Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[NH:2]1[C:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[CH2:7][CH2:6][C:5]=2[C:4]([CH2:15][N+:16]([CH3:19])([CH3:18])C)=[N:3]1.[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[N:30]1[CH2:35]CNC[CH2:31]1.C(N(C(C)C)CC)(C)C.O>CN(C=O)C>[N:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[N:30]1[CH2:35][CH2:18][N:16]([CH2:15][C:4]2[C:5]3[CH2:6][CH2:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[C:10]=3[NH:2][N:3]=2)[CH2:19][CH2:31]1
Reactant: C[N+](C)(C)Cc1n[nH]c2c1CCc1ccccc1-2
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)CCc1c(CN3CCN(c4ccc5ccccc5n4)CC3)n[nH]c1-2

Procedure:
A solution of (4,5-dihydro-1H-benzo[g]indazol-3-ylmethyl)-trimethylammonium iodide (0.4 g), 1-(quinolin-2-yl)piperazine (0.23 g) and diisopropylethylamine (0.30 cm3) in DMF (10 cm3) was heated under argon at 80° C. for 48 hours. The mixture was cooled, poured into water (50 cm3) and extracted with 10% ethyl acetate-diethyl ether (2×25 cm3). The extracts were dried (MgSO4), filtered and concentrated. Flash column chromatography on silica gel, eluting with 5% methanol-dichloromethane+1% ammonia, removed baseline material. Preparative thin layer chromatography on silica, eluting with 3% methanol-dichloromethane+1% ammonia, gave the title compound, which was crystallised as the oxalate salt from ethanol to give brown granules (0.026 g; 5%), m.p. 154°-155° C. (from EtOH); Found: C, 64.6; H, 5.5; N, 13.7. C25H25N5.1.25(CO2 H)2.0.15(H2O) requires C, 64.7; H, 5.5; N, 13.7%. δH (360 MHz; d6 -DMSO) 2.73 (2H, t, J 7.7, --CH2 --), 2.84 (4H, broad s, 2 x NCH2CH2N), 2.90 (2H, t, J 7.7, --CH2 --), 3.79 (4H, broad s, 2 x NCH2CH2N) 7.18-7.30 (5H, m, 5 of ArH), 7.51-7.59 (2H, m, 2 of ArH), 7.65 (1H, d, J 7.6, 1 of ArH), 7.71 (1H, d, J 7.9, 1 of ArH) and 8.06 (1H, d, J 9.2, 1 of ArH); m/z (CI+ ; NH3) 396 (MH+ ; 40%) and 214 (100).
Reaction SMILES: [Cl-:1].[Cl-].[CH3:3][Zr:4]([CH3:26])(=[SiH2:25])([CH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[C:16]1[CH3:24])[CH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:14].[H][H]>ClCCl.[Pt]=O>[Cl-:1].[Cl-:1].[CH3:26][Zr:4]([CH3:3])(=[SiH2:25])([CH:5]1[C:13]2[CH:8]([CH2:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][CH:6]1[CH3:14])[CH:15]1[C:23]2[CH:18]([CH2:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH:16]1[CH3:24]
Reactant: CC1=Cc2ccccc2C1[Zr](C)(C)(=[SiH2])C1C(C)=Cc2ccccc21
Reactant: [H][H]
Agent: O=[Pt]
Agent: [Cl-]
Solvent: ClCCl
Product: CC1CC2CC=CC=C2C1[Zr](C)(C)(=[SiH2])C1C2=CC=CCC2CC1C
Reaction time: 8 h

Procedure:
A 0.5 g portion of dimethylsilylenebis(2-methylindenyl)zirconium dichloride obtained in Example 1 was dissolved in 250 ml of dichloromethane and introduced into a 1.0 liter autoclave, and 0.5 g of platinum oxide was then introduced. Hydrogen pressure was increased to 50 kg/cm2 ·G to carry out hydrogenation at 30° C. for 4 hours. After the reaction was completed, the slurry was filtered to separate the platinum catalyst, and the solvent was removed by distillation. The product was dissolved in 200 ml of toluene, and the solution was concentrated into about 50 ml, which was left standing overnight at -20° C. to form crystals. The crystals formed were filtered, and desiccated to give 0.22 g of the title product.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH:12][C:13](=[O:31])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([B:22]4[O:26]C(C)(C)C(C)(C)[O:23]4)=[CH:18][CH:17]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]>N#N>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([NH:12][C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([B:22]([OH:23])[OH:26])=[CH:18][CH:17]=3)=[O:31])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: CC1(C)OB(c2ccc(COC(=O)Nc3ccc4nc(C#N)sc4c3)cc2)OC1(C)C
Agent: N#N
Product: N#Cc1nc2ccc(NC(=O)OCc3ccc(B(O)O)cc3)cc2s1
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Compound 9 (61 mg, 0.14 mmol, 1 equiv.) was dissolved in N2-sparged tetrahydrofuran (THF, 10 mL) prior to addition of concentrated HCl (0.8 mL) and N2-sparged deionized water (8 mL). The reaction mixture was stirred for one hour prior to the addition of an additional 8 mL DI H2O. After 15 min, the THF was removed under vacuum, and the precipitate that formed was collected via filtration and rinsed with DI H2O. To remove residual starting material, the crude product was precipitated from diethyl ether to yield 49 mg (73%) of a white powder. 1H NMR (400 MHz, d6-Acetone): δ5.27 (2H, s), 7.22 (2H, s), 7.45 (2H, d, J=8.0 Hz), 7.80 (1H, dd, J=9.4, 2.2 Hz), 7.92 (2H, d, J=8.4 Hz), 8.17 (1H, d, J=9.6 Hz), 8.63 (1H, d, J=2.0 Hz).
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[Li].[Na].[C:7]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:8][C:9]([CH3:11])=[O:10]>O1CCCC1>[CH2:14]([O:13][C:7](=[O:12])[CH2:8][C:9](=[O:10])[CH2:11][CH:1]([OH:4])[CH:2]=[CH2:3])[CH3:15]
Reactant: CCOC(=O)CC(C)=O
Reactant: C=CCO
Agent: [Li]
Agent: [Na]
Solvent: C1CCOC1
Product: C=CC(O)CC(=O)CC(=O)OCC

Procedure:
The allyl alcohol, 8, is reoxidized to the aldehyde, 9, by Swern oxidation, followed by an aldol condensation to the sodium lithium dianion of ethyl acetoacetate at -78° C. in tetrahydrofuran. (See Kraus, et al, J. Org. Chem., 48: 2111 (1983)) to form the 5-hydroxy-3-oxo-6-heptenoic acid-ethyl ester, 10.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])O.N>CCOCC.[Zn].C(#N)C.CCOC(C)=O.CCCCCC.CO.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([NH2:2])=[C:4]([CH2:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH:5]=1
Reactant: Nc1ccc(Cl)cc1C(O)c1ccccc1F
Agent: Cl
Agent: N
Agent: [Zn]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Nc1ccc(Cl)cc1Cc1ccccc1F
Reaction time: 1 h

Procedure:
In a 5 l. three-necked flask fitted with stirrer, reflux condenser and thermometer is placed 2.5 l. of 6 N hydrochloric acid. It is heated to 50°-75° C. and 300-340 g of crude 2-amino-5-chloro- α-(2-fluorophenyl)benzenemethanol from the first example is added to the stirred acid. A dark oil may form. 400-425 g of zinc dust is added in portions with continued heating during 15-20 min. The temperature should be 90°-100° C. The addition of the zinc dust is mildly exothermic. The reaction mixture is then stirred and heated under reflux for 1 hr. TLC(10% MeOH/CHCl3) of an aliquot basified with ammonia and extracted with ether should show little or no starting material and a faster spot due to product. Only traces of zinc should remain. The reaction is cooled in an ice bath with stirring to 5°-10° C. A granular yellowish precipitate forms. This precipitate is collected in a sintered glass funnel and transferred to a 4 l separatory funnel. It is dissolved in 1.5 l. of ether and 500 ml of water. Traces of zinc are ignored. If there is enough to clog the stop cock it may be necessary to filter if off. The mixture is made basic by addition of 300 ml of concentrated ammonium hydroxide. A white precipitate is formed in the aqueous layer and then redissolves. The aqueous layer is separated; the ether layer is washed with 500 ml of water, dried over potassium carbonate, and concentrated in vacuo to leave an orange oil. 250 ml of toluene is added and the solution reconcentrated in vacuo. It is dissolved in 400-500 ml of ether. Gaseous hydrogen chloride is bubbled into this solution, first at room temperature and then with cooling in an ice bath. The mixture becomes cloudy and then with swirling crystals form. When it appears to be saturated with HCl, the mixture is allowed to stand in an ice bath for 1 hr. The solid is collected to give crude product. TLC(10% MeOH/CHCl3, and 25% EtOAc/hexane) should indicate reasonable purity. An analytical sample, m.p. 175°-181° C., was prepared by recrystallization from acetonitrile.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH2:25])(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:14][O:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][S:22]([C:19]1[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=1)(=[O:24])=[O:23]
Reactant: COC(=O)CCCCCCCCCBr
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCNS(=O)(=O)c1ccc(Cl)cc1
Yield: 39.9 %

Procedure:
A mixture of methyl 10-bromodecanoate (1.5 g, 0.006 mol), 4-chlorobenzenesulphonamide (3.44 g, 0.018 mol), potassium carbonate (6.2 g, 0.045 mol) and dimethylformamide (50 ml) was heated at 100°-120° C. for 3 hours. After cooling, the inorganic material was removed by filtration. The filtrate was evaporated to dryness and the residue was extracted with dichloromethane. The residual oil obtained by evaporation was chromatographed on silica gel in petroleum ether (40°-60° C.) and the solid obtained on evaporation of the eluate was recrystallised (ether-pet. ether 40°-60°) to give the title compound (0.9 g, m.p. 68°-70° C.).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=1[C:11]#[N:12].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C1C=CN=CC=1)C.ClCCl>[C:20]([NH:12][CH2:11][C:10]1[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:9]=1[NH2:8])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Nc1ccc([N+](=O)[O-])cc1CNC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
Triethylamine (116 ml, 0.835 mol) and DMAP (2.0 g, 0.016 mol) are added to 2-amino-5-nitrobenzonitrile (68 g, 0.33 mol) in dichloromethane (1 litre). The mixture is cooled to +5° C., and benzoyl chloride (38.8 ml, 0.33 mol) in dichloromethane (50 ml) is added. The resulting mixture is stirred for 2 hours and then concentrated. The residue is taken up in 10/1 water/ethanol (550 ml) and the product is filtered off and recrystallized from isopropyl ether. Yield: 88.5 g (97%); IR (KBr): 3375, 3213, 1638, 1547, 1319 cm−1; 1H-NMR (d6-DMSO) 8.15 (m, 1H); 7.85 (m, 4H); 7.51 (m, 4H); 6.68 (m, 3H); 4.30 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:10][N:9]=[C:8]([C:11]([O:13]CC)=O)[CH:7]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1.O>C(O)C>[CH:16]1([NH:19][C:11]([C:8]2[CH:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)[O:10][N:9]=2)=[O:13])[CH2:18][CH2:17]1
Reactant: CCOC(=O)c1cc(-c2cccs2)on1
Reactant: NC1CC1
Solvent: O
Solvent: CCO
Product: O=C(NC1CC1)c1cc(-c2cccs2)on1
Temperature: 80 °C
Yield: 64 %

Procedure:
To a solution of ethyl 5-(thiophen-2-yl)isoxazole-3-carboxylate (220 mg, 1 mmol) in absolute ethanol (5 mL) was added cyclopropylamine (285 mg, 5 mmol). The reaction was sealed and heated to 80° C. for 24 hours. The reaction was allowed to cool to room temperature and water (1 mL) was added. The product was collected by vacuum filtration as a white crystalline solid (150 mg, 64% yield). δH (400 MHz, d6 DMSO): 8.85 (1H, d), 7.83 (1H, d), 7.76 (1H, d), 7.24 (1H, d), 7.18 (1H, s), 2.83 (1H, m), 0.58-0.71 (4H, m).
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:26])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][Mg]Br>C1COCC1>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]([OH:26])[CH3:31])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:28])([F:29])[F:30])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[Mg]Br
Reactant: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 99.6 %

Procedure:
To 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (Preparation 88A, 0.425 g, 1.036 mmol) in THF (5 mL), cooled to −50° C. was added methylmagnesium bromide (3.0M in diethyl ether) (0.380 mL, 1.139 mmol) over a period of 2 min. The contents were allowed to come to room temperature over a period of 30 min. The reaction mixture was re-cooled to −50° C. and 0.15 mL of methylmagnesium bromide was added and the contents allowed to come to room temperature over a period of 10 min. The reaction mixture was quenched by the slow addition of sat. aq ammonium chloride (3 mL) and extracted into EtOAc (2×15 mL). The EtOAc layer was dried over sodium sulfate and concentrated to yield 1-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethanol (0.44 g, 1.032 mmol, 100% yield) as a tan colored solid. LC/MS M+1=427.
Reaction SMILES: II.[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:50])[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:31]2[C:30]3[C:25](=[CH:26][C:27]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=3)[NH:24][C:23]=2[N:22]=[C:21]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]3([C:46]([F:49])([F:48])[F:47])[NH:45][NH:44]3)[CH:38]=2)[N:20]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C(N(CC)CC)C>C(Cl)Cl>[C:3]([O:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][N:14]([CH3:50])[CH2:15][CH2:16][CH2:17][NH:18][C:19]1[C:31]2[C:30]3[C:25](=[CH:26][C:27]([C:32]([O:34][CH3:35])=[O:33])=[CH:28][CH:29]=3)[NH:24][C:23]=2[N:22]=[C:21]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]3([C:46]([F:47])([F:48])[F:49])[N:44]=[N:45]3)[CH:38]=2)[N:20]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C4(C(F)(F)F)NN4)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Agent: II
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[nH]c1nc(Cc3cccc(C4(C(F)(F)F)N=N4)c3)nc(NCCCN(C)CCCNC(=O)OC(C)(C)C)c12
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
Iodine (27.8 mg, 0.110 mmol) was added to a 5 mL round-bottomed flask protected from light and pre-charged with methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(3-(trifluoromethyl)diaziridin-3-yl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (70 mg, 0.104 mmol) and triethylamine (43.6 μL, 0.313 mmol) in DCM (2 mL) to give a light yellow solution. After stirring at 20° C. for 15 minutes, the solvent was evaporated and the residue purified by flash chromatography to give methyl 4-((3-((3-((tert-butoxycarbonyl)amino)propyl)(methyl)amino)propyl)amino)-2-(3-(3-(trifluoromethyl)-3H-diazirin-3-yl)benzyl)-9H-pyrimido[4,5-b]indole-7-carboxylate (65 mg, 0.097 mmol, 93% yield) as a light yellow foam: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 9H) 1.53 (dt, J=13.8, 7.0 Hz, 2H) 1.70-1.82 (m, 2H) 2.15 (br. s., 3H) 2.24-2.34 (m, 2H) 2.34-2.42 (m, 2H) 2.87-2.98 (m, 2H) 3.55-3.66 (m, 2H) 3.88 (s, 3H) 4.10 (s, 2H) 6.76 (br. s., 1H) 7.14 (d, J=8.2 Hz, 1H) 7.27 (s, 1H) 7.43 (t, J=7.8 Hz, 1H) 7.49-7.58 (m, 2H) 7.83 (dd, J=8.2, 1.4 Hz, 1H) 7.99 (d, J=1.4 Hz, 1H) 8.27 (d, J=8.2 Hz, 1H) 12.06 (s, 1H); MS m/z 669.2 (M+H)+; HPLC 97.6% @ 220 nm and 97.3% @ 254 nm, RT=2.18 minutes.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:22])[CH2:18][CH:19]([CH3:21])[CH3:20])=[N:15][CH:16]=1)=O)(C)(C)C>O1CCOCC1.ClCCl>[NH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[O:22])[CH2:18][CH:19]([CH3:20])[CH3:21])=[N:15][CH:16]=1
Reactant: CC(C)CC(=O)c1ccc(CNC(=O)OC(C)(C)C)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)CC(=O)c1ccc(CN)cn1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
Add 4N hydrogen chloride in dioxane (0.5 mL) to a solution of 5-tert-butoxycarbonylaminomethyl-2-(3-methyl-butyryl)-pyridine (60 mg, 0.2 mmol) in anhydrous dichloromethane (2 mL) and stir the solution overnight. Concentrate in vacuo and partition the residue between saturated aqueous NaHCO3 and dichloromethane. Extract the aqueous phase with dichloromethane (2×15 mL) and EtOAc (2×15 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to obtain the title compound (37 mg, 95%) that was used without any further purification.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.Cl[C:23]([O:25][CH3:26])=[O:24]>C(Cl)Cl>[CH3:26][O:25][C:23]([N:12]1[CH2:11][CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([S:2][CH3:1])[CH:4]=2)[CH2:14][CH2:13]1)=[O:24]
Reactant: COC(=O)Cl
Reactant: CSc1cccc(C2=CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CC=C(c2cccc(SC)c2)CC1
Temperature: 0 °C

Procedure:
4-(3-Methylsulfanyl-phenyl)-1,2,3,6-tetrahydropyridine (2 g) and NEt3 (1 g) were dissolved in CH2Cl2 (75 ml) and cooled to 0° C. Methyl chloroformate (0.96 g) dissolved in CH2Cl2 (20 ml) was added dropwise and the reaction mixture was then allowed to reach room temperature. After an additional two hours at room temperature the reaction mixture was washed with 10% Na2CO3 solution, dried (MgSO4), filtered and concentrated by evaporation. The oily residue was chromatographed on a silica column using CH2Cl2:MeOH (19:1 (v/v)) as eluent, 4-(3-methylsulfanyl-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid methyl ester (1.4 g). MS m/z (relative intensity, 70 eV) 263 (M+45), 248 (89), 129 (83), 128 (bp), 59 (96).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:16])[C:12]([Br:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9]C.[Br-].[Al+3].[Br-].[Br-].Cl>C1(C)C=CC=CC=1>[OH:9][C:8]1[CH:7]=[CH:6][C:5]([C:11](=[O:16])[C:12]([Br:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C(=O)C(C)(C)Br)cc1OC
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)C(C)(C)Br)ccc1O
Temperature: 0 °C
Yield: 91.4 %

Procedure:
A solution of 3',4'-dimethoxy-2-bromoisobutyrophenone (11.5 g) and aluminium bromide (21.8 g) in toluene (220 ml) was refluxed for 15 min. After cooling the reaction mixture was poured into ice (300 g) and 1N hydrochloric acid (200 ml). The organic phase was separated and dried over Na2SO4. The solvent was evaporated in vacuo yielding a pale yellow oil (10.0 g).
Reaction SMILES: [OH:1][C@@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1O>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[O:1][C@H:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CC[C@H](O)C(=O)OC
Reactant: Cc1ccc(Cl)c(O)c1
Product: CC[C@@H](Oc1cc(C)ccc1Cl)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the (S)-methyl 2-hydroxybutanoate instead of the (S)-methyl 2-hydroxypropanoate and the 2-chloro-5-methylphenol instead of the m-cresol.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1.CN1CCOCC1.[CH3:46][O:47][C:48]([NH:50][C@H:51]([C:55](O)=[O:56])[CH:52]([CH3:54])[CH3:53])=[O:49].[B-](F)(F)(F)F.CN(C(ON1C(=O)C=CC=C1)=[N+](C)C)C>CN(C=O)C.C(Cl)Cl.C1COCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH:38][C:55](=[O:56])[C@H:51]([CH:52]([CH3:53])[CH3:54])[NH:50][C:48]([O:47][CH3:46])=[O:49])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under an argon atmosphere, 321 mg (0.60 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane (Example 21b) and 182 mg (1.8 mmol) of NMM in 5.8 ml of DMF are added to 126 mg (0.72 mmol) of N-methoxycarbonyl-(L)-valine and 178 mg (0.60 mmol) of TPTU in 3 ml of DMF; the mixture is stirred at room temperature for 15 hours and worked up analogously to Example 3. TLC: Rf =0.15 (methylene chloride/THF 4:1); HPLC20-100 : tRet =14.5; FAB MS (M+H)+ =697.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[N:3]=1.[CH2:21]([N:23](CC)CC)[CH3:22].ClCC#N>CC(C)=O>[C:21]([CH2:22][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][C:4]=1[NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)#[N:23]
Reactant: Cc1ccc(C(=O)O)c(Nc2cccc([N+](=O)[O-])c2)n1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)OCC#N)c(Nc2cccc([N+](=O)[O-])c2)n1
Yield: 89.7 %

Procedure:
To a suspension of 6-methyl-2-(3-nitrophenylamino)-nicotinic acid (15.06 g, 55.11 mmol) in acetone (220ml) was added triethylamine (6.13 g, 60.6 mmol) and chloroacetonitrile (4.58 g, 60.6 mmol), and the mixture was heated under reflux overnight. The reaction mixture was filtered to remove an insoluble. The filtrate was evaporated. The resultant residue was washed successively with 1N aqueous sodium hydroxide and water, and dried to give 6-methyl-2-(3-nitrophenylamino)nicotinic acid cyanomethyl ester (15.44 g, 90%).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][CH2:5]O>>[CH3:1][N:2]([CH3:1])[C@@H:3]1[CH2:4][CH2:5][CH2:5][CH2:4][C@H:3]1[NH2:2]
Reactant: CCO
Reactant: CNC
Product: CN(C)[C@@H]1CCCC[C@H]1N
Reaction time: 19 h

Procedure:
A solution of the benzylamino compound was hydrogenated in two batches each containing 30.5 g. (0.131 mole), 175 ml. EtOH, 3.5 g Pd--C and 56.5 g. (0.394 mole) of 70% HClO4, at initial pressure of 51.5 p.s.i. for 19 hours. The two batches were combined, filtered through Celite and evaporated in vacuo at 45°. The residue was cooled in ice, basified with 40% KOH to pH 11. The resulting thick suspension was extracted with ether (5×200 ml), the ether extract was dried (MgSO4) and evaporated through a 9" Vigreux. The residue was distilled at 13 mm to give 32.5 g. (87% yield), b.p. 77°-78.5°. Vpc 100% at 3.8 mm. ir and nmr was identical to those of the sample prepared by the reaction of 7-azabicyclo[3.1.0]heptane with dimethylamine.