Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[ClH:19].CO>CO>[ClH:19].[CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C2CC2)CC1
Agent: Cl
Solvent: CO
Product: O=C(C1CC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a stirred mixture of compound tert-butyl 4-(cyclopropanecarbonyl)piperazine-1-carboxylate (3.7 g, 14.5 mmol) in methanol (15 mL) was added hydrochloride/methanol (15 mL, 3M)) at 0° C. After the addition, the mixture was allowed to stir at room temperature overnight. The mixture was concentrated to give cyclopropyl(piperazin-1-yl)methanone hydrochloride (2.74 g, yield 100%) as an off-white solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.71-0.76 (m, 4H), 1.96-2.03 (m, 1H), 3.04-3.16 (m, 4H), 3.69-4.08 (m, 4H), 9.58 (s, 2H); LC-MS (ESI) m/z: 155 (M+1)+.
Reaction SMILES: FC(F)(F)OC1C=CC(OC2C=CC(N)=CC=2C)=CC=1.CC(C(C)=O)C(OCC)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:42][C:43]([F:67])([F:66])[O:44][C:45]1[CH:65]=[CH:64][C:48]([O:49][C:50]2[C:51]([CH3:63])=[C:52]3[C:57](=[CH:58][CH:59]=2)[N:56]=[C:55]([CH3:60])[C:54]([CH3:61])=[C:53]3[OH:62])=[CH:47][CH:46]=1>C1(C)C(C)=CC=CC=1>[F:66][C:43]([F:42])([F:67])[O:44][C:45]1[CH:65]=[CH:64][C:48]([O:49][C:50]2[CH:59]=[C:58]3[C:57](=[CH:52][C:51]=2[CH3:63])[N:56]=[C:55]([CH3:60])[C:54]([CH3:61])=[C:53]3[OH:62])=[CH:47][CH:46]=1
Reactant: Cc1nc2ccc(Oc3ccc(OC(F)(F)F)cc3)c(C)c2c(O)c1C
Agent: CCOC(=O)C(C)C(C)=O
Agent: Cc1cc(N)ccc1Oc1ccc(OC(F)(F)F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: Cc1cc2nc(C)c(C)c(O)c2cc1Oc1ccc(OC(F)(F)F)cc1
Yield: 100 %

Procedure:
A solution of 2.2 g of 4-(4-trifluoromethoxyphenoxy)-3-methyl-aniline, 2.6 g of ethyl 2-methylacetoacetate, and 1.52 g of p-toluenesulfonic acid dissolved in 81 mL of xylene was heated under reflux for 12 hr. This reaction solution was cooled, and the precipitated crystals were then collected by filtration and were washed with distilled water and n-hexane to give 3.88 g of a mixture of 6-(4-trifluoromethoxyphenoxy)-4-hydroxy-2,3,5-trimethyl-quinoline with 6-(4-trifluoromethoxyphenoxy)-4-hydroxy-2,3,7-trimethyl-quinoline (yield 100%). The crystals of the mixture (2.9 g) thus obtained were stirred in 30 mL of acetic anhydride with heating at 120 to 125° C. for 2 hr. The reaction solution was concentrated, ethyl acetate was then added to the concentrate, and the mixture was washed with saturated brine. The solvent was then removed under the reduced pressure, and the crude product was purified by column chromatography on silica gel (BW300, manufactured by Fuji Sylysia Chemical Ltd., solvent: n-hexane/ethyl acetate) to give 0.4 g of 4-acetoxy-6-(4-trifluoromethoxyphenoxy)-2,3,5-trimethyl-quinoline (yield 12.4%) and 0.19 g of 4-acetoxy-6-(4-trifluoromethoxyphenoxy)-2,3,7-trimethyl-quinoline (yield 6%).
Reaction SMILES: [CH2:1]([N:8]([CH2:12][CH:13]([OH:16])[CH2:14][Cl:15])[CH2:9][CH2:10]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>[OH-].[Na+]>[CH2:1]([N:8]1[CH2:9][CH2:10][O:16][CH:13]([CH2:14][Cl:15])[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCN(Cc1ccccc1)CC(O)CCl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: ClCC1CN(Cc2ccccc2)CCO1
Temperature: 150 °C
Reaction time: 0.42 h
Yield: 70.6 %

Procedure:
To 3-benzyl-6-chloro-3-azahexane-1,5-diol (164 g) was added dropwise under ice-cooling over 30 minutes conc. sulfuric acid (205 ml, 1.99 mol) in the absence of a solvent and allowed to rise to room temperature and stirred for 25 minutes. The reaction mixture was heated at 150° C. for 45 minutes. After cooling, ice-water (1000 ml) was added to the reaction mixture under ice-cooling and then 50% aqueous sodium hydroxide (1000 ml) was added dropwise over one hour. After insolubles were filtered off, the filtrate was extracted with chloroform (1000 ml×3). The organic layer was washed successively with purified water (1000 ml) and a saturated aqueous solution of sodium chloride (1000 ml), dried over potassium carbonate and the solvent was distilled off under reduced pressure. The residue was chromatographed over silica gel and the fraction from ethyl acetate-hexane (1/6) gave 4-benzyl-2-chloromethylmorpholine (107.25 g) as a colorless oil. A total yield of the two steps=72%.
Reaction SMILES: [CH2:1]([O:3][CH:4]([N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[C:9]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[N:8]=[C:7]1[C:26](=[O:28])[CH3:27])[CH3:5])[CH3:2].[BH4-].[Na+].Cl.[Cl-].[Na+]>>[CH2:1]([O:3][CH:4]([N:6]1[C:10]([C:11]2[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][CH:16]=2)=[C:9]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[N:8]=[C:7]1[CH:26]([OH:28])[CH3:27])[CH3:5])[CH3:2]
Reactant: CCOC(C)n1c(C(C)=O)nc(-c2ccc(F)cc2)c1-c1ccc(SC)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Product: CCOC(C)n1c(C(C)O)nc(-c2ccc(F)cc2)c1-c1ccc(SC)cc1
Temperature: 0 °C
Reaction time: 20 h
Yield: 91.3 %

Procedure:
To a solution of 1-[(1-ethoxyethyl)-4-(4-fluorophenyl)-5-[4-(methylthio)phenyl)-1H-imidazol-2-yl]ethanone (Step 1) (1.08 g.; 2.9 mmol) at 25° C. was added sodium borohydride (109.7 mg; 2.9 mmol). After stirring for 20 hours, the reaction mixture was cooled to 0° C. and 50 ml of a 1% aqueous solution of hydrochloric acid was added. This solution was saturated with solid sodium chloride and extracted with 100 ml, then 2×50 ml of methylene chloride. The organics were combined then washed with 50 ml of a saturated, aqueous solution of sodium bicarbonate. The organic extracts were dried (MgSO4), filtered and evaporated under reduced pressure to provide 1.06 g of a light yellow foam, which was purified by flash chromatography (SiO2, 75% ethyl acetate/hexane) to provide 907 mg of the desired protected alcohol.
Reaction SMILES: Cl.[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([CH2:9][NH2:10])=[O:8].C(=O)(O)[O-].[Na+].[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:10][CH2:9][C:7]([C:3]2[O:2][CH:6]=[CH:5][CH:4]=2)=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: NCC(=O)c1ccco1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(NCC(=O)c1ccco1)c1ccc(F)cc1
Yield: 67 %

Procedure:
23.4 g of (2-furylcarbonyl)methylamine hydrochloride, 29.3 g of sodium bicarbonate and 23.0 g of 4-fluorobenzoyl chloride are treated in the same manner as described in Preparation 1-(1). 24.0 g of N-(4-fluorobenzoyl)-(2-furylcarbonyl)methylamine are thereby obtained. Yield: 66.8%
Reaction SMILES: C([Mg]Cl)(C)C.[C:6]([NH2:10])([CH3:9])([CH3:8])[CH3:7].CCC.[CH3:14][Si:15](OC)([O:18][CH3:19])[O:16][CH3:17]>O1CCCC1>[CH3:14][Si:15]([NH:10][C:6]([CH3:9])([CH3:8])[CH3:7])([O:18][CH3:19])[O:16][CH3:17]
Reactant: CC(C)(C)N
Reactant: CO[Si](C)(OC)OC
Agent: CC(C)[Mg]Cl
Solvent: CCC
Solvent: C1CCOC1
Product: CO[Si](C)(NC(C)(C)C)OC
Temperature: 25 °C

Procedure:
A thermometer an addition funnel and a condenser were fitted to a stirrer-equipped one liter, four-necked flask. The flask was charged with one mol of isopropylmagnesium chloride in 500 ml of tetrahydrofuran (THF). The addition funnel was charged with 1.02 mol (75 g) of tert-butylamine which was slowly added to the stirred isopropylmagnesium chloride. The reaction was mildly exothermic and there was immediate evolution of propane gas. After completion of the addition (2 hours), the contents were refluxed for 30 minutes to complete the evolution of the gas. The reaction mixture was cooled to room temperature and one mol (135 g) of methyltrimethoxysilane was added to the stirred reaction mixture over a period of one hour. The reaction was mildly exothermic and the contents were refluxed at a pot temperature of 75° C. for 30 minutes to complete the reaction. The methyl(t-butylamino)dimethoxysilane was filtered under nitrogen atmosphere from the magnesium methoxychloride. The salt cake was washed with diethyl ether (2×200 ml) to obtain the residual methyl(t-butylamino)dimethoxysilane. The solvent was distilled to a pot temperature of 90° C. and the residue was distilled under reduced pressure to yield 138 g of methyl(t-butylamino)dimethoxysilane as a colorless oil (purity>98%); bp 107° C./135 mm. The yield was 82% of theoretical.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH:22]=O)[CH:18]=3)[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]1.C(O)C.C([BH3-])#N.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:22][N:24]4[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]4)[CH:18]=3)[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)C1CCNCC1
Reactant: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3n2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CN4CCC(C(=O)O)CC4)ccc3n2)CC1
Temperature: 25 °C

Procedure:
To the solution of 2-(4-tert-butyl-cyclohexyloxy)-quinoline-6-carbaldehyde (350 mg, 1.1 mmol) and piperidine-4-carboxylic acid (145 mg, 1.12 mmol) in ethanol (8 mL, 100 mmol) was heated to reflux for 2 h. The yellow solution was cooled to rt and sodium cyanoborohydride (84.8 mg, 1.35 mmol) was added and was heated to reflux for 1 h. After cooled down to rt, citric acid was added and concentrated down. The solid was suspended in water and filtrate, and the collected solid was washed thoroughly with water. HPLC purification of the solid gives the product. 77 mg, yield: 16%. ESI-MS (M+1)+: 425.00.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:21])[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:22]([OH:24])=[O:23].[CH2:26]([OH:30])[CH:27]([OH:29])[CH3:28]>ClCCl>[CH3:1][C:2]1([CH3:25])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([C@H:13]([NH2:21])[C:14]3[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=3)=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:22]([OH:24])=[O:23].[CH2:26]([O-:30])[CH:27]([O-:29])[CH3:28]
Reactant: CC(O)CO
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccc(O)cc3)C(=O)N2[C@H]1C(=O)O
Solvent: ClCCl
Product: CC([O-])C[O-]
Temperature: 25 °C

Procedure:
Dichloromethane (63 ml; methanol-free) was added to amoxycillin trihydrate (3.5 g; purity by HPLC 86%; water 12.9%) with stirring at room temperature and, then, followed by the addition of 1,2-propanediol (22 ml). The reaction mixture was further stirred for about 20 min at the same temperature. The product was filtered and, then, washed on the filter with dichloromethane (100 ml). Thereafter, the product was suspended in dichloromethane (80 ml) and stirred for about 20 min at room temperature. The resulting suspension was filtered, washed on the filter with dichloromethane (100 ml) and, then, dried under vacuum overnight.
Reaction SMILES: [CH2:1]([NH2:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:12](O)(=[O:20])[CH:13]([CH:15]([C:17](O)=[O:18])[OH:16])[OH:14]>C1(C)C=CC=CC=1>[CH2:1]([N:11]1[C:17](=[O:18])[CH:15]([OH:16])[CH:13]([OH:14])[C:12]1=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCN
Reactant: O=C(O)C(O)C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCN1C(=O)C(O)C(O)C1=O
Temperature: 100 °C

Procedure:
N-Decyl DL-tartarimide was prepared by the reaction of n-decyl amine with DL-tartaric acid. DL-Tartaric acid (10.143 g, 67.579 mmole) and toluene (17.332 g) were weighed into a 250 mL 3-necked round-bottomed flask equipped with a teflon-coated magnetic stir bar. A Claisen adapter was placed in the center neck, a Dean-Stark trap was placed on top of the Claisen adapter, and a condenser was placed in the neck of the Dean-Stark trap. A nitrogen inlet adapter was placed on the condenser. In the left neck was placed a pressure-equalizing addition funnel containing n-decyl amine (10.630 g, 67.578 mmole) and toluene (6.257 g, added to ensure complete transfer of the amine). In the right neck was placed a rubber septum which held a thermocouple. The apparatus was purged with nitrogen for 10-15 minutes and then heated to ˜100° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].O.[CH3:11][S:12]S(C)(=O)=O.C(OCC)(=O)C>C(O)C.[Cl-].[Na+].C(O)(=O)C>[CH3:11][S:12][S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CSS(C)(=O)=O
Reactant: O=C(O)CCCCCS
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CSSCCCCCC(=O)O
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A reaction flask was cooled in an ice bath and charged with 6-mercaptohexanoic acid (500 mg, 3.37 mmol) and water (2 mL). The solution was stirred as methyl methanethiolsulfonate (468 mg, 3.71 mmol) dissolved in ethanol (1 mL) was added. The reaction was stirred overnight at room under an argon atmosphere. The reaction mixture was then diluted with saturated sodium chloride (400 mL) and extracted into ether (3×150 mL). The combined extracts were washed with the sodium chloride solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The product was isolated via silica flash chromatography eluting with a 1:0.9:0.1 mixture of hexanes:ethyl acetate:acetic acid to give 482 mg (73.5% yield) of compound 53. 1H NMR (CDCl3, ref. 7.26 ppm) δ 1.473 (2H, m), 1.702 (4H, m), 2.359 (2H, t), 2.405 (3H, s), 2.708 (2H, t).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[CH:18])=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1>>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][CH2:16][C:17]#[C:18][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[CH:11][C:10]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCSc1ccc(OCC(=O)OC(C)(C)C)c(C)c1
Reactant: Fc1ccc(I)cc1
Product: Cc1cc(SCC#Cc2ccc(F)cc2)ccc1OCC(=O)OC(C)(C)C

Procedure:
In analogy to the procedure described in example 5B], (2-methyl-4-prop-2-ynylsulfanyl-phenoxy)-acetic acid tert-butyl ester (example 5A]) and 1-fluoro-4-iodo-benzene gave the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14](N)=[CH:13][CH:12]=3)=[O:5])[CH3:2].N([O-])=O.[Na+].[BrH:24]>O.[Cu]Br>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][C:14]([Br:24])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: Br
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(N)cc12
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(Br)cc12
Temperature: 80 °C
Yield: 35 %

Procedure:
1 mmole of 6-amino-β-carbolin-3-carboxylic acid ethyl ester is diazotized at 0° C. in 2 ml of 24% aqueous hydrobromic acid with 1 mmole of sodium nitrite in 1 ml of water. This mixture is added dropwise to a solution of 40 mg of copper (I) bromide in 1 ml of 48% aqueous hydrobromic acid at room temperature. After addition is complete, the mixture is heated to 80° C. The temperature is increased to 100° C. until nitrogen evolution has ceased. 10 ml of water is then added and filtration with suction is carried out. The residue is stirred with ammonia and filtered with suction. It is then extracted by boiling with ethanol and concentrated by evaporation. By chromatography on silica gel with an eluant comprising 9 parts of chloroform and 1 part of ethanol, 6-bromo-β-carbolin-3-carboxylic acid ethyl ester of melting point 308°-313° C. is obtained in 35% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C(N(CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:22])[CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.2 %

Procedure:
A solution of 0.299 g (0.001 mol) of N-benzyloxycarbonylphenylalanine (Z-Phe), 0.08 g (0.001 mol) of pyridine and 0.256 g (0.001 mol) of DSC in 10 ml of acetonitrile was stirred at ambient temperature. After silica gel TLC. showed that Z-Phe (the free acid form) disappeared in the solution, the reaction solution was admixed with 0.075 g (0.001 mol) of glycine (Gly-OH) and 0.101 g (0.001 mol) of triethylamine, followed by stirring at ambient temperature for 24 hours. The resultant reaction mixture was concentrated to a small volume, admixed with ethyl acetate, washed with aqueous 4% NaHCO3, with 1 N-HCl and with a saturated aqueous solution of sodium chloride, followed by drying over anhydrous sodium sulfate. The dried solution was filtered and the filtrate was distilled to remove the solvent, affording a colorless crystalline substance. Recrystallization of this solid substance from ethyl acetate-petroleum ether gave 0.30 g of N-benzyloxycarbonylphenylalanylglycine (Z-Phe-Gly-OH) as a colorless crystalline substance. Yield 83.4%.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:16](=[O:56])[NH:17][C@H:18]([C:23]([N:25]1[C@H:36]([C:37](=[O:55])[NH:38][C@:39]2([C:44]([NH:46][S:47]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)(=[O:49])=[O:48])=[O:45])[CH2:41][C@H:40]2[CH:42]=[CH2:43])[CH2:35][C@:27]2([C:32]([CH3:34])([CH3:33])[C:28]32[CH2:31][CH2:30][CH2:29]3)[CH2:26]1)=[O:24])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.Cl>O1CCOCC1>[N:50]1([S:47]([NH:46][C:44]([C@@:39]2([NH:38][C:37]([C@@H:36]3[CH2:35][C@:27]4([C:32]([CH3:33])([CH3:34])[C:28]54[CH2:31][CH2:30][CH2:29]5)[CH2:26][N:25]3[C:23](=[O:24])[C@@H:18]([NH:17][C:16](=[O:56])[C@@H:8]([NH2:7])[C:9]3([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:55])[CH2:41][C@H:40]2[CH:42]=[CH2:43])=[O:45])(=[O:49])=[O:48])[CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C1(C)CCCCC1)C(C)(C)C)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Agent: Cl
Solvent: C1COCCO1
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](N)C1(C)CCCCC1)C(C)(C)C)C(C)(C)C21CCC1)C(=O)NS(=O)(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of [(S)—((S)-1-{(5R,8S)-10,10-Dimethyl-8-[(1R,2S)-1-(pyrrolidine-1-sulfonylaminocarbonyl)-2-vinyl-cyclopropylcarbamoyl]-7-aza-dispiro[3.0.4.1]decane-7-carbonyl}-2,2-dimethyl-propylcarbamoyl)-(1-methyl-cyclohexyl)-methyl]-carbamic acid tert-butyl ester (0.219 g; 0.27 mmol) and 2.0 mL HCl (4 M in dioxane) in 2 mL dioxane was stirred at ambient temperature for 2 h. The mixture was concentrated under reduced pressure and co-evaporated 2 times with DCM to yield the title compound which was used in the next step without further purification. LC-MS (method E): Rt=1.64 min; M/z=717 [M+]; HPLC (method A3): Rt=4.82 min
Reaction SMILES: Br[C:2]1(Br)[C:10]2[C:9]([C:11]#[N:12])=[CH:8][CH:7]=[N:6][C:5]=2[NH:4][C:3]1=[O:13].CC(O)=O>CC#N.[Zn]>[O:13]=[C:3]1[NH:4][C:5]2[N:6]=[CH:7][CH:8]=[C:9]([C:11]#[N:12])[C:10]=2[CH2:2]1
Reactant: N#Cc1ccnc2c1C(Br)(Br)C(=O)N2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CC#N
Product: N#Cc1ccnc2c1CC(=O)N2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 3,3-dibromo-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-4-carbonitrile (4 g) in CH3CN (75 mL) was added AcOH (2 mL) followed by Zinc dust (4, 63 mmol). Mixture was stirred for 2 h at RT and was filtered. Solvent was evaporated and MeOH was added. A solid precipitated, which was filtered and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[O-:18][C:19]#[N:20].[Na+].C(O)(=O)/C=C\C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([C:19]([NH2:20])=[O:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: N#C[O-]
Reactant: COC1=Cc2ccccc2Nc2ccccc21
Agent: O=C(O)/C=C\C(=O)O
Agent: [Na+]
Solvent: ClCCl
Product: COC1=Cc2ccccc2N(C(N)=O)c2ccccc21
Reaction time: 24 h

Procedure:
50.0 g (0.224 moles) of 10-methoxyiminostilbene was dissolved in 750.0 ml of dichloromethane. 185.0 g (2.846 moles) of sodium cyanate and 75.0 g (0.65 moles) of maleic acid were added to the above solution at a temperature ranging from about 25° C. to about 30° C. The reaction mass was stirred for about 24 hours. After completion of the reaction (determined by HPLC/TLC) the reaction mass was filtered and washed three times with 100 mL of dichloromethane. The dichloromethane layer was evaporated to get a residue of about 150 g to about 200 g.
Reaction SMILES: C[O:2][C:3]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([O:17]C)[CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[C:9]([OH:17])[CH:10]=[CH:11][CH:12]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1C(=O)c1cccc(OC)c1-2
Agent: Br
Solvent: CC(=O)O
Product: O=C1c2cccc(O)c2-c2cccc(O)c21
Yield: 85.2 %

Procedure:
In a manner analogous to Example 1D, prepare a solution of 1,5-dimethoxy-fluoren-9-one (0.65 g, 2.7 mmole) in 15 mL glacial acetic acid and react with 15 mL hydrogen bromide to obtain the title compound (m.p. 2361°-238° C. (dec.), yield 0.50 g, 2.3 mmole, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8]1.[ClH:23].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:23].[ClH:23].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@@H:9]([NH2:12])[CH2:8]1
Reactant: COc1cccc(CN2CC[C@@H](NC(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cccc(CN2CC[C@@H](N)C2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl [(3R)-1-(3-methoxybenzyl)-3-pyrrolidinyl]carbamate (739 mg) in ethyl acetate (3.7 mL) was added 4N HCl-ethyl acetate (6.0 mL), which was stirred at room temperature for 1.5 hours. The mixture was concentrated to give (3R)-1-(3-methoxybenzyl)-3-pyrrolidinamine dihydrochloride (702 mg) as a off-white amorphous.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[CH:20][CH:21]=1
Reactant: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CBr)cc1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccc(F)cc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 80 mg (0.19 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(4-fluoro-benzyloxy)-1H-pyridin-2-one (example 7.1b) in 1.5 mL DMF is added at RT 63 μL (0.77 mmol) pyrrolidine. The reaction mixture is stirred overnight at RT and is directly transferred to a reverse HPLC for purification (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).