Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28](=[O:41])(=[O:40])[NH:29]C(OCC5C=CC=CC=5)=O)=[CH:26][C:20]=4[S:19](=[O:43])(=[O:42])[N:18]=3)[C:7]2=[O:44])[CH2:4][CH2:3][CH2:2]1>O1CCCC1.CO.[Pd]>[CH:1]1([NH:5][N:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([OH:16])=[C:8]([C:17]3[NH:22][C:21]4[CH:23]=[CH:24][C:25]([NH:27][S:28]([NH2:29])(=[O:40])=[O:41])=[CH:26][C:20]=4[S:19](=[O:42])(=[O:43])[N:18]=3)[C:7]2=[O:44])[CH2:2][CH2:3][CH2:4]1
Reactant: O=C(NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3ccccc3n(NC3CCC3)c1=O)N2
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.6 %

Procedure:
A solution of the product of Example 465 (0.790 g, 1.2 mmol) in tetrahydrofuran (80 mL) and methanol (20 mL) was treated with 10% palladium on carbon (200 mg) and stirred for 24 hours at 25° C. under a hydrogen atmosphere. The reaction was filtered through Celite® (diatomaceous earth) and the filtrate concentrated under reduced pressure to provide the title compound (0.500 g, 83% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.58 (m, 1 H) 1.67 (m, 1 H) 2.03 (m, 4 H) 3.78 (m, 1 H) 6.56 (s, 1 H) 7.39 (s, 2 H) 7.44 (t, J=7.54 Hz, 1 H) 7.52 (m, 1 H) 7.64 (m, 2 H) 7.89 (t, J=7.91 Hz, 1 H) 8.07 (d, J=8.82 Hz, 1 H) 8.17 (d, J=8.46 Hz, 1 H) 10.06 (s, 1 H) 14.09 (s, 1 H) 15.14(s, 1 H). MS (ESI−) m/z 503 (M−H)−.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:19]=O.Cl.Cl.[CH:27]([CH:40]1[CH2:45][NH:44][CH2:43][CH2:42][N:41]1[CH3:46])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O>[CH:27]([CH:40]1[CH2:45][N:44]([CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[O:16][CH3:15])[CH2:43][CH2:42][N:41]1[CH3:46])([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccccc1C=O
Reactant: CN1CCNCC1C(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1CN1CCN(C)C(C(c2ccccc2)c2ccccc2)C1
Yield: 73.8 %

Procedure:
A 1M solution of sodium triacetoxyborohydride in N,N-dimethylformamide (75 μl) was added portionwise to a mixture of 2-methoxybenzaldehyde (7.5 mg) and a solution of 2-benzhydryl-1-methylpiperazine dihydrochloride (17.0 mg) in N,N-dimethylformamide (50 μl) at 0° C. and the whole was stirred at 0° C. to 5° C. for 1 hour and further at 5° C. to room temperature for 1 hour. The mixture was extracted with aqueous 0.25N sulfuric acid solution and washed with ethyl acetate. The combined solution was applied on solid phase extraction column cartridge (C18, 200 mg) and eluted with water and acetonitrile successively. The eluate was concentrated in vacuo to give 2-benzhydryl-4-(2-methoxybenzyl)-1-methylpiperazine (14.3 mg).
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([C:11]([O:13]C)=[O:12])=[N:9][CH:10]=1)([F:4])[CH3:3].O.O.[OH-].[Li+]>O1CCOCC1>[F:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1)([F:4])[CH3:3]
Reactant: COC(=O)c1cnc(C(C)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(F)(F)c1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.7 %

Procedure:
Methyl 5-(1,1-difluoroethyl)pyrazine-2-carboxylate (0.65 g, approx. purity 85%) was dissolved in dioxan (2 mL) and water (2 mL) was added, followed by lithium hydroxide monohydrate (54 mg, portionwise). After stirring at RT for 90 mins, the mixture was concentrated to 2 mL and Et2O (20 mL) added. The mixture was then extracted with NaOH (1 N, aq., 20 mL), and the aqueous portions acidified with 6N HCl to pH 2. The aqueous portion was then extracted with EtOAc, dried over MgSO4 and evaporated to afford the title compound as a white solid (119 mg). 1H NMR (400 MHz, CDCl3) δ ppm 2.11 (t, J=18.8 Hz, 3H), 9.01 (d, J=1.3 Hz, 1H), 9.47 (d, J=1.3 Hz, 1H)
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([O:8]C(=O)C)[CH3:7])(=[O:3])[CH3:2].[C:12](OC)(=[O:14])C>CO>[C:1]([O:4][CH3:5])(=[O:3])[CH3:2].[CH3:12][OH:14].[CH2:5]([OH:4])[CH:6]([OH:8])[CH3:7]
Reactant: CC(=O)OCC(C)OC(C)=O
Solvent: COC(C)=O
Solvent: CO
Product: CC(O)CO
Temperature: 62 °C

Procedure:
A suspension is prepared from 800 parts of 1,2-diacetoxypropane, 960 parts of methanol and 176 parts of cation exchanger (®Lewatit SPC 108) in a stirred reactor, provided with a distillation unit, by stirring at 300 rpm, and the mixture is heated at 62° C. (The exchange resin is a sulfonated styrene/divinylbenzene copolymer resin; it has a macro-porous structure and a particle size of from 0.3 to 15 mm). 910 parts of the azeotropic mixture of methanol and methyl acetate, of boiling point 54° C., are distilled off in the course of 4 hours. The ion exchanger is then filtered off. Distillation gives 470 parts of a methyl acetate/methanol mixture and 376 parts of 1,2-propanediol.
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][C:21](=[CH:23][C:24]#[N:25])[CH2:20]1)([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.[NH:26]1[CH:30]=[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]3[N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:38]=[CH:39][C:32]=23)[CH:28]=[N:27]1.C(#N)C.N12CCCN=C1CCCCC2>>[Si:1]([O:18][CH:19]1[CH2:22][C:21]([CH2:23][C:24]#[N:25])([N:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]4[N:37]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:38]=[CH:39][C:32]=34)[CH:28]=[N:27]2)[CH2:20]1)([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:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Reactant: CC(C)(C)[Si](OC1CC(=CC#N)C1)(c1ccccc1)c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)[Si](OC1CC(CC#N)(n2cc(-c3ccnc4c3ccn4COCC[Si](C)(C)C)cn2)C1)(c1ccccc1)c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of (3-{[tert-butyl(diphenyl)silyl]oxy}cyclobutylidene)acetonitrile (4.0 g, 8.7 mmol, from Step 4 of Example 1a) and 4-(1H-pyrazol-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine (1.50 g, 4.77 mmol, US 20090181959) in acetonitrile (10 mL, 200 mmol) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.68 mL, 4.6 mmol). The reaction was stirred overnight. A further portion of 1,8-diazabicyclo[5.4.0]undec-7-ene (0.7 mL, 5 mmol) was added and the reaction was allowed to continue for an additional 72 hours. Acetonitrile was removed in vacuo. Flash chromatography on silica gel, eluting with 0%-30% EtOAc/Hexanes, was used to purify product, which was obtained as a mixture of diastereomers (2 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.33 (d, J=5.0 Hz, 1H major), 8.29 (d, J=5.0 Hz, 1H minor), 8.06 (s, 1H major), 8.03 (s, 1H major), 8.00 (s, 1H minor), 7.93 (s, 1H minor), 7.70-7.31 (m, 10H major and 10H minor), 7.19 (d, J=5.0 Hz, 1H major), 7.11 (d, J=5.0 Hz, 1H minor), 6.74 (d, J=3.6 Hz, 1H major), 6.63 (d, J=3.7 Hz, 1H minor), 5.71 (s, 2H major), 5.69 (s, 2H minor), 4.49-4.39 (m, 1H minor), 4.33 (tt, J=7.0, 7.0 Hz, 1H major), 3.67-3.45 (m, 2H major and 2H minor), 3.22 (s, 2H minor), 3.11-2.95 (m, 2H minor), 2.92-2.77 (m, 6H major), 2.65-2.50 (m, 2H minor), 1.08 (s, 9H minor), 1.03 (s, 9H major), 0.98-0.80 (m, 2H major and 2H minor), −0.06 (s, 9H major), −0.08 (s, 9H minor); LCMS (M+H)+: 662.1.
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[OH:11])[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C)C=O>[S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[O:11][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:4][CH2:3][CH2:2]1
Reactant: Oc1cccc2c1SCCC2
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc2c1SCCC2
Temperature: 60 °C
Yield: 98.1 %

Procedure:
Under argon and with stirring, 1.5 g (9.02 mmol) of 8-thiochromanol are dissolved in 5 cm3 of dimethylformamide (DMF). 3.74 g (27.06 mmol) of K2CO3 are added and then 1.94 g (9.92 mmol) of ethyl 4-bromobutyrate dissolved in 6 cm3 of DMF are added dropwise. The mixture is heated at 60° C. for 5 hours. The DMF is evaporated off. The residue is taken up in H2O. The product is extracted with CH2Cl2 and then dried over MgSO4. Purification over a silica column (eluant: ether/petroleum ether 3: 7) yields 2.48 g of the title compound (white solid).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:45])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][C:35]([OH:37])=[O:36])[N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:18])[CH3:17]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[C:25]([CH3:45])=[C:26]4[C:31](=[CH:32][CH:33]=3)[CH:30]([CH2:34][C:35]([OH:37])=[O:36])[NH:29][CH2:28][CH2:27]4)[N:20]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH:16]([CH3:17])[CH3:18]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(Cl)c3)n2)ccc2c1CCNC2CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Trifluoroacetic acid (1.0 ml, 13.0 mmol) was added dropwise at 25° C. under nitrogen to a solution of (6-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl)acetic acid (Preparation 22; 75 mg, 0.138 mmol) in dichloromethane (3 ml) and the mixture was stirred at room temperature for 1 h. The solvent was removed in vacuo and the residue co-evaporated with toluene, dried for 20 min under vacuum then triturated with diethyl ether to give a pale brown solid (45 mg). Purification by MDAP gave the title compound (8.2 mg) as a white solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([O:31]CC)=O)=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([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.[CH:43]([NH2:46])([CH3:45])[CH3:44]>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([NH:46][CH:43]([CH3:45])[CH3:44])=[O:31])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:15])([CH3:16])[CH3:17])([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
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reactant: CC(C)N
Product: CC(C)NC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and isopropylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:11][S-:12].[Na+].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:12][CH3:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: C[S-]
Reactant: N#Cc1cc(Cl)ccc1F
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(Cl)cc1C#N
Yield: 96.6 %

Procedure:
(Step 1) A mixture of 5-chloro-2-fluorobenzonitrile (5.0 g) and sodium methanethiolate (2.48 g) was stirred in N,N-dimethylformamide (20 ml) at 60° C. for 1 hr. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give 5-chloro-2-(methylsulfanyl)benzonitrile (5.7 g).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:27][CH2:26][CH:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:31][C:32]([NH2:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:42][S:43](Cl)(=[O:45])=[O:44].C(=O)(O)[O-].[Na+]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:23][CH2:24][CH:25]([CH2:28][CH2:29][O:30][S:43]([CH3:42])(=[O:45])=[O:44])[CH2:26][CH2:27]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:31][C:32]([NH2:34])=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCC(CCO)CC3)cc2)cc1NCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)OCCC1CCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Reaction time: 2 h
Yield: 62.7 %

Procedure:
60 mg of 4-(benzylamino)-6-({4-[4-(2-hydroxyethyl)piperidin-1-yl]phenyl}amino)pyridine-3-carboxyamide (the compound of Example 57), 18 mg of triethylamine and 2 mg of 4-dimethylaminopyridine were dissolved in 5 mL of tetrahydrofuran, to which 18 mg of methanesulfonyl chloride was added under ice cooling, and stirred at the same temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to the reaction mixture, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:methanol=5:1) to obtain 44 mg (62%) of the title compound as a light brown crystalline powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18]>Cl>[CH2:20]([O:19][C:17]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)=[O:18])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)Nc1ccc(C(=O)O)cc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
A mixture composed of 4-aminobenzoic acid (10 g), 1N aqueous sodium bicarbonate solution (365 cc) and ethyl chloroformate (7 cc) is left stirring for 30 minutes at 5° C. 2.5N hydrochloric acid (150 cc) is then added to the reaction mixture. The precipitate formed is separated by filtration, washed with water (3×200 cc) and dried at 40° C. under reduced pressure (0.07 kPa). 4-(Ethoxycarbonylamino)benzoic acid (13.8 g), m.p. 207° C., is obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:2].C([O-])(=O)C.[Na+].[Br:20]Br>CC(O)=O>[Br:20][CH:1]([C:3]1[C:4](=[O:14])[N:5]([CH3:13])[C:6]2[C:11]([N:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:2]
Reactant: BrBr
Reactant: CCc1nc2ccccc2n(C)c1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(Br)c1nc2ccccc2n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of a 3-ethyl-1-methyl-1H-quinoxalin-2-one (1 g) and anhydrous sodium acetate (0.523 g) in glacial AcOH (10 mL) was added dropwise over 10 min. a solution of bromine (0.273 mL) in glacial AcOH (6 mL). The resulting pale yellow suspension was stirred at rt under nitrogen for 2 h, cooled to 0° C., filtered and washed with cold-water to give the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[CH2:13][CH:14]([N:17]=C(C1C=CC=CC=1)C1C=CC=CC=1)[C:15]#[N:16])[CH2:2][CH:3]=[CH2:4].Cl>C1COCC1.O>[NH2:17][CH:14]([CH2:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[O:5][CH2:1][CH2:2][CH:3]=[CH2:4])[C:15]#[N:16]
Reactant: C=CCCOc1ccc(F)cc1CC(C#N)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C=CCCOc1ccc(F)cc1CC(N)C#N
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a solution of 3-(2-(but-3-en-1-yloxy)-5-fluorophenyl)-2-((diphenylmethylene)amino)propanenitrile (1.39 g, 3.49 mmol, 1 equiv) in THF (14 mL) was added 1 N HCl (3.84 mL, 3.84 mmol, 1.1 equiv). After 3 h, the reaction was diluted with water and washed with ether. The aqueous layer was then neutralized with 1 N NaOH and extracted with DCM (×3). The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to provide the product (0.60 g, 73%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.00-6.92 (m, 2H), 6.85-6.77 (m, 1H), 5.90 (ddt, J=17.1, 10.2, 6.8 Hz, 1H), 5.20 (dd, J=17.1, 1.5 Hz, 1H), 5.15 (d, J=11.0 Hz, 1H), 4.12 (t, J=7.3 Hz, 1H), 4.03 (t, J=6.3 Hz, 2H), 3.05 (d, J=7.3 Hz, 2H), 2.57 (q, J=6.5 Hz, 2H), 2.19 (br. s., 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([CH:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]3=C=O)[NH:16]OC(C3CC3)C)[C@H:4]2[S:3]1.CCOCC>C(O)=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:11](=[O:32])[CH:12]([NH:13][C:14](=[O:31])[CH:15]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH2:16])[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(NOC(C)C3CC3)C3C=CC=CC3=C=O)[C@H]2S1
Solvent: CCOCC
Solvent: O=CO
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(N)c3ccccc3)[C@H]2S1
Reaction time: 1.5 h
Yield: 74.7 %

Procedure:
A solution of 2-methyl-7-[N-(1-cyclopropylethoxy)-carbonyl-2-phenylglycyl]amino-3-cephem-4-caboxylic acid (2.0 g) in formic acid (10 ml) was stirred for 2.5 hours at room temperature. After the reaction was completed, ether (30 ml) was added to the reaction mixture, and the supernatent was removed three times by decantation. Colorless powder was collected by filtration and washed with ether. Thus obtained powder was suspended in a mixture of acetonitrile (15 ml) and water (1 ml), and the suspension was stirred for 1.5 hours under ice-cooling. The precipitate was collected by filtration and dried to give 2-methyl-7-(2-phenylglycyl)amino-3-cephem-4-carboxylic acid (1.13 g), mp 168.5° to 171° C.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]2[N:6]=[C:7]([NH:10][C@H:11]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH2:13][CH2:12]3)[O:8][CH2:9][C:4]=2[CH:3]=1.[C-:22]#[N:23].O>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C@H:11]1([NH:10][C:7]2[O:8][CH2:9][C:4]3[CH:3]=[C:2]([C:22]#[N:23])[CH:21]=[CH:20][C:5]=3[N:6]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1
Reactant: [C-]#N
Reactant: Brc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)COC(N[C@@H]1CCc3ccccc31)=N2
Temperature: 160 °C
Yield: 41.1 %

Procedure:
A stirred mixture of (6-bromo-4H-benzo[d][1,3]oxazin-2-yl)-(R)-indan-1-yl-amine (Example 32) (2.0 g, 5.83 mmol), zink cyanide (1.03 mg, 8.77 mmol) and tetrakis-(triphenylphosphine)-palladium (673 mg, 0.58 mmol) in N,N-dimethylformamide (20 ml) was heated at 160° C. for 15 min in a microwave reactor. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2×70 ml). The combined organic layers were washed with brine (2×20 ml), dried (magnesium sulfate) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as light yellow foam (693 mg, 41%). MS (ISN): m/e=288.2 (M−H−).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH2:4][C:5]([OH:11])([CH3:10])[CH2:6][CH2:7][CH2:8][CH3:9].N1C=CN=C1.CN(C)C=O.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>CCCCCC>[I:1]/[CH:2]=[CH:3]/[CH2:4][C:5]([CH3:10])([O:11][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: C[Si](C)(C)Cl
Reactant: CCCCC(C)(O)C/C=C/I
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCC(C)(C/C=C/I)O[Si](C)(C)C
Reaction time: 8 h

Procedure:
To a stirred mixture of 24.5 g (55.6 mmoles) of 1-iodo-4-hydroxy-4-methyl-trans-1-octene (Example 130), 13.6 g (200 mmoles) of imidazole, and 75 ml of dimethylformamide is added 10.9 g (100 moles) of chlorotrimethylsilane. After standing overnight the mixture is poured into 250 ml of hexane. The mixture is washed thoroughly with water followed by brine and dried over magnesium sulfate. After removal of the solvent, the product is distilled to give a colorless liquid, bp 67.5°-68° C. (0.07 mm).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH2:36])=[N+:2]=[N-:3].[Cl:37][C:38]1[CH:39]=[C:40]2[C:45](=[C:46]([Cl:48])[CH:47]=1)[CH2:44][N:43]([CH3:49])[CH2:42][CH:41]2[C:50]1[CH:51]=[C:52]([S:56](Cl)(=[O:58])=[O:57])[CH:53]=[CH:54][CH:55]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH:36][S:56]([C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([CH:41]2[C:40]3[C:45](=[C:46]([Cl:48])[CH:47]=[C:38]([Cl:37])[CH:39]=3)[CH2:44][N:43]([CH3:49])[CH2:42]2)[CH:51]=1)(=[O:58])=[O:57])=[N+:2]=[N-:3]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Reactant: [N-]=[N+]=NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCN=[N+]=[N-])c2)C1
Reaction time: 1 h
Yield: 99.7 %

Procedure:
A solution of 32-azido-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontan-1-amine (436.9 mg, 0.777 mmol) in dry DMF (3.5 mL) under N2 was cooled to 0° C. A solution of 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (300 mg, 0.706 mmol) and DIEA (273.2 mg, 2.118 mmol) in DMF (3 mL) was added dropwise. After 60 minutes LCMS indicated complete conversion and the solvent was removed to give N-(32-azido-3,6,9,12,15,18,21,24,27,30-decaoxadotriacontyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (620 mg) as a yellow oil which was used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([O:11][C:12](=[O:23])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21]Cl)[CH:16]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:16]=1)=[O:23])([CH3:10])([CH3:9])[CH3:8]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CCl)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(CN2CCOCC2)c1

Procedure:
Morpholine (2.3 ml) was added to a solution of (3-chloromethyl-benzyl)-carbamic acid tert-butyl ester (Intermediate 5, 1.7 g) in THF (20 ml) and the mixture heated at reflux under nitrogen for 6 hours. Concentration of the reaction under vacuum gave N-tert-butyloxycarbonyl-3-(4-morpholinylmethyl)benzylamine (1.94 g).
Reaction SMILES: [Na].[CH3:2][O:3][CH2:4][CH2:5][OH:6].F[C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1.Cl>O>[CH3:2][O:3][CH2:4][CH2:5][O:6][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:18])[NH:13][CH:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: O=c1[nH]cnc2cc(F)ccc12
Reactant: COCCO
Agent: Cl
Agent: [Na]
Solvent: O
Product: COCCOc1ccc2c(=O)[nH]cnc2c1
Yield: 58 %

Procedure:
Sodium (400 mg, 17 mmol) was added carefully to 2-methoxyethanol (10 ml) and the mixture heated at reflux for 30 minutes. 7-Fluoro-3,4-dihydroquinazolin-4-one (750 mg, 4.57 mmol) was added to the resulting solution and the mixture heated at reflux for 15 hours. The mixture was cooled and poured into water (250 ml). The mixture was acidified to pH4 with concentrated hydrochloric acid. The resulting solid product was collected by filtration, washed with water and then with ether, and dried under vacuum to give 7-(2-methoxyethoxy)-3,4-dihydroquinazolin4-one (580 mg, 58%).