Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=1[S:35](Cl)(=[O:37])=[O:36]>CC(C)=O>[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[C:28]=1[S:35]([O:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([NH:9][C:10](=[O:11])[NH:12][CH2:13][CH2:14][O:15][CH3:16])=[N:8][C:4]=2[CH:3]=1)(=[O:36])=[O:37]
Reactant: COCCNC(=O)Nc1nc2cc(O)ccc2[nH]1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COCCNC(=O)Nc1nc2cc(OS(=O)(=O)c3c(C)cc(C)cc3C)ccc2[nH]1
Reaction time: 20 h
Yield: 38.8 %

Procedure:
To a suspension of 200 mg of 1-(5-hydroxy-1H-benzimidazol-2-yl)-3-(2-methoxyethyl)urea in 50 cm3 of acetone are added 0.162 cm3 of triethylamine and 192 mg of 2,4,6-trimethylbenzenesulfonyl chloride. After stirring for about 20 hours at a temperature in the region of 20° C., 95 mg of 2,4,6-trimethylbenzenesulfonyl chloride and 0.08 cm3 of triethylamine are added. After stirring for a further 3 hours at the same temperature, 95 mg of 2,4,6-trimethylbenzenesulfonyl chloride are added and the suspension is stirred for about 20 hours. After concentrating to dryness under reduced pressure (13 kPa), the residue is taken up in 50 cm3 of water and extracted with three times 40 cm3 of ethyl acetate. The organic phases are dried over magnesium sulfate, filtered and concentrated under reduced pressure. After flash chromatography on a column of silica [eluent: dichloromethane/methanol (95/5 by volume)], 134 mg of a resin are obtained, which resin is solidified in 7 cm3 of diisopropyl ether and 7 cm3 of diethyl ether. After filtration and drying under reduced pressure (13 kPa) over phosphorus pentoxide, 123 mg of 2-{[(2-methoxyethyl)carbamoyl]amino}-1H-benzimidazol-5-yl 2,4,6-trimethylbenzenesulfonate are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([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.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:72][C@@H:73]1[C:76](=[O:77])[NH:75][C@@H:74]1[CH2:78][N:79]1[CH:83]=[C:82]([CH2:84][NH:85][C:86](=[O:92])[O:87][C:88]([CH3:91])([CH3:90])[CH3:89])[N:81]=[N:80]1>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[C:88]([O:87][C:86]([NH:85][CH2:84][C:82]1[N:81]=[N:80][N:79]([CH2:78][C@@H:74]2[C@H:73]([NH:72][C:23](=[O:24])/[C:22](=[N:21]\[O:20][C:17]3([C:15]([O:14][CH:1]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:16])[CH2:19][CH2:18]3)/[C:26]3[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[S:29][CH:30]=3)[C:76](=[O:77])[NH:75]2)[CH:83]=1)=[O:92])([CH3:91])([CH3:89])[CH3:90]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Reactant: CC(C)(C)OC(=O)NCc1cn(C[C@H]2NC(=O)[C@H]2N)nn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCc1cn(C[C@H]2NC(=O)[C@H]2NC(=O)/C(=N\OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)c2csc(NC(=O)OC(C)(C)C)n2)nn1
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 80.7 %

Procedure:
To a slurry of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (1.32 g, 2.46 mmol) in DCM (12 mL) at 0° C. was added DIPEA (1.08 mL, 6.16 mmol) followed by HATU (0.984 g, 2.59 mmol). The reaction mixture was warmed to room temperature and tert-butyl ((1-(((2R,3S)-3-amino-4-oxoazetidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)methyl)carbamate (0.73 g, 2.5 mmol) was added as a solution in DCM:DMF (1.7:1, 9.6 mL). After stirring for 1.3 h, a color change from yellow to dark purple was observed, whereupon it was diluted with DCM, washed with water, brine, dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography (EtOAc-Heptane, 0-90%), affording the title compound (1.62 g, 81%) as a purple foam. LCMS: R=1.05 min, m/z=816.5 (M+1) Method 2m_acidic.
Reaction SMILES: Cl[C:2]([C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)([C:25]1[N:26]([CH3:30])[CH:27]=[N:28][CH:29]=1)[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[C:8](=[O:17])[CH:7]=[C:6]2[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1.C([O-])([O-])=O.[K+].[K+].[NH:44]1[CH:48]=[CH:47][N:46]=[N:45]1>CN(C=O)C.O>[Cl:24][C:20]1[CH:19]=[C:18]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:31]4[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=4)([C:25]4[N:26]([CH3:30])[CH:27]=[N:28][CH:29]=4)[N:45]4[N:46]=[CH:47][CH:48]=[N:44]4)[CH:4]=3)[N:9]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[C:8](=[O:17])[CH:7]=2)[CH:23]=[CH:22][CH:21]=1.[Cl:24][C:20]1[CH:19]=[C:18]([C:6]2[C:5]3[C:10](=[CH:11][CH:12]=[C:3]([C:2]([C:31]4[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=4)([C:25]4[N:26]([CH3:30])[CH:27]=[N:28][CH:29]=4)[N:44]4[CH:48]=[CH:47][N:46]=[N:45]4)[CH:4]=3)[N:9]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[C:8](=[O:17])[CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: c1c[nH]nn1
Reactant: Cn1cncc1C(Cl)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cncc1C(c1ccc(Cl)cc1)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1)n1ccnn1
Product: Cn1cncc1C(c1ccc(Cl)cc1)(c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2CC1CC1)n1nccn1
Temperature: 80 °C
Yield: 34 %
Yield: 9 %

Procedure:
A solution of 6-[Chloro-(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-methyl]-4-(3-chloro-phenyl)-1-cyclopropylmethyl-1H-quinolin-2-one (0.094 g, 0.17 mmol) in DMF (7 mL) was treated with K2CO3 (0.24 g, 0.17 mmol) and 1,2,3-triazole (0.061 mL, 1.03 mmol). The reaction mixture was heated at 80° C. for 12 hours, diluted with H2O (2 mL), and extracted with EtOAc (2 mL). The organic phase was washed with brine (2 mL), dried (MgSO4), filtered, and concentrated in vacuo to give a yellow oil. Purification by radio chromatography (silica, CH2Cl2:CH3OH:NH4OH 98:1.8:0.2) gave 4-(3-Chloro-phenyl)-6-[(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-2-yl-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (34 mg, 34%) and 4-(3-Chloro-phenyl)-6-[(4-chloro-phenyl)-(3-methyl-3H-imidazol-4-yl)-[1,2,3]triazol-1-yl-methyl]-1-cyclopropylmethyl-1H-quinolin-2-one (9.5 mg, 9%) as yellow oils.
Reaction SMILES: CN1C(=O)CC(CCC)=N1.ClC1C2C(=CC=CC=2)[N+]([O-])=CC=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]/[C:26](=[C:34]2/[C:35]([CH2:41][CH2:42][CH3:43])=[N:36][N:37]([CH3:40])[C:38]/2=[O:39])/[CH:25]=1.[C:44]([NH:47][C:48]1[CH:53]=[CH:52][C:51]([SH:54])=[CH:50][CH:49]=1)(=[O:46])[CH3:45]>C(OC(=O)C)(=O)C.C(O)C>[CH3:40][N:37]1[C:38](=[O:39])/[C:34](=[C:26]2\[NH:27][C:28]3[C:33]([C:24]([S:54][C:51]4[CH:50]=[CH:49][C:48]([NH:47][C:44](=[O:46])[CH3:45])=[CH:53][CH:52]=4)=[CH:25]\2)=[CH:32][CH:31]=[CH:30][CH:29]=3)/[C:35]([CH2:41][CH2:42][CH3:43])=[N:36]1
Reactant: CC(=O)Nc1ccc(S)cc1
Reactant: CCCC1=NN(C)C(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Agent: CCCC1=NN(C)C(=O)C1
Agent: [O-][n+]1ccc(Cl)c2ccccc21
Solvent: CC(=O)OC(C)=O
Solvent: CCO
Product: CCCC1=NN(C)C(=O)/C1=C1/C=C(Sc2ccc(NC(C)=O)cc2)c2ccccc2N1
Temperature: 180 °C

Procedure:
1-Methyl-3-n-propyl 2-pyrazolin-5-one (0.2 g, 1.4 mmol) and 4-chloroquinoline N-oxide (1.4 mmol) were stirred in acetic anhydride (2 mL) at ambient temperature for 2-3 hours. The reaction mixture was concentrated and carried out to the next step without further purification. The resulting (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-1-methyl-3-propyl-1H-pyrazol-5(4H)-one (0.71 mmol) was dissolved in ethanol (0.5 mL) and 4-acetamidothiophenol (0.13 g, 0.78 mmol) was added. The reaction mixture was heated to 180° C. using a microwave reactor for 5-10 minutes. The mixture was then concentrated and purified by LC-MS to give Example 56. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.67 (t, J=7.45 Hz, 3H) 1.23-1.32 (m, J=7.52, 7.52, 7.52, 7.52 Hz, 2H) 2.00 (t, J=7.58 Hz, 2H) 2.09 (s, 3H) 3.29 (s, 3H) 6.53 (s, 1H) 7.52-7.57 (m, 1H) 7.67-7.76 (m, 3H) 7.80-7.90 (m, 3H) 8.06 (d, J=8.08 Hz, 1H) 10.34 (s, 1H); ESI-MS: m/z calc'd for C24H24N4O2S 432.54. found 433.3 (M+H)+.
Reaction SMILES: [CH2:1]1[O:9][C:4]([CH2:7][CH3:8])([CH2:5]Br)[O:3][CH2:2]1.[I-:10].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:1]1[O:9][C:4]([CH2:7][CH2:8][I:10])([CH3:5])[O:3][CH2:2]1
Reactant: [I-]
Reactant: CCC1(CBr)OCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(CCI)OCCO1
Reaction time: 8 h
Yield: 94.2 %

Procedure:
A solution of 4 bromo-2-butanone ethylene ketal (16.4 mmol,3.2 g) in acetone (30 mL) was treated with sodium iodide (24 mmol, 3.7 g) and sodium carbonate (50 mmol, 5.1 g) and was reluxed overnight. The resulting mixture was filtered, washed with acetone (10 mL) and evaporated to dryness to a white solid. The residue was triturated with a mixture of 1:1 ether: pet ether (20 mL), stirred 30 min., filtered and evaporated to give 3.74 g (94%) of a pale yellow oil. LR-ES (C13H22O4): 243 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27].O>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: NCCCCO
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCO
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a stirred mixture of 4-chloro-3-nitroquinoline (100.0 g, 479 mmol) and triethylamine (72.8 g, 719 mmol) in dichloromethane (700 mL) was added dropwise 4-amino-1-butanol (42.7 g, 479 mmol). After the addition was complete, water (500 mL) was added to the reaction mixture to cause the product to precipitate. More water (2 L) was added, and the mixture was stirred overnight and then filtered. The organic solution was dried over sodium sulfate, concentrated under reduced pressure, and combined with the product isolated by filtration to provide 4-(3-nitroquinolin-4-ylamino)butan-1-ol (113 g) as a bright yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2=[N:14][C:15]3[N:16]([CH3:24])[C:17](=[O:23])[N:18]([CH3:22])[C:19](=[O:21])[C:20]=3[N:12]2[C:11]([OH:25])=[C:10]([CH2:26][CH2:27][CH3:28])[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:32])=[N-]>C(Cl)(Cl)Cl>[CH3:24][N:16]1[C:15]2[N:14]=[C:13]3[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:9](=[O:29])[C:10]([CH2:26][CH2:27][CH3:28])=[C:11]([O:25][CH3:32])[N:12]3[C:20]=2[C:19](=[O:21])[N:18]([CH3:22])[C:17]1=[O:23]
Reactant: C=[N+]=[N-]
Reactant: CCCc1c(O)n2c3c(=O)n(C)c(=O)n(C)c3nc2n(Cc2ccccc2)c1=O
Solvent: ClC(Cl)Cl
Product: CCCc1c(OC)n2c3c(=O)n(C)c(=O)n(C)c3nc2n(Cc2ccccc2)c1=O
Reaction time: 1.5 h

Procedure:
Dissolve 9-benzyl-1,3-dimethyl-6-hydroxy-7-(n-propyl)pyrimido[2,1-f]purine-2,4,8(1H,3H,9H)-trione (3 g.) in 200 ml chloroform at 0° and treat with an ethereal solution of diazomethane. Stir solution at 0° for 1.5 hours and destroy the excess diazomethane by the addition of acetic acid. Wash the chloroform solution with a solution of sodium bicarbonate and remove the chloroform under reduced pressure. Chromatograph the solid obtained on silica gel using 1% methanol in chloroform to give the title compound, m.p. 199°-201° C.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([CH3:11])[CH2:8][CH2:9][NH2:10].[C:18]1(=O)[O:23][C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12>>[C:18]1(=[O:23])[N:10]([CH2:9][CH2:8][CH:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[C:21](=[O:22])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12
Reactant: CC(CCN)c1ccccc1-c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Product: CC(CCN1C(=O)c2ccccc2C1=O)c1ccccc1-c1ccccc1

Procedure:
2.25 g of 3-p-biphenylyl-butylamine and 5 g of phthalic anhydride are heated at 120°for 90 minutes, cooled and worked up in the customary manner to give 1-phthalimido-3-p-biphenylyl-butane, m.p. 120°- 123°.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1.[NH2:10][CH2:11][C@@H:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>CN(C)C=O.C(N(C(C)C)CC)(C)C>[CH3:30][C:27]([O:26][C:24](=[O:25])[C@H:12]([CH2:11][NH:10][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[N:5]=[CH:4][N:3]=1)[NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])([CH3:28])[CH3:29]
Reactant: Cc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(Cl)ncnc1NC[C@H](NC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: 120 °C
Yield: 53.5 %

Procedure:
A mixture of 325 mg (2 mmoles) of 4,6-dichloro-5-methyl-pyrimidine (marketed by SPECS), 600 mg (2 mmoles) of (1,1-dimethylethyl) 3-amino-N-[(phenylmethoxy)carbonyl]alaninate (prepared according to J. Med. Chem. (2001), 44(8), 1158-1176) in 3 ml of dimethylformamide and 3 ml of diisopropylethylamine is heated at 120° C. overnight. The reaction medium is concentrated to dryness under vacuum and the residue is taken up in a mixture of water, ethyl acetate and a saturated solution of sodium bicarbonate. The organic phase is separated and the aqueous phase reextracted with ethyl acetate. The combined organic phases are dried over magnesium sulphate then the solvent is evaporated off under vacuum. The residue is chromatographed on silicagel eluting with a gradient of heptane (100%) to a mixture of heptane-ethyl acetate (50-50). 450 mg (Yield=53%) of expected product is obtained in the form of an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>C1CCCCC1.CCOC(C)=O>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=2)=[CH:13][CH:12]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: COc1ccc(B(O)O)cc1
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: COc1ccc(-c2ccc(=O)[nH]c2)cc1
Yield: 69.2 %

Procedure:
According to Scheme 5 Step 1: The title compound was prepared from 5-bromopyridin-2(1H)-one (1 eq, 17.2 mmol, 3.00 g, Example 1 Step 1) and 4-methoxyphenylboronic acid (1.5 eq, 25.9 mmol, 3.93 g) according to the procedure described for Example 2 Step 2. Reaction conditions: 4.5 hours at 120° C. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 70 g SiO2) using pure AcOEt then AcOEt/MeOH 95/5 as eluent to afford 5-(4-methoxyphenyl)-(1H)-pyridin-2-one (11.9 mmol, 2.40 g, 69%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: ClCCCOCc1ccccc1
Temperature: 0 °C
Yield: 97.9 %

Procedure:
In a 2 l flask, a mixture of 3-chloropropanol (56.7 g), benzyl bromide (102.6 g) and dry THF (600 ml) is stirred and cooled with ice/salt mixture. Potassium tert-butoxide (70 g) is added in portions (5-10 g), maintaining the internal temperature at about 0° C. After the mixture is stirred for 3 more hours at room temperature, the solvent is evaporated. Addition of 1N HCl (1 l), extraction with ether (1 l), and evaporation of solvent gives crude material (113.6 g), which is distilled under vacuum to give 1-chloro-3- benzyloxypropane (108.4 g) b.p.0.01 60°-80° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]([CH3:19])([NH2:18])[CH3:17])=[CH:11][CH:10]=[C:9]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:8]=2)([O-:3])=[O:2].C(N(CC)CC)C.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:17][C:16]([NH:18][CH:39]=[O:40])([CH3:19])[CH2:15][NH:14][C:13]1[C:12]2[C:7](=[CH:8][C:9]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:10][CH:11]=2)[N:6]=[CH:5][C:4]=1[N+:1]([O-:3])=[O:2].[CH2:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CC(C)(N)CNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1CCCCC1
Product: CC(C)(CNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12)NC=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of N1-(3-nitro-7-phenylquinolin-4-yl)-2-methylpropane-1,2-diamine (3.56 g, 10.6 mmol) in dichloromethane (100 mL) was cooled to 0° C. Triethylamine (3.0 mL, 21 mmol) and cyclohexanecarbonyl chloride (1.55 mL, 11.6 mmol) were sequentially added. The reaction was allowed to warm to ambient temperature and stirred for two hours. The reaction was washed sequentially with water (2×100 mL) and brine (100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 65:35 hexanes:ethyl acetate) to provide 3.33 g of cyclohexane N-[1,1-dimethyl-2-(3-nitro-7-phenylquinolin-4-ylamino)ethyl]carboxamide as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[N:20]1([CH2:26][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[N:20]1([CH2:26][C:27]2[CH:34]=[CH:33][C:30]([C:31]3[NH:1][C:2]4=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]5[C@@H:15]6[CH2:16][C@@H:12]([CH:13]=[CH:14]6)[C@@H:11]5[C:17]([NH2:19])=[O:18])=[C:7]4[N:8]=3)=[CH:29][CH:28]=2)[CH2:21][CH2:22][O:23][CH2:24][CH2:25]1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Product: NC(=O)[C@@H]1[C@H](Nc2ccnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Yield: 31.5 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 4-morpholin-4-ylmethyl-benzaldehyde (43.5 mg, 0.212 mmol) were reacted to produce 27 mg (32%) of the title compound. mp: 240-244° C., 1H NMR (300 MHz, DMSO-d6): 13.06 (s, 1H), 8.09 (d, J=8 Hz, 2H), 7.91 (d, 1H), 7.67 (s, 1H), 7.45 (d, J=8 Hz, 1H), 7.16 (s, 1H), 6.88 (m, 1H), 6.41 (d, J=8 Hz, 1H), 6.33 (s, 1H), 3.88 (br s, 1H), 3.59 (br s, 4H), 3.52 (s, 2H), 2.88 (s, 1H), 2.76 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.38 (s, 4H), 2.23 (d, J=8 Hz, 1H), 1.43 (d, J=8 Hz, 1H). MS: 445 (M+H), HPLC: 1.51 min (G method).
Reaction SMILES: [F:1][C:2]([F:5])(Br)Br.C(N(P(N(CC)CC)N(CC)CC)CC)C.[CH:22](/[CH:25]1[CH2:30][CH2:29][CH:28]([CH:31]2[CH2:36][CH2:35][CH:34]([CH:37]=O)[CH2:33][CH2:32]2)[CH2:27][CH2:26]1)=[CH:23]\[CH3:24].Cl>C1COCC1>[F:1][C:2]([F:5])=[CH:37][CH:34]1[CH2:35][CH2:36][CH:31]([CH:28]2[CH2:29][CH2:30][CH:25](/[CH:22]=[CH:23]/[CH3:24])[CH2:26][CH2:27]2)[CH2:32][CH2:33]1
Reactant: FC(F)(Br)Br
Reactant: C/C=C/C1CCC(C2CCC(C=O)CC2)CC1
Agent: CCN(CC)P(N(CC)CC)N(CC)CC
Agent: Cl
Solvent: C1CCOC1
Product: C/C=C/C1CCC(C2CCC(C=C(F)F)CC2)CC1

Procedure:
Difluorodibromomethane (29.9 g) was dissolved in THF (100 ml), and then a tris(diethylamino)phosphine (63.4 g) THF (20 ml) solution and an (E)-4′-(prop-1-en-1-yl)-[1,1′-bi(cyclohexane)]-4-carbaldehyde (20.0 g) THF (20 ml) solution were sequentially added dropwise in an ice bath under a nitrogen atmosphere. After completion of the reaction, 1 N hydrochloric acid was added, and extraction was carried out with toluene. An organic layer was washed with a saturated aqueous solution of sodium chloride, a saturated aqueous solution of sodium hydrogencarbonate and water, and then the resultant solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and thus a colorless oily matter was obtained. The resultant material was subjected to silica gel column chromatography (heptane) and recrystallization using Solmix A-11 (registered trademark) (Japan Alcohol Trading Co., Ltd.), and thus compound (1-B) was obtained as a white needle crystal (7.7 g).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]12([CH:23]([O:52][Si](C(C)(C)C)(C)C)[CH2:24][N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[C:40]([C:45]#[N:46])=[CH:41][CH:42]=[CH:43][CH:44]=5)=[CH:35][CH:34]=4)=[C:28]([CH2:47][CH2:48][CH2:49][CH3:50])[N:27]=[C:26]3[CH3:51])[CH2:22][CH:17]3[CH2:18][CH:19]([CH2:21][CH:15]([CH2:16]3)[CH2:14]1)[CH2:20]2>C(OCC)(=O)C>[C:13]12([CH:23]([OH:52])[CH2:24][N:25]3[C:30](=[O:31])[C:29]([CH2:32][C:33]4[CH:34]=[CH:35][C:36]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:45]5[NH:3][C:4](=[O:7])[O:5][N:46]=5)=[CH:37][CH:38]=4)=[C:28]([CH2:47][CH2:48][CH2:49][CH3:50])[N:27]=[C:26]3[CH3:51])[CH2:20][CH:19]3[CH2:21][CH:15]([CH2:16][CH:17]([CH2:18]3)[CH2:22]1)[CH2:14]2
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(CC(O[Si](C)(C)C(C)(C)C)C23CC4CC(CC(C4)C2)C3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(CC(O)C23CC4CC(CC(C4)C2)C3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 21.5 %

Procedure:
A mixture of hydroxylammonium chloride (0.90 g), sodium hydrogen carbonate (1.44 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for 30 min, 4′-{[1-(2-(1-adamantyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.56 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.17 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 3.9 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was extracted with 1 M hydrochloric acid and ethyl acetate, and the ethyl acetate layer was washed with saturated brine and concentrated. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.11 g, 24%).