, 2H), 3.81 (ABq, 2H, JAB=15.7 Hz), 3.71-3.62 (m, 2H), 3.59-3.53 (m, 1H), 3.38-3.30 (m, 1H), 3.29-3.20 (m, 1H), 3.12-2.80 (m, 5H), 1.91-1.80 (m, 2H). LRMS (ES)+: 377.4 (M+H)+.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:11]=[C:10]([CH3:12])[O:9][N:8]=1.[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21]Br)[CH2:17][CH2:16]1>O1CCCC1>[Br:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH:18]([CH2:21][CH2:12][C:10]2[O:9][N:8]=[C:7]([CH3:6])[CH:11]=2)[CH2:17][CH2:16]1
Reactant: BrCC1CCC(CBr)CC1
Reactant: Cc1cc(C)on1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(CCC2CCC(CBr)CC2)on1
Reaction time: 0.5 h
Yield: 58 %

Procedure:
Butyllithium (23.3 ml, 8.0M in tetrahydrofuran) was added dropwise to a solution of 18.3 g of 3,5-dimethylisoxazole in 800 ml of tetrahydrofuran held at -77° C. under nitrogen, and the mixture was stirred for 30 minutes. 1,4-bis(Bromomethyl)cyclohexane (50.4 g) was then added, and the reaction mixture was stirred for 3 hours at -70° C. and at room temperature overnight. The product was isolated and purified by chromatography to give 31 g (58%) of 5-[2-(4-bromomethylcyclohexyl)ethyl]-3-methylisoxazole as a liquid used directly in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:29]=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:29]=[N:30][C:31]2[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:21](=[O:23])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Reactant: CCNCc1cnc2ccccc2c1
Product: CCN(Cc1cnc2ccccc2c1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-quinolin-3-ylmethyl-amine
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3](=O)/[CH:4]=[CH:5]/OCC.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[NH2:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:11][C:2]([Cl:1])([Cl:10])[C:3]1[CH:4]=[CH:5][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[N:21]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CCO/C=C/C(=O)C(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: ClC(Cl)(Cl)c1ccn2c(n1)nc1ccccc12
Temperature: 25 °C
Yield: 100.4 %

Procedure:
(E)-1,1,1-trichloro-4-ethoxybut-3-en-2-one (6.1 g, 28.0 mmol) was added to a solution containing 1H-benzo[d]imidazol-2-amine (3.73 g, 28.0 mmol) and Triethylamine (3.91 mL, 28.0 mmol) in Toluene (Volume: 100 mL). Heated the reaction to 120° C. for 2 hours. Let the reaction cool to room temperature and concentrated under vacuum. Diluted with water and filtered. Collected solid and dried under vacuum to afford crude 2-(trichloromethyl)benzo[4,5]imidazo[1,2-a]pyrimidine (8.04 g, 28.1 mmol, 100% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=O.OCC1C=CC(/[CH:20]=[CH:21]/[C:22]([O:24]C)=[O:23])=CC=1>>[CH3:20]/[C:21](=[CH:1]\[C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([CH2:6][OH:8])[CH:4]=1)/[C:22]([OH:24])=[O:23]
Reactant: COC(=O)/C=C/c1ccc(CO)cc1
Reactant: O=Cc1cccc(C(=O)O)c1
Product: C/C(=C\c1cccc(CO)c1)C(=O)O

Procedure:
The title compound was prepared from 3-formylbenzoic acid by the same methodology used to make Intermediate A.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[N:6]([CH3:23])[C:5]1=[O:24])[C:14](=[O:17])[CH:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]3.Br[CH2:26][CH2:27][CH2:28][Cl:29]>O>[Cl:29][CH2:28][CH2:27][CH2:26][C:13]1([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][C:7]3[N:6]([CH3:23])[C:5](=[O:24])[N:4]([CH3:3])[C:8]=3[CH:9]=2)[C:14]1=[O:17]
Reactant: CCOC(=O)C1CCc2cc3c(cc2C1=O)n(C)c(=O)n3C
Reactant: ClCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C1(CCCCl)CCc2cc3c(cc2C1=O)n(C)c(=O)n3C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
60% Oily sodium hydride (832 mg) was added to a solution of ethyl (±)-1,3-dimethyl-2,5-dioxo-2,3,5,6,7,8-hexahydro-1H-naphtho[2,3-d]imidazole-6-carboxylate (5.0 g) obtained in Reference Example 138 in dimethylformamide,and the mixture was stirred at 60° C. for 1 hour. 1-Bromo-3-chloropropane was added thereto, and the mixture was stirred at 60° C. for 4 hours. The reaction mixture was allowed to cool, and water was added to decompose excessive sodium hydride. Then, the mixture was extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a pale yellow oil.