Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:37]([O:39][CH3:40])=[O:38])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][C@@H:16](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[N:46]([Si](C)(C)C)=[N+:47]=[N-:48]>>[N:46]([C@@H:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:37]([O:39][CH3:40])=[O:38])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)=[N+:47]=[N-:48]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@H](OS(=O)(=O)c1ccc(C)cc1)COc1ccccc1-3
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N=[N+]=[N-])COc1ccccc1-3
Temperature: 65 °C
Reaction time: 20 h
Yield: 84 %

Procedure:
To a solution of the foregoing product from step 1 in dry THF (0.06 M) azidotrimethylsilane (3.5 eq.) and tetrabutylammonium triphenyldifluorosilicate (3.5 eq.) were added. The reaction was stirred for 20 h at 65° C. then 1 more eq. of azidotrimethylsilane was added and the mixture stirred at 65° C. for 36 h. The volatiles were evaporated in vacuo and the crude dissolved in EtOAc was washed with hydrochloric acid (1 N), sodium hydrogen carbonate (saturated solutions) and brine. Drying over Na2SO4, filtration and concentration in vacuo gave the crude product, which was purified by flash chromatography on silica gel (5:95 EtOAc/PE) to afford the title compound as white foam (84%); MS (ES+) m/z 431 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:49]=[CH:48][C:11]([CH2:12][C:13]3[N:14]([C:26]4[CH:27]=[C:28]([N:32]5[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]5)[CH:29]=[CH:30][CH:31]=4)[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[N:17]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.NC(N)=[S:52]>C(O)C.O.CCOC(C)=O>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:16]1[N:17]=[C:13]([CH2:12][C:11]2[CH:48]=[CH:49][C:8]([C:5]3[N:6]=[N:7][C:2]([SH:52])=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:14]([C:26]2[CH:27]=[C:28]([N:32]3[S:36](=[O:38])(=[O:37])[N:35]([CH2:39][O:40][CH2:41][CH2:42][Si:43]([CH3:46])([CH3:45])[CH3:44])[C:34](=[O:47])[CH2:33]3)[CH:29]=[CH:30][CH:31]=2)[CH:15]=1
Reactant: NC(N)=S
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Cl)nn4)cc3)c2)S1(=O)=O
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2cccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(S)nn4)cc3)c2)S1(=O)=O

Procedure:
5-{3-[2-[4-(6-Chloro-pyridazin-3-yl)-benzyl]-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one (76 mg, 0.1 mmol) was dissolved in 1 mL dry ethanol. Thiourea (76 mg, 1 mmol) was added and the mixture was refluxed under nitrogen over night. At completion, the reaction mixture was then diluted with water/EtOAc. The combined organic layer was washed with water, and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give 5-(3-{4-(2,4-dichloro-phenyl)-2-[4-(6-mercapto-pyridazin-3-yl)-benzyl]-imidazol-1-yl}-phenyl)-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one, which was then treated as described in general procedure K using 1-bromo-2-cyclohexylethane (79 μL, 0.5 mmol) to give 5-{3-[2-{-4-[6-(2-cyclohexyl-ethylsulfanyl)-pyridazin-3-yl]-benzyl}-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-3-one.
Reaction SMILES: Br[CH2:2][CH:3]=[O:4].[CH3:5][CH:6]([NH2:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O>[CH3:5][CH:6]([NH:12][CH2:2][CH:3]=[O:4])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)CCC(C)N
Reactant: O=CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)CCC(C)NCC=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
The diethylacetal of 2-bromoacetaldehyde (40 grams) and 1,4-dimethylpentylamine (50 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at a temperature of about 100° C. for a period of about 3 hours. After this time sodium hydroxide (10 grams) dissolved in water (100 ml) was added and the resulting mixture stirred for about 30 minutes. The reaction mixture was then extracted with ether. The ether extract was separated, dried over magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product the diethylacetal of 2-(1,4-dimethylpentylamino)acetaldehyde having a boiling point of 95° C. at 1 mm of Hg pressure.
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[N:10]1([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[N:11]1
Reactant: c1cnc2cn[nH]c2c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ncc2ncccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Tert-butyl bromoacetate (0.55 mL, 3.69 mmol) was added to 1H-pyrazolo[4,3-b]pyridine (220 mg, 1.85 mmol) and Cs2CO3 (723 mg, 2.22 mmol) in anhydrous DMF (7 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (3×30 mL), brine (30 mL), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography on silica gel (hexane:EtOAc 80:20) to afford a colourless gum in 51% yield, 220 mg.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][CH:11]=1>C1COCC1>[OH:17][CH:16]([C:13]1[CH:12]=[CH:11][C:10]([C:9]([O:8][CH3:7])=[O:18])=[CH:15][CH:14]=1)[CH2:1][CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)CC(C)C)cc1
Temperature: -40 °C

Procedure:
In a 22 L reactor methyl-4-formylbenzoate (500 g) is dissolved in THF (5 L). The solution is cooled to −40° C., and isobutylmagnesium bromide (2.0 M in Et2O, 1.67 L) is added by addition funnel, maintaining the internal temperature less than −20° C. The reaction is followed by HPLC and when the amount of methyl-4-formylbenzoate is found to be less than 1%, the reaction is quenched with MeOH (148 mL) while maintaining the internal temp below 2° C. The reaction is charged with 5 M HCl (700 mL) while maintaining the internal temp below 10° C. Transfer the resultant biphasic mixture to a 12 L With bottom valve, rinsing with 300 mL of heptane. The resulting layers are separated and the organic layer is washed with 1 M HCl (500 mL). The aqueous layers are combined and extracted with tert-butyl methyl ether (500 mL). The combined organic extracts are concentrated in vacuo. The resulting residue is diluted with heptane (800 mL) and concentrated in vacuo to dry the material azeotropically. The resulting oil is purified by silica gel chromatography to give 246.3 g (37%) of the desired carbinol as a yellow oil that solidifies on standing in the refrigerator to a white waxy solid. 1H NMR (500 MHz, CDCl3): δ 8.0 (d, 2H), 7.4 (d, 2H), 4.8 (dd, 1H), 3.9 (s, 3H), 1.85 (s, 1H), 1.71 (m, 2H), 1.48 (m, 1H), 0.95 (d, 6H).
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([CH3:24])([CH3:23])[CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])=O)(C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C.CO[C:45]([C:51]1[CH:56]=[CH:55][C:54](C)=[CH:53][CH:52]=1)=[C:46]([C:49]#[N:50])[C:47]#[N:48]>C(#N)C.C(O)C>[CH2:16]([O:15][C:13](=[O:14])[NH:12][CH2:11][C:10]([N:9]1[C:49]([NH2:50])=[C:46]([C:47]#[N:48])[C:45]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)=[N:8]1)([CH3:24])[CH3:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=C(C#N)C#N)c1ccc(C)cc1
Reactant: CC(C)(CNC(=O)OCc1ccccc1)NNC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(CNC(=O)OCc1ccccc1)n1nc(-c2ccccc2)c(C#N)c1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 1B (310 mg, 0.92 mmol) was dissolved in 1 mL of dry acetonitrile. Tosic acid (875 mg, 4.6 mmol) was dissolved in 3 mL of dry acetonitrile. Molecular sieves were added to both solutions and stood for 30 minutes. The solution of tosic acid was then added the other mixture and the reaction was stirred at room temperature for 3 hours. After that time the reaction was filtered and the solid washed with acetonitrile and CH2Cl2). The filtrate was concentrated to afford a thick colourless oil. It was dissolved in 2 mL of ethanol. Triethylamine (640 μL, 1.48 mmol) and 2-(Methoxy-p-tolyl-methylene)-malononitrile (182 mg, 0.92 mmol) were successively added. The reaction was then heated at 60° C. for 3 hours. After cooling down, the reaction was concentrated. Water and EtOAc were then added and the aqueous phase was extracted three times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The oily residue obtained was purified by flash chromatography on SiO2 using 100% CH2Cl2 then CH2Cl2/MeOH 99:1. A colourless oil that solidifies slowly overnight was obtained (m=270 mg, 73%). NMR (ppm, CDCl3): δ 1.58 (s, 6H), 2.36 (s, 3H), 3.77 (d, J=6.63 Hz, 2H), 4.40 (br s, 2H), 5.08 (s, 2H), 5.59 (br t, J=5.94 Hz, 1H), 7.20 (d, J=8.55 Hz, 2H), 7.31 (m, 5H), 7.74 (d, J=8.13 Hz, 2H). 13C NMR (ppm, CDCl3): δ 21.35, 24.18, 50.56, 63.17, 66.99, 76.34, 115.22, 126.09, 128.15, 128.22, 128.33, 128.55, 129.42, 136.34, 139.11, 149.13, 151.57, 156.96. LCMS (+esi): 404.3 (M+H+).
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[C:16]([NH:26][C@H:27]([C:31]([OH:33])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O[CH2:35][CH2:36][CH2:37][C:38]([CH3:52])([CH3:51])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)=[O:40]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:16]([NH:26][C@H:27]([C:31]([O:33][CH2:35][CH2:36][CH2:37][C:38]([CH3:51])([CH3:52])[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=1)=[O:40])=[O:32])[CH:28]([CH3:29])[CH3:30])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)C(C)(C)CCCO)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C(C)(C)CCCOC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)cc1
Reaction time: 1 h
Yield: 71.8 %

Procedure:
To a mixture of DCC (9.41 g, 46 mmol), DMAP (0.586 g, 4.8 mmol) and N-CBz-L-valine (12.1 g, 48 mmol) in CH2Cl2 (200 mL) at 0° C., was added dropwise a solution of 4-methoxybenzyl 5-hydroxy-2,2-dimethyl-valerate (6.40 g, 24 mmol) in CH2Cl2 (50 mL). After 1 h at 0° C., the temperature of the reaction mixture was allowed to assume room temperature and then the mixture was stirred for 5h at room temperature. The mixture was filtered through a glass filter and the solvent was removed under reduced pressure. The crude product was column chromatographed (silica gel, 1→4% MeOH in CH2Cl2), to give 8.61 g 4-methoxybenzyl 5-(N-CBz-L-valyloxy)-2,2-dimethylvalerate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14](OC)=[O:15])[CH2:10][O:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.O>[CH2:12]([O:11][CH2:10][CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:14][OH:15])[CH3:13]
Reactant: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOCC(CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl N-(tert-butoxycarbonyl)-O-ethylserinate (2.7 g, 10.9 mmol) in THF (40 mL) was added lithium aluminum hydride (0.84 g, 22 mmol) at 0° C. The reaction mixture was allowed to warm to ambient temperature. After 1 hour, the reaction mixture was diluted with water, filtered, and concentrated under reduced pressure to give tert-butyl (1-ethoxy-3-hydroxypropan-2-yl)carbamate which was used without further purification. MS ESI calc'd. for C10H22NO4 [M+H]+ 220. found 220. 1H NMR (400 MHz, CDCl3) δ 5.21 (s, 1H), 3.78-3.59 (m, 3H), 3.58-3.56 (m, 2H), 3.52-3.45 (m, 2H), 1.44 (s, 9H), 1.18 (t, J=6.8 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[N+:18]([O-])=O.CN(C=O)C.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29]>CCCCCC>[NH2:18][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:9]=1[O:8][CH3:7])[C:13]([NH:29][C:28]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:27]=1[F:26])=[O:15]
Reactant: Nc1ccc(F)cc1F
Reactant: COc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(C(=O)Nc2ccc(F)cc2F)cc1N
Yield: 86 %

Procedure:
Prepared according to the procedure described for Example 1 using oxalyl chloride (3.0 mL, 34.39 mmol), 4-methoxy-3-nitrobenzoic acid (5.00 g, 25.36 mmol), DMF (1.0 mL, 12.92 mmol), and 2,4-difluoroaniline (5.2 mL, 51.07 mmol) to afford the product (6.07 g), m.p. 166-168° C. after trituration in hexane.
Reaction SMILES: [CH2:1]([CH:8]([C:20]1[N:24](CC2C=CC(OC)=CC=2)[N:23]=[N:22][N:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>O>[CH2:1]([CH:8]([C:20]1[NH:24][N:23]=[N:22][N:21]=1)[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Cn2nnnc2C(CC(=O)c2ccc(Cl)c(Cl)c2)Cc2ccccc2)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC(Cc1ccccc1)c1nnn[nH]1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
5-[1-benzyl-3-(3,4-dichlorophenyl)-3-oxo-propyl]-1(4-methoxybenzyl)-1H-tetrazole (1.6 g, 3.3 mmol), from the previous step) and TFA (20 ml) were mixed and stirred at room temperature under nitrogen atmosphere for 40 hours. The mixture was diluted with water (100 ml) and extracted with methylene chloride (3×200 ml). The organic layers were combined, washed with water (2×100 ml), brine (1×100 ml) and dried over anhydrous sodium sulphate. The solvent was removed under vacuum and the residue was flash chromatographed by using cyclohexane/ethyl acetate 0÷20 as eluent. The title compound was obtained as a colourless solid (0.6 g, 50%) (m.p. 172°-174° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH3:22])=[C:15]([O:18][CH2:19][CH3:20])[CH:16]=3)[CH:11]=[C:10]([CH2:23][OH:24])[C:9]=2[CH2:25][OH:26])[CH:5]=[CH:4][N:3]=1.O.O.[NH2:29][NH2:30]>>[NH:29]([C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([O:21][CH3:22])=[C:15]([O:18][CH2:19][CH3:20])[CH:16]=3)[CH:11]=[C:10]([CH2:23][OH:24])[C:9]=2[CH2:25][OH:26])[CH:5]=[CH:4][N:3]=1)[NH2:30]
Reactant: CCOc1cc2c(-c3ccnc(Cl)c3)c(CO)c(CO)cc2cc1OC
Reactant: NN
Solvent: O
Product: CCOc1cc2c(-c3ccnc(NN)c3)c(CO)c(CO)cc2cc1OC
Temperature: 25 °C

Procedure:
A suspension of 1-(2-chloro-4-pyridyl)-2,3-bis(hydroxymethyl)-6-methoxy-7-ethoxynaphthalene (16.0 g) in hydrazine hydrate (50 ml) is refluxed for four hours. The mixture is cooled to room temperature, and then thereto is added water. The precipitated crystals are collected by filtration, washed with water, and dried to give 1-(2-hydrazino-4-pyridyl)-2,3-bis(hydroxymethyl)-6-methoxy-7-ethoxynaphthalene (14.5 g).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].S(=O)(=O)(O)O.[CH3:25]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:25])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCBr
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCCCCCCCCCBr

Procedure:
A mixture of 22 g. of 16-bromohexadecanoic acid and 200 ml. of methanol is treated with 1.0 ml. of concentrated sulfuric acid and stirred under reflux for 24 hours. The mixture is treated with 10 g. of sodium acetate and the solvent is evaporated. The residue is partially soluble in 300 ml. of ether and the mixture is filtered. The ether solution is dried over magnesium sulfate and evaporated. The residue is crystallized from petroleum ether to yield methyl 16-bromohexadecanoate as a white solid.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[CH2:5].Cl[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(=O)(O)(O)O.C=CC1C=CC=CC=1>>[CH3:11][CH:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:2]=2)[CH2:5]1
Reactant: C=Cc1ccccc1Cl
Reactant: ClCCc1ccccc1
Agent: O=P(O)(O)O
Solvent: C=Cc1ccccc1
Product: CC1CC(c2ccccc2)c2ccccc21

Procedure:
A mixture of 115 parts of o-chlorostyrene and 35 parts of o-chloroethylbenzene is added to 652 parts of 89 per cent strength by weight aqueous phosphoric acid at 40° to 45° C whilst stirring vigorously. A mixture of 90 parts of styrene, 115 parts of o-chlorostyrene and 35 parts of o-chloroethylbenzene is added to the resulting emulsion at a temperature of 40° to 45° C over 5 hours. After completion of the addition, the mixture is stirred for a further 2 hours at 40° to 45° C. The organic phase is separated off, washed with 200 parts of 3 per cent strength by weight sodium hydroxide solution and fractionated. 24.9 parts of 1-methyl-3-phenylindan (b.p. 145° to 146° C (10 mm)), 63.1 parts of 1-methyl-3-(o-chloro)-phenylindan (b.p. 165° to 168° C (10 mm), nD25 : 1.5890) and 31 parts of 1-methyl-3-(o-chloro)-phenyl-7-chloroindan (b.p. 195° to 200° C (10 mm)) are isolated.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]([NH:23][CH3:24])=[O:22])=[CH:13][C:12]2=[O:25])[CH2:5][CH2:4]1.C([BH3-])#N.[Na+].[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[CH3:39])[CH:34]=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.CO>[F:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][C:38]=1[CH3:39])[CH2:34][NH:2][CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][N:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([C:21]([NH:23][CH3:24])=[O:22])=[CH:13][C:12]2=[O:25])[CH2:5][CH2:4]1
Reactant: Cc1ccc(C=O)cc1F
Reactant: CNC(=O)c1cc(=O)n(CCN2CCC(N)CC2)c2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CNC(=O)c1cc(=O)n(CCN2CCC(NCc3ccc(C)c(F)c3)CC2)c2ccccc12
Reaction time: 3 h

Procedure:
To 3.0 mL of methanol suspension containing 0.12 g of 1-(2-(4-aminopiperidin-1-yl)ethyl)-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide hydrochloride, 38 mg of sodium cyanoborohydride, 37 μL of 3-fluoro-4-methylbenzaldehyde and 69 μL of acetic acid were added at room temperature and stirred at the same temperature for 3 hours. Chloroform and aqueous saturated sodium hydrogen carbonate solution were added to be adjusted to pH 10, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [gradient elution of chloroform:methanol=100:0-70:30], to give 26 mg of 1-(2-(4-((3-fluoro-4-methylbenzyl)amino)piperidin-1-yl)ethyl)-N-methyl-2-oxo-1,2-dihydroquinoline-4-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11](=[O:13])[CH:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])[O:14][CH3:15])=[CH:20][CH:19]=1)#[N:16]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COc1ccc(F)c(C(OC)C(=O)O)c1
Product: COc1ccc(F)c(C(OC)C(=O)NCc2ccc(C#N)cc2)c1

Procedure:
(RS)-(2-Fluoro-5-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-5-methoxy-phenyl)-2-methoxy-acetamide. Colorless gum.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:32]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCCCCCNCCCCCC
Solvent: CN(C)C=O
Product: CCCCCCN(CCCCCC)Cc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2c(Cl)cccc2-3)no1
Yield: 56.5 %

Procedure:
1.13 g (3 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one were stirred at room temperature overnight with 1.7 g (9 mmol) of dihexylamine and 15 ml of N,N-dimethylformamide. By evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate there was obtained 0.89 g (56%) of (S)-8-chloro-1-(5-dihexylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride (amorphous).
Reaction SMILES: CC1C=CC=CC=1C(O)=O.C(OCC)(=O)C.CCCCCC.[Si]([O:30][C:31]1[CH:32]=[C:33]([O:62][Si](C(C)(C)C)(C)C)[C:34]2[CH2:45][S:44][CH2:43][C@@H:42]([C:46]([O:48][CH3:49])=[O:47])[NH:41][C:40](=[O:50])[C@@H:39]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:38][O:37][C:36](=[O:59])[C:35]=2[C:60]=1[CH3:61])(C(C)(C)C)(C)C.[F-].[NH4+]>CO>[OH:30][C:31]1[CH:32]=[C:33]([OH:62])[C:34]2[CH2:45][S:44][CH2:43][C@@H:42]([C:46]([O:48][CH3:49])=[O:47])[NH:41][C:40](=[O:50])[C@@H:39]([NH:51][C:52]([O:54][C:55]([CH3:56])([CH3:57])[CH3:58])=[O:53])[CH2:38][O:37][C:36](=[O:59])[C:35]=2[C:60]=1[CH3:61]
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Agent: Cc1ccccc1C(=O)O
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CSCc2c(O)cc(O)c(C)c2C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3,5-Bis (tert-butyldimethylsilyloxy)-6-[[[(R)-2-[(S)-1-tertbutoxyformamido)-3-hydroxypropionylamino]-2-methoxycarbonylethyl]thio]methyl]-2-methylbenzoic acid was lactonized in analogous manner to the procedure described in Example 1 to afford, upon chromatographic purification on silica gel using ethyl acetate/hexane (1: 3, v/v) as eluent, tert-butyl (4R, 7S)-12,14-bis (tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-4-methoxycarbonyl-11-methyl-6, 10-dioxo-9, 2,5-benzooxathiaazacyclododecine-7-carbamate as a pale yellow foam. To a solution of 21.4 g of this material in 300 ml of methanol were added 3.3 g of ammonium fluoride, and the mixture was stirred for 30 minutes at room temperature. The solvent was evaporated in vacuo. The residue chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent, and the purified product was crystallized from ethyl acetate/hexane to afford 11.0 g of tert-butyl (4R,7S)-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-4-methoxycarbonyl-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate.