Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([Cl:29])=[CH:28][C:22]=2[N:21]=1)[CH2:13][CH2:14][C:15]1[NH:19][N:18]=[N:17][N:16]=1)=O)C1C=CC=CC=1.I[Si](C)(C)C.CO>ClCCl>[Cl:29][C:27]1[CH:26]=[CH:25][C:23]2[NH:24][C:20]([C@@H:12]([NH2:11])[CH2:13][CH2:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)=[N:21][C:22]=2[CH:28]=1
Reactant: O=C(N[C@@H](CCc1nnn[nH]1)c1nc2cc(Cl)ccc2[nH]1)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CO
Product: N[C@@H](CCc1nnn[nH]1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2.10 g (4.45 mmol) (1S)—N-(benzyloxycarbonyl)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)-propylamine in 30 ml dichloromethane are combined with 1.9 ml (13.4 mmol) iodo-trimethylsilane and stirred for 16 hours at ambient temperature. Then 20 ml of methanol are added, the mixture is stirred for a further 30 minutes at ambient temperature and the reaction mixture is evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/(ethanol/conc. ammonia 95:5)=70/30→60:40).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10](O)=[O:11])=[CH:5][CH:4]=1.S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([Cl:16])=[O:11])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(C)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: COc1ccc(C(C)C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
Under an argon atmosphere, 2-(4-methoxyphenyl)propanoic acid (synthesized by the process of I. Shiina, et al., Eur. J. Org. Chem., 5887-5890 (2008)) (1.20 g, 6.66 mmol) was dissolved in thionyl chloride (6.00 mL, 82.6 mmol) and the solution was heated to reflux for 27 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give the crude product of 2-(4-methoxyphenyl)propanoyl chloride (16) as a colorless oil. The product was used in the following reaction without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14](O)[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([Br:18])[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrC(Br)(Br)Br
Reactant: CC(O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(Br)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 114.3 %

Procedure:
In dichloromethane (20 ml) was dissolved N-tert-butoxycarbonyl-4-(1-hydroxyethyl)piperidine (0.92 g). After addition of carbon tetrabromide, (1.62 g), triphenylphosphine (1.58 g) was slowly added under ice-cooling. The mixture was stirred at room temperature for 2 hours, at the end of which time the dichloromethane was distilled off. The residue was diluted with ethyl acetate and an aqueous solution of NaHCO3 and the insoluble matter was filtered off. The filtrate was extracted with ethyl acetate, washed with aqueous NaCl solution, dried over MgSO4, and concentrated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate =8:1) to provide the title compound as colorless oil (1.34 g). 1H-NMR (CDCl3) δ: 1.0-1.3(3H,m), 1.4;5(9H,s), 1.6-1.9(4H,m), 2.6-2.8(2H,brm), 3.45(2H,t,J=6.8Hz), 4.0-4.2(2H,brm).
Reaction SMILES: C([O:5][C:6](=[O:52])[CH:7]([CH:28]([C:30](=[O:51])[C@H:31]([CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])[NH:32][C:33](=[O:35])[CH3:34])[NH2:29])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C>FC(F)(F)C(O)=O.ClCCl>[C:33]([NH:32][C@H:31]([C:30]([CH:28]([NH2:29])[CH:7]([CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)[C:6]([OH:52])=[O:5])=[O:51])[CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])(=[O:35])[CH3:34]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)OC(C)(C)C)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(C(=O)O)C(N)C(=O)[C@H](CCCCNC(=O)OCc3ccccc3)NC(C)=O)CCCC2)CC1
Reaction time: 8 h

Procedure:
The t-butyl ester from Example 1 (571 mg, 0.783 mmol) was dissolved in a mixture of trifluoroacetic acid (2 ml) and dichloromethane (1 ml). The solution was kept at 4° C. overnight, then concentrated to dryness under vacuum, and the residue was azeotroped six times with dichloromethane. The resulting crude product was then taken up in ethyl acetate and washed with water until the washings were neutral. The organic phase was dried (MgSO4) and evaporated under vacuum to afford the title compound (442 mg, 84%) as a white foam. Found: C,61.89; H,7.76; N,7.93. C35H52N4O9 (0.5 H2O) requires C,61.65; H,7.69; N,8.22%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([CH:25]=[CH2:26])[CH:3]=1.C(Cl)Cl.[H][H]>CO.[OH-].[OH-].[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:14][CH2:13][CH2:12][NH:11][C:10]3[N:15]([CH3:24])[N:16]=[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)[C:9]2=3)=[C:4]([CH2:25][CH3:26])[CH:3]=1
Reactant: C=Cc1cc(Cl)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(Cl)ccc1C1SCCNc2c1c(-c1ccccn1)nn2C

Procedure:
A mixture of 4-(4-chloro-2-vinyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo-[3,4-e][1,4]thiazepine (0.100 g, 0.26 mmol, Preparation #18) and palladium hydroxide on carbon (0.073 g, 20 wt % on dry basis, ˜0.1 mmol), in methanol (5 mL) and DCM (2 mL) was treated with hydrogen (1 atm.), at rt, overnight. Then the mixture was filtered over diatomaceous earth and concentrated in vacuo. The residue was purified by prep-HPLC (Table 2, Method b) to give 4-(4-chloro-2-ethyl-phenyl)-1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepine as an off white solid: LC-MS (Table 1, Method a) Rt=4.03 min; m/z 385 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) δ 1.38 (3 H, t, J=7.5 Hz) 2.71 (1 H, ddd, J=15.1, 6.3, 2.7 Hz) 2.83 (1 H, ddd, J=15.1, 8.8, 2.8 Hz) 2.94 (1 H, dq, J=15.1, 7.5 Hz) 3.10 (1 H, dq, J=15.1, 7.5 Hz) 3.18-3.27 (1 H, m) 3.52-3.60 (1 H, m) 3.79 (1 H, br s) 3.84 (3 H, s) 6.78 (1 H, s) 6.99 (1 H, dd, J=8.4, 2.2 Hz) 7.07 (1 H, ddd, J=7.4, 4.9, 0.9 Hz) 7.13 (1 H, d, J=8.4 Hz) 7.20 (1 H, d, J=2.2 Hz) 7.59 (1 H, td, J=7.8, 1.7 Hz) 7.79 (1 H, dt, J=8.0, 0.9 Hz) 8.44 (1 H, ddd, J=4.8, 1.7, 0.9 Hz).
Reaction SMILES: N[C:2]([C:6]1[S:7][C:8]([Cl:11])=[CH:9][CH:10]=1)=[CH:3][C:4]#[N:5].Cl.C[OH:14]>>[Cl:11][C:8]1[S:7][C:6]([C:2](=[O:14])[CH2:3][C:4]#[N:5])=[CH:10][CH:9]=1
Reactant: CO
Reactant: N#CC=C(N)c1ccc(Cl)s1
Agent: Cl
Product: N#CCC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 9.2 g. portion of β-amino-5-chloro-2-thiopheneacrylonitrile is dissolved in 100 ml. of methanol. A 50 ml. portion of 1 N hydrochloric acid is added and the mixture is stirred at room temperature for 3 hours. The precipitate is collected giving 5-chloro-β-oxo-2-thiophenepropionitrile.
Reaction SMILES: [C:1]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([Li])CCC.C[Sn:22](Cl)(C)C.[Li]>O1CCCC1>[SnH3:22][SH:12]1[C:11]([C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:15][CH:14]=[CH:13]1
Reactant: CCCCCCCCC#Cc1cccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC#CC1=CC=C[SH]1[SnH3]
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 94 %

Procedure:
To a 1 L schlenk flask with egg-shaped stirbar in a glove box, the 2-decynylthiophene 22a (57.44 mmol, 12.658 g) was added by pipette. On a schlenk line, tetrahydrofuran (300 mL) was cannula transferred to the reaction vessel through a septum. The reaction mixture was cooled to −78° C. and n-butyl lithium (35.9 mL, 1.6 M solution in hexanes,) was added dropwise via syringe and the reaction mixture stirred for 45 min. The reaction vessel was fitted with an addition funnel and trimethyltin chloride (57.4 mL, 1.0 M solution in tetrahydrofuran) was cannula transferred to the funnel under positive argon pressure through a septum. The trimethyltin chloride solution was added dropwise to the stirring lithium salt solution over a period of 15 min. at −78° C. The reaction mixture was allowed to warm to ambient temperature with stirring overnight. The solvent was removed in vacuo on the schlenk line and trapped in a 1 L schlenk flask. The resulting residue was dissolved in diethyl ether (500 mL) washed with brine (3×200 mL), dried over magnesium sulfate, filtered and the solvent removed by roto-evaporation to afford 1-stannyl-5-decynyl-thiophene 22b as a light brown oil (20.6 g, 94% yield). 1H NMR (CDCl3) δ 7.20 (d, 1H), 7.00 (d, 2H), 2.43 (t, 2H), 1.60 (m, 2H), 1.44 (m, 2H), 1.30 (m, 8H), 0.899 (t, 3H), 0.37 (s, 9H); GC/MS (M+) 384 m/z, (M+-CH3) 369 m/z.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:29]=[CH:30]/[O:31]C)[C:5]([O:27][CH3:28])=[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=3)=[N:11][N:12]=2)[CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C.O>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:21])[CH3:22])=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=3)=[N:11][N:12]=2)[C:5]([O:27][CH3:28])=[C:4]([CH2:29][CH:30]=[O:31])[CH:3]=1
Reactant: CO/C=C/c1cc(F)cc(-c2nnc(-c3ccc(OC(C)C)c(C(F)(F)F)c3)s2)c1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1c(CC=O)cc(F)cc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.1 %

Procedure:
To a solution of 2-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D34) (170 mg) and sodium iodide (109 mg) in acetonitrile (20 mL) stirred under nitrogen at room temperature was added TMSCl (0.093 mL) dropwise. The reaction mixture was stirred at room temperature for 10 min. Water was added. The aqueous solution was extracted with EA for 3 times. The organic phase was washed with saturated Na2S2O3 solution and saturated brine, dried over sodium sulphate and evaporated in vacuo to afford the crude product [5-fluoro-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(methyloxy)phenyl]acetaldehyde (D35) (170 mg) as a yellow oil. MS (ES): C21H18F4N2O3S requires 454. found 455.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7]([NH:10][CH3:11])(=[O:9])=[O:8].C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C1COCC1>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][S:7](=[O:9])(=[O:8])[NH:10][CH3:11])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: CNS(=O)(=O)CCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)CCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 10 h
Yield: 41 %

Procedure:
To a solution of 5-hydroxy-N-methylpentane-1-sulfonamide (Example 21; 6.4 mmol) and triethyl amine (19.2 mmol) in THF (15 ml) was added para toluenesulfonyl chloride (5.9 mmol) in THF (5 ml) at room temperature and the reaction mixture was stirred for 10 hours. The reaction mixture was washed by saturated NaHCO3 solution and then brine. The organic layer was dried over MgSO4, filtered off and concentrated. The residue was purified by flash column chromatography (SiO2; eluent: petroleum ether/ethyl acetate from 100/0 to 50/50) to give the pure title compound (0.9 gr; 41% yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1([C:39]2[CH:44]=[CH:43][C:42]([C:45](=[O:47])[CH3:46])=[CH:41][CH:40]=2)[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:36]1[CH2:37][CH2:38][N:33]([C:39]2[CH:40]=[CH:41][C:42]([C:45](=[O:47])[CH3:46])=[CH:43][CH:44]=2)[CH2:34][CH2:35]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: CC(=O)c1ccc(N2CCN(C(=O)[C@@H]3C[C@H](NCc4ccc(F)cc4F)CN3Cc3ccccc3)CC2)cc1
Yield: 8.1 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(4-piperazine-1-yl-phenyl)-ethanone instead of 2-piperazin-1-yl-benzonitrile, to the title compound (5.8 mg, 8.1%) as light yellow oil. MS m/e=559.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([O:18]CC=C)=[CH:14][C:11]=3[C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1.Cl[C:25]1[CH:30]=CC=C[C:26]=1Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH2:30][CH:25]=[CH2:26])[C:11]=3[C:12]=2[CH3:13])=[O:7])=[CH:22][CH:23]=1
Reactant: C=CCOc1ccc2oc(C(=O)c3ccc(F)cc3)c(C)c2c1
Reactant: Clc1ccccc1Cl
Product: C=CCc1c(O)ccc2oc(C(=O)c3ccc(F)cc3)c(C)c12
Yield: 76 %

Procedure:
A solution of 2-(p-fluorobenzoyl)-3-methyl-5-allyloxybenzofuran (2.77 gm; 9.2 mmoles) in ortho-dichlorobenzene (15 mL) was refluxed under nitrogen for a period of 4 hours. On cooling, the reaction product crystallized. Some hexane was added and the crystals were filtered, washed with hexane and air-dried to yield 2.1 gm (76%) of 2-(p-fluorobenzoyl)-3-methyl-4-allyl-5-hydroxybenzofuran, mp. 164°-166° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][N:12]1[CH:17]2[CH2:18][CH2:19][CH:13]1[CH2:14][CH:15]([NH2:20])[CH2:16]2.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[C:25]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[N:24][N:23]=1>>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26]([C:25]([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)=[N:24][N:23]=[C:22]2[NH:20][CH:15]2[CH2:16][CH:17]3[N:12]([CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH:13]([CH2:19][CH2:18]3)[CH2:14]2)=[CH:27][CH:28]=1
Reactant: COc1ccc(-c2nnc(Cl)c3cc(OC)ccc23)cc1
Reactant: NC1CC2CCC(C1)N2Cc1ccc2ccccc2c1
Product: COc1ccc(-c2nnc(NC3CC4CCC(C3)N4Cc3ccc4ccccc4c3)c3cc(OC)ccc23)cc1

Procedure:
This compound is obtained according to the procedure described in 1.4. by reacting N-[8-(naphthalen-2-ylmethyl)-8-azabicyclo[3.2.1]oct-3-yl]amine and 1-chloro-7-methoxy-4-(4-methoxyphenyl)phthalazine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11]C.Br.C(O)(=O)C>O>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: COc1ccc([N+](=O)[O-])cc1C
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc([N+](=O)[O-])ccc1O

Procedure:
2-Methyl-4-nitroanisole (4.0 g)in 50 ml 1:1 hydrobromic acid:acetic acid is heated 12 hours at 120°. Solvent is stripped, the residue taken up in water and ethyl acetate, the mixture is filtered to remove insolubles, and the layers are separated. The organic phase is dried, filtered, and stripped to afford 2-methyl-4-nitrophenol. NMR (CDCl3): δ2.3 (3H,s), 6.8 (1H,d), 7.9 (1H,d of d), 8.0 (1H,d).
Reaction SMILES: [NH2:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12.[C:22](OC(=O)C)(=[O:24])C>C(O)=O>[CH:22]([NH:1][C@@H:2]1[C:20](=[O:21])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][O:10][C:11](=[O:16])[CH2:12][C:13](=[O:15])[CH3:14])[CH2:7][S:8][C@H:3]12)=[O:24]
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(=O)CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Reaction time: 1 h

Procedure:
In 60 ml of formic acid is dissolved 3.2 g of 7β-amino-3-(3-oxobutyryloxymethyl)-3-cephem-4-carboxylic acid and the solution is cooled to 0°-5° C. With stirring, 20 ml of acetic anhydride is added dropwise to the solution during 30 minutes. The mixture is stirred at the same temperature for 30 minutes and then at room temperature for 1 hour. The solvent is evaporated off under reduced pressure and the residue is dissolved in methyl ethyl ketone. The solution is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then evaporated off under reduced pressure and a diisopropylether-hexane mixture is added to the residue to bring about solidification. The solid is then collected by filtration to give 3.1 g of the above-identified compound as a light-yellow powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][C:20]([OH:22])=[O:21].[CH2:23](O)[CH2:24][CH3:25].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[CH3:11])[C:7](=[O:12])[N:6]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[CH:5]2[CH2:19][C:20]([O:22][CH2:23][CH2:24][CH3:25])=[O:21]
Reactant: Cc1cc2c(cc1C)C(CC(=O)O)N(c1cccnc1)C2=O
Reactant: CCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCCOC(=O)CC1c2cc(C)c(C)cc2C(=O)N1c1cccnc1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
To a solution of 5,6-dimethyl-3-carboxymethyl-2-(3-pyridyl)isoindolin-1-one [IUPAC name: 2-[5,6-dimethyl-3-oxo-2-(3-pyridinyl)-2,3-dihydro-1H-isoindol-1-yl]acetic acid] (74 mg, 0.25 mmol), n-propyl alcohol (16 mg, 0.27 mmol) and 4-dimethylaminopyridine (3 mg, 0.025 mmol) in dichloromethane was added 1-ethyl-3-(3-dimethylamino-propyl)carbodiimide hydrochloride (53 mg, 0.27 mmol) at 5° C. and the temperature was raised to 25° C. over a period of 1.5 hrs. The reaction solution was concentrated under reduced pressure, and water was added to the residue, followed by extracting with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution, successively water, dried, and concentrated under reduced pressure to give 34 mg of the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]([CH3:9])[CH3:8])[NH:4][N:3]=1.[C:10]1([CH:16]([C:22](OCC)=[O:23])[C:17](OCC)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(N(CCCC)CCCC)CCC.[OH-].[Na+]>[CH:7]([C:5]1[N:6]=[C:2]2[N:1]=[C:17]([OH:18])[C:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:22]([OH:23])[N:3]2[N:4]=1)([CH3:9])[CH3:8]
Reactant: CC(C)c1nc(N)n[nH]1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)c1nc2nc(O)c(-c3ccccc3)c(O)n2n1
Reaction time: 0.5 h

Procedure:
A solution of 5.00 g 3-amino-5-isopropyl-1,2,4-triazol and 11.24 g diethyl phenylmalonate in 18 ml N,N-dibutylbutan-1-amine is stirred at 185° C. over night. The solution is diluted with 20% w/w NaOH solution, the resulting mixture is stirred for 30 min. The aqueous layer is washed with diethylether, acidified at 0° C. with concentrated HCl until precipition of the product is complete. The precipitate is collected by filtration to yield the product, which is used without further purification.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]#[C:9]Br.[OH-].[Na+]>>[N:1]1([C:9]#[N:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCCNCC1
Reactant: N#CBr
Agent: [Na+]
Agent: [OH-]
Product: N#CN1CCCCCC1

Procedure:
In the manner given in Example 1, hexahydroazepine is treated with cyanogen bromide and aqueous sodium hydroxide to give 1-hexahydroazepinecarbonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The above ester (3.45 g, 16 mM) was dissolved in THF (100 ml), treated with 1M NaOH (25 ml), and stirred at ambient temperature for 5 hours. After removal of the solvent, the residue was treated with water (50 ml), acidified with 2H sulfuric acid, and extracted with ethyl acetate (3×60 ml). The combined organic extracts were washed with aqueous NaH2PO4, brine, and dried over MgSO4. Evaporation gave 3-methoxy-5-nitrobenzoic acid, which was allylated essentially as in Example 1, except that the chromatographic purification used a mixture of petrol/ethyl acetate (6:1), to give allyl 3-methoxy-5-nitrobenzoate. Nmr (CDCl3): δ 3.95 (s, 3H); 4.87 (dt, 2H); 5.31-5.48 (m, 2H); 5.95-6.15 (m, 1H); 7.89 (t, 1H); 7.92 (t, 1H); 8.46 (t, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[BH4-].[Na+].O>C(O)C>[OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([CH2:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1
Reactant: NC(=O)CC1CCC(=O)c2sccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)CC1CCC(O)c2sccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
Twenty-seven g (0.129 M) of 4,5,6,7-Tetrahydro-7-oxobenzo[b]thien-4-ylacetamide is dissolved in absolute ethanol (270 ml) and treated with sodium borohydride (4.9 g, 0.129 M). The mixture is stirred at room temperature overnight, water (250 ml) is added and stirring continued for 2 hours. The bulk of the ethanol is evaporated and the precipitated solid is filtered off, washed twice with water (total 50 ml) and air dried to afford the title compound (13.73 g, 50.4% yield) as an off white solid, m.p. 175° C. to 179° C. dec.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7]2.[C:20](Cl)(Cl)=[O:21].CN>C1COCC1>[O:21]=[C:20]1[N:10]2[C:11]3[C:6]([CH2:7][CH:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:9]2)=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1]1
Reactant: O=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NC1CNc2c(N)cccc2C1
Agent: CN
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1Cc2cccc3[nH]c(=O)n(c23)C1
Reaction time: 0.08 h

Procedure:
t-Butyl (8-amino-1,2,3,4-tetrahydro-3-quinolyl)carbamate (2.70 g) was dissolved in THF (100 mL) and stirred while a solution of phosgene in THF (20.7 mL of 0.40 M, 0.093 mol) was added. After 5 minutes, methylamine (2.08 g, 0.020 mol) was added and the solution stirred for an additional 10 minutes. The THF was removed under reduced pressure and the material was partitioned between chloroform (250 mL) and water (20 nil,). The chloroform was washed with 4N sodium hydroxide (5 mL) and evaporated. The crude material was combined with that of an earlier reaction (0.002 mol scale) and purified by chromatography on silica gel in 1% methanol: chloroform to give 2.28 g of product. Crystallization from methanol:ether (1:1) gave 1.60 g (54%) white solid, mp 235°-36° C. Anal. Calc'd for C15H19N3O3 : C, 62.26; H, 6.62; N, 14.52. Found: C, 61.65; H, 6.94; N, 14.23.