Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[N:2].[ClH:3].[C:4]([O:8]C(=O)[C@H](CCCNCOC=NC(OC(C)(C)C)=O)N)(C)(C)[CH3:5].N#N.[C:30]([O:34][C:35](=[O:51])[C@H:36]([CH2:45][CH2:46][CH2:47][NH:48][C:49]#[N:50])[NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])([CH3:33])([CH3:32])[CH3:31]>>[N:1]#[N:2].[ClH:3].[C:30]([O:34][C:35](=[O:51])[C@H:36]([CH2:45][CH2:46][CH2:47][NH:48][CH:49]=[N:50][O:8][CH2:4][CH3:5])[NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])([CH3:31])([CH3:32])[CH3:33].[N:1]#[N:2].[C:30]([O:34][C:35](=[O:51])[C@H:36]([CH2:45][CH2:46][CH2:47][NH:48][C:49]#[N:50])[NH:37][C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])([CH3:31])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N=COCNCCC[C@H](N)C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@@H](CCCNC#N)C(=O)OC(C)(C)C
Agent: Cl
Agent: N#N
Product: CCON=CNCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 75 %

Procedure:
By the method described above for the preparation of N2 -(tert-butoxycarbonyl)-N5 -(iminomethoxymethyl)-L-ornithine tert-butyl ester hydrochloride, 1.05 g (3.35 mmol) of N2 -(tert-butoxycarbonyl)-N5 -cyano-L-ornithine tert-butyl ester produced 0.95 g (75%) N2 -(tert-butoxycarbonyl)-N5 -(ethoxyiminomethyl)-L-ornithine tert-butyl ester hydrochloride (TLC, silica gel, methanol:dichloromethane/1:4, Rf=0.61) and 1.195 g (3.2 mmol) of N2 -(tert-butoxycarbonyl)-N5 -cyano-L-ornithine tert-butyl ester produced 0.63 g (63%) N2 -(tert-butoxycarbonyl)-N5 -(iminoisopropoxymethyl)-L-ornithine tert-butyl ester hydrochloride (TLC, silica gel, methanol: dichloro methane/1:4, Rf=0.53). Mass Spectrum (CI) 360 (MH+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O.[ClH:20]>O>[NH2:12][C:7]1[C:8]([Cl:20])=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][C:3]1[C:2]([F:1])=[CH:18][CH:17]=[CH:16][C:15]=1[F:19]
Reactant: O=[N+]([O-])c1cnccc1NCc1c(F)cccc1F
Reactant: Cl
Solvent: O
Product: Nc1c(NCc2c(F)cccc2F)ccnc1Cl
Temperature: 90 °C

Procedure:
A 3-neck 5-L flask, equipped with a thermometer, reflux condenser, nitrogen inlet and a mechanical stirrer was charged with 4-[(2,6-difluorobenzyl)amino]3-nitropyridine(146g, 0.55mol) and concentrated hydrochloric acid(1.4L, 16.8mol). The solution was heated on a steam bath to 90° C. and stannous chloride dihydrate(659g, 2.92mol) was added portionwise. After heating the suspension at 90° C. for 1.5 hours, the condenser was replaced with a distillation apparatus and approximately 1.5L of H2O removed by distillation at 100mm Hg. The remaining suspension was cooled in an ice bath and neutralized to pH 7 with concentrated ammonium hydroxide. The pasty solid was collected by filtration and dried overnight on a Buechner funnel. The still damp solid was transferred to a 12-L flask equipped with a mechanical stirrer and reflux condenser and charged with ethyl acetate. With rapid stirring, the suspension was heated at reflux for 3.5 hours on a steam bath, cooled slightly, filtered using positive nitrogen pressure, and the filtrate concentrated in vacuo. The resulting oily solid was slurried in ethyl ether, solids collected by filtration and dried overnight on a Buechner funnel to yield 123g (83.1%) of 3-amino-2-chloro-4-[(2,6-difluorobenzyl)amino]pyridine. TLC (silica gel, EtOAc/ether, 1:1) Rf =0.71; mp=221°-2230° C.; 1H NMR (DMSO-d6): 4.36(d,J=5.1 Hz, 2H, CH2), 4.84 (s, 2H, NH2), 6.06(t, J=5.1 Hz, 1H, NH), 6.54(d,J=5.4Hz, 1H, C-5H), 7.01-7.65 (m, 3H, C-3'H, C-4'H, C-5'H), 7.44 (d, J=5.3 Hx, 1H, C-6H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C)[C:3]=1[C:4]#[N:5].[S:24](Cl)(=[O:27])(=[O:26])[NH2:25]>>[S:24](=[O:27])(=[O:26])([O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]([NH:1][S:24](=[O:27])(=[O:26])[NH2:25])[C:3]=1[C:4]#[N:5])[NH2:25]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCOc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Product: N#Cc1c(NS(N)(=O)=O)cccc1OCCCCCOS(N)(=O)=O
Yield: 26 %

Procedure:
Prepared as in Example 215a from 2-amino-6-(5-(tert-butyldimethylsilyloxy)pentyloxy)benzonitrile (Example 241b) and sulfamoyl chloride in 26% yield. MS 379 (MH+).
Reaction SMILES: [Ca:1].[CH3:2][C:3]([CH3:16])=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1>C(O)C>[Ca:1].[CH3:2][C:3]([CH3:16])=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12]([O-:14])=[O:13])=[CH:7][CH:6]=1
Reactant: CC(C)=Cc1ccc(C(C)C(=O)O)cc1
Agent: [Ca]
Solvent: CCO
Product: CC(C)=Cc1ccc(C(C)C(=O)[O-])cc1
Yield: 186.5 %

Procedure:
Calcium (0.34 g) in 30 ml of anhydrous ethanol was added to a stirred solution of 2-(4-dimethylvinylphenyl) propionic acid (4 g) in 50 ml of ethanol at room temperature. After refluxing for 1 hour, the clear reaction mixture was cooled and maintained at 0° for 10 hours. The title salt was collected by suction filtration and dried under reduced pressure to yield a white crystalline solid (3.85 g) m.p. 120°-122°. I.R. C=O stretch 1550-1560 cm-1.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:16]([CH3:21])([CH3:20])[CH2:17][CH2:18][CH3:19])[C:14]=1[OH:15])[CH:10]=O)([CH3:6])[CH2:3][CH2:4][CH3:5].[C:22]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:23]C(O)=O.N1CCCCC1.Cl>O.N1C=CC=CC=1>[CH3:20][C:16]([C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([C:2]([CH3:6])([CH3:1])[CH2:3][CH2:4][CH3:5])[C:14]=1[OH:15])[CH:10]=[CH:23][C:22]([O:28][CH2:29][CH3:30])=[O:27])([CH3:21])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(C)(C)c1cc(C=O)cc(C(C)(C)CCC)c1O
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: CCCC(C)(C)c1cc(C=CC(=O)OCC)cc(C(C)(C)CCC)c1O

Procedure:
Ethyl 3,5-bis(1,1-dimethylbutyl)-4-hydroxycinnamate was prepared by heating a mixture of 29 grams of 3,5-bis(1,1-dimethylbutyl)-4-hydroxybenzaldehyde, 40 grams of ethyl hydrogen malonate, 50 milliliters pyridine and 3 milliliters of piperidine at 90° to 95° C. for 7 hours. The reaction mixture was poured into a solution of 50 milliliters of concentrated hydrochloric acid in 100 milliliters of water. The oil which precipitated was separated by extraction with petroleum ether and the extract was stripped under vacuum to a pot temperature of 50°C./14 mm. The viscous residue weighed 39 grams.
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1.N1C=CN=CC=1>C1COCC1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)=[CH:12][CH:11]=1
Reactant: BrC1CCCCC1
Reactant: COc1ccc([Mg]Br)cc1
Solvent: c1cnccn1
Solvent: C1CCOC1
Product: COc1ccc(C2CCCCC2)cc1
Yield: 96 %

Procedure:
Bromocyclohexane (81.8 mg, 0.5 mmol) and a THF solution (0.85 mL, 0.88 M, 0.75 mmol) of 4-methoxyphenylmagnesium bromide were used as starting materials, and reacted as in Entry 1. Conditions: The THF solution of 4-methoxyphenylmagnesium bromide was added dropwise at 25° C. over 20 minutes. 1H-NMR analysis was conducted using pyrazine (19.0 mg, 0.24 mmol) as an internal standard (yield 96%).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[Cl:37][CH2:38][C:39](O)=[O:40]>CN(C)C1C=CN=CC=1.ClCCl>[Cl:37][CH2:38][C:39]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])=[O:40]
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reactant: O=C(O)CCl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)=CCC(OC(=O)CCl)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3ml of dry dichloromethane. To the resulting solution was added 94.5 mg (1 mmole) of monochloroacetic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. The resulting product was separated and purified according to the procedure as described in Example 1 to obtain 218 mg (Yield: 60%) of the title compound having the following structure as a red oil.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:13]([C:23](OC)=[O:24])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[C@@H:13]([CH2:23][OH:24])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@H](OCOCc2ccccc2)C[C@@H]1CO
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.3 %

Procedure:
To a mixture of (2R,4R)-1-tert-butyl 2-methyl 4-(benzyloxymethoxy)pyrrolidine-1,2-dicarboxylate (2.29 g, 6.27 mmol, EXAMPLE 79 Step 1) and lithium chloride (586 mg, 13.8 mmol) in ethanol (25 mL) was added sodium borohydride (522 mg, 13.8 mmol) at 0° C., and the mixture was stirred at room temperature for 24 h. Then, the mixture was poured into water, and the aqueous layer was extracted with ethyl acetate three times. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residual oil was purified by silica gel column chromatography (ethyl acetate/hexane 1:2 to 2:3) to give 1.72 g (81%) of the title compound as a colorless oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:20][OH:21])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[O:12])[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[C:31]([C:33]1[CH:34]=[CH:35][C:36]([O:44][CH3:45])=[C:37](/[CH:39]=[CH:40]/[C:41](O)=[O:42])[CH:38]=1)#[N:32].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>ClCCl>[F:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([CH:8]2[CH2:7][CH2:6][N:5]([CH2:4][C@H:3]([NH:2][C:41](=[O:42])/[CH:40]=[CH:39]/[C:37]3[CH:38]=[C:33]([C:31]#[N:32])[CH:34]=[CH:35][C:36]=3[O:44][CH3:45])[CH2:20][OH:21])[CH2:10][CH2:9]2)=[O:12])=[CH:18][CH:17]=1
Reactant: N[C@H](CO)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: COc1ccc(C#N)cc1/C=C/C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C#N)cc1/C=C/C(=O)N[C@H](CO)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
To a solution of [1-((S)-2-amino-3-hydroxy-propyl)-piperidin-4-yl]-(4-fluoro-phenyl)-methanone hydrochloride (1.8 g, 5.7 mmol) and diisopropylethylamine (2.0 ml, 11.4 mmol) in dichloromethane (45 ml) is added (E)-3-(5-cyano-2-methoxy-phenyl)-acrylic acid (1.1 g, 5.7 mmol) followed by 2-(1H benzotriazol-1-yl)-1,1,3,3,-tetramethyluronium tetrafluoroborate (1.83 g, 5.7 mmol). The reaction mixture is stirred at ambient temperature for 4.5 hours, then filtered and the filtrate washed with water (50 ml), saturated sodium bicarbonate solution (50 ml), water (50 ml) and brine (50 ml). The organic phase is dried over magnesium sulphate, the solvent evaporated and the residue purified by flash silica chromatography (dichloromethane:methanol; 98:2 to 92:8 elution gradient) to afford the product, [MH]+466.1.
Reaction SMILES: C(OC(C1C(O)=C2C=C(C3C=CC(F)=CC=3)N(C3C=CC=CC=3)C2=CN=1)=O)C.C([O:31][C:32]([C:34]1[C:38]([Br:39])=[C:37]([Br:40])[N:36]([CH3:41])[C:35]=1[CH2:42][N:43](C(OC(C)(C)C)=O)[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=O)C>>[CH2:48]([O:47][C:45]([C:44]1[C:32]([OH:31])=[C:34]2[C:38]([Br:39])=[C:37]([Br:40])[N:36]([CH3:41])[C:35]2=[CH:42][N:43]=1)=[O:46])[CH3:49]
Reactant: CCOC(=O)CN(Cc1c(C(=O)OCC)c(Br)c(Br)n1C)C(=O)OC(C)(C)C
Agent: CCOC(=O)c1ncc2c(cc(-c3ccc(F)cc3)n2-c2ccccc2)c1O
Product: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2C

Procedure:
Prepared in analogy to that of 2-(4-fluoro-phenyl)-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester from 4,5-Dibromo-2-[(tert-butoxycarbonyl-ethoxycarbonylmethyl-amino)-methyl]-1-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. The title compound, ESI MS (m/z): 377 (M+H+).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:10][CH:9]([CH:11]=[O:12])[C:6]2([CH2:8][CH2:7]2)[NH:5]1>CO.O>[OH:12][CH2:11][CH:9]1[C:6]2([CH2:8][CH2:7]2)[NH:5][C:4](=[O:3])[CH2:10]1
Reactant: O=CC1CC(=O)NC12CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C1CC(CO)C2(CC2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium borohydride (1.4 g, 6.6 mmol) was added to a stirred solution of 5-oxo-4-azaspiro[2.4]heptane-7-carbaldehyde (0.51 g, 3.3 mmol) in methanol (8 mL) and water (12 mL) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was dried over sodium sulfate and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (1:10 methanol in dichloromethane, Rf=0.4) to give 7-(hydroxymethyl)-4-azaspiro[2.4]heptan-5-one. 1H NMR (400 MHz, CD3OD) δ 3.65-3.42 (m, 2H), 2.73-2.55 (m, 1H), 2.46-2.22 (m, 2H), 1.11-0.92 (m, 1H), 0.83-0.59 (m, 3H).
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][CH:7]([CH2:20][OH:21])[CH2:6]1)[CH2:2][CH2:3][CH3:4].Cl[CH2:23][C:24]([N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[O:25].[OH-].[Na+].O>CS(C)=O>[CH2:1]([N:5]1[CH2:10][CH:9]([CH2:11][O:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:8][CH:7]([CH2:20][O:21][CH2:23][C:24]([N:26]([CH2:30][CH2:31][CH3:32])[CH2:27][CH2:28][CH3:29])=[O:25])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CC(CO)OC(COCc2ccccc2)C1
Reactant: CCCN(CCC)C(=O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCN1CC(COCC(=O)N(CCC)CCC)OC(COCc2ccccc2)C1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A mixture of 16.2 g of 4-butyl-6-[(phenylmethoxy)methyl]-2-morpholinemethanol (0.055 mole) and 9.81 g of 2-chloro-N,N-dipropylacetamide (0.055 mole) are dissolved in 200 ml of dry dimethyl sulfoxide and the mixture stirred at room temperature under nitrogen. Slowly, 1.0 g of sodium hydroxide (0.04 mole) is added to the dimethyl sulfoxide mixture and the reaction allowed to stir at ambient temperature (23°). After stirring for 10 minutes an exothermic reaction begins to take place and an ice-bath is used to maintain the reaction temperature below 30°. After stirring for 1 hour the ice-bath is removed and the reaction allowed to stir at room temperature for 18 hours. The excess NaH is destroyed by adding 5 ml of methanol and the entire reaction mixture is then poured into 400 ml of water. The product is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined and washed with 4×300 ml portions of water. The CHCl3 layer is separated, dried over anhydrous Na2SO4, and the CHCl3 removed in vacuo yielding 22.4 g (94%) of the title compound as a yellow oil. The resulting oil is purified on a neutral Alumina III column (500 g), 40% chloroform/hexane yielding 12.9 g (54%) of product as a pale yellow oil. The 12.9 g of product are dried in vacuo (80° @0.2 mm) to give the desired product.
Reaction SMILES: C1C=CC=CC=1.[OH:7][N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OCC)(=O)C.O>[CH3:25][S:26]([O:7][N:8]1[C:12]2[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=2[N:10]=[N:9]1)(=[O:28])=[O:27]
Reactant: On1nnc2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: CS(=O)(=O)On1nnc2ccc(Cl)cc21
Yield: 31.2 %

Procedure:
Into benzene (14 ml) is suspended 1-hydroxy-6-chloro-1,2,3-benzotriazole (3.4 g) and thereto is added triethylamine (2.8 ml). To the solution is added methanesulfonyl chloride (2.3 g) with stirring under ice-cooling and the mixture is stirred at the same temperature for 20 minutes and further at room temperature for 5 hours. To the reaction mixture are added water (20 ml) and ethyl acetate (30 ml) and the ethyl acetate layer is separated. the water layer is again extracted with ethyl acetate (20 ml). The ethyl acetate extracts are combined, washed with a small amount of a saturated aqueous sodium hydrogen carbonate and water in order and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under a reduced pressure, and the residue is washed with petroleum ether (10 ml) to give colorless crystals of 1-methanesulfonyloxy-6-chloro-1,2,3-benzotriazole (1.55 g), melting point: 174°-175° C. (decomp). The remaining water layer after extracted with ethyl acetate, wherein precipitates are observed, is regulated at pH 1 with concentrated hydrochloric acid. The precipitates are separated by filtration and washed with water to give the desired product (2.4 g) as colorless crystals, melting point: 157°-158° C. (decomp).
Reaction SMILES: C(OC([N:11]1[CH2:17][C@@H:16]2[C@@:13]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:14][C@@H:15]2[CH3:18])[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.O1CCCC1.[C].[Pd]>[C:23]([O:22][C:20]([NH:19][C@@:13]12[CH2:14][C@H:15]([CH3:18])[C@@H:16]1[CH2:17][NH:11][CH2:12]2)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: C[C@H]1C[C@@]2(NC(=O)OC(C)(C)C)CN(C(=O)OCc3ccccc3)C[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H]1C[C@@]2(NC(=O)OC(C)(C)C)CNC[C@@H]12

Procedure:
(1S,5R,6S)-1-tert-Butoxycarbonylamino-6-methyl-3-azabicyclo[3.2.0]heptane-3-carboxylic acid benzyl ester (1.4 g, 3.8 mmol) was dissolved in a mixed solvent of methanol (20 mL) and tetrahydrofuran (10 mL). A small amount of 10% palladium-carbon (50% wet) was added, and the mixture was stirred in a hydrogen atmosphere for three hours. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to give 0.85 g (quantitative) of the title compound as a colorless oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].CO>C(O)C.ClCCl.[C].[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnccc1Nc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: Nc1cnccc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
4-Phenylamino-3-nitropyridine (1.40 g, 6.51 mmol) was dissolved in the mixed solvent of 15 ml of ethanol and 10 ml of dichloromethane. After the atmosphere was replaced with nitrogen, 0.10 g of 10% palladium-carbon was added thereto. After the atmosphere was replaced with hydrogen, hydrogen addition was conducted with stirring at room temperature for about 15 hours. Palladium-carbon was removed by filtration and the filtered cake was washed with ethanol. The filtrate and the washings were combined and then concentrated. The residue was purified by silica gel column chromatography [eluent: dichloromethane: methanol=2:1 (v/v)]to obtain 1.07 g of a light brown solid (yield: 88.7%).
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=[O:15])=[CH:12][CH:11]=2)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Li+].Cl>CO.O>[CH:1]1([O:7][CH:8]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)[CH3:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(C(C)OC2CCCCC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(OC1CCCCC1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To the solution of methyl 4-(1-(cyclohexyloxy)ethyl)benzoate (60 mg, 0.23 mmol) in methanol and water (50 mL/10 mL) was added lithium hydroxide (100 mg, 4.2 mmol), the solution was stirred at room temperature for 12 hours. Then the solution was acidified by hydrogen chloride (1 N/mol) pH to 6, extracted with dichloromethane (80 mL*3), evaporated the solvent to give 4-(1-(cyclohexyl oxy)ethyl)benzoic acid (47 mg 82%).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[NH:4][C:5](=[S:13])[N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7]=1[NH2:8].[CH2:15](C(CC)(CC)C([O-])([O-])[O-])[CH3:16]>>[CH2:9]([N:6]1[C:7]2[N:8]=[C:15]([CH3:16])[NH:1][C:2]=2[C:3](=[O:14])[NH:4][C:5]1=[S:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Reactant: CC(C)Cn1c(N)c(N)c(=O)[nH]c1=S
Product: Cc1nc2c([nH]1)c(=O)[nH]c(=S)n2CC(C)C
Temperature: 130 °C
Yield: 95 %

Procedure:
A mixture of 5,6-diamino-1-isobutyl-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (Example 6 (c), 0.70 g, 3.26 mmol) and triethylorthoacetate (10 mL) was heated at 130° C. for 2 h and 40 minutes. Then the reaction mixture was cooled on an ice-bath, the solid filtered off and washed with ethanol (4×2 mL). The solid was dried in vacuo yielding the title compound (0.71 g, 95%).
Reaction SMILES: [CH3:1][C:2]([CH3:14])([C:10]([CH3:13])=[CH:11][CH3:12])[CH2:3][CH2:4]/[CH:5]=[CH:6]/[C:7]([OH:9])=O.ClC(OCC)=O.[CH2:21]([N:23](CC)CC)[CH3:22].C(N)C.[Cl-].[Na+]>C1COCC1>[CH2:21]([NH:23][C:7](=[O:9])/[CH:6]=[CH:5]/[CH2:4][CH2:3][C:2]([CH3:1])([CH3:14])[C:10]([CH3:13])=[CH:11][CH3:12])[CH3:22]
Reactant: CCN(CC)CC
Reactant: CC=C(C)C(C)(C)CC/C=C/C(=O)O
Agent: CCN
Agent: CCOC(=O)Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC=C(C)C(C)(C)CC/C=C/C(=O)NCC
Yield: 22 %

Procedure:
4-(2,2,3-Trimethyl-3-penten-1-yl)-2E-butenoic acid 1 eq, ethyl chloroformate 1.5 eq, triethylamine 1.5 eq, ethylamine 1.5 eq as a 2.0M solution in THF, quench with 10% sodium chloride solution, yield=22%.
Reaction SMILES: [C:1]([C:9](=[CH:12]N(C)C)[C:10]#[N:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)O.[NH2:20][C:21]([NH2:23])=[NH:22].C[O-].[Na+]>CO>[NH2:22][C:21]1[N:23]=[CH:12][C:9]([C:10]#[N:11])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:20]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C(C#N)C(=O)c1ccccc1
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Product: N#Cc1cnc(N)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
Following the method of Earley et al. (J. Het. Chem. 1983, 20, 1195), to a stirred solution of 6.9 g (34.4 mmol) 2-benzoyl-3-dimethylaminoacrylonitrile and 20.6 g (114 mmol) guanidine carbonate in 50 ml methanol was added 43 ml (232 mmol) sodium methylate (5.4 M in methanol) and the mixture stirred at room temperature for 2 h. The reaction mixture was then concentrated in vacuo. The residue was resuspended in ethyl acetate and water, and the aqueous phase acidified to pH 8 by addition of hydrochloric acid. The phases were separated and the aqueous phase extracted twice more with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was triturated in a mixture of ethyl acetate, ether, dichloromethane and ethanol, and the resulting crystals were then additionally recrystallised from ethanol/ether to afford 2.83 g (41%) 2-amino-5-cyano-6-phenylpyrimidine as a light yellow crystalline solid. EI-MS m/e (%): 196 (M+, 100), 195 ([M—H]+, 40), 170 ([M—CN]+, 36).
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12](=[O:13])[CH:11]=[CH:10][C:9]1=[O:14].CO[CH2:17][N:18]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:19][Si](C)(C)C>C(Cl)Cl>[CH2:24]([N:18]1[CH2:19][CH:10]2[C:9](=[O:14])[NH:8][C:12](=[O:13])[CH:11]2[CH2:17]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: O=C1C=CC(=O)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C2CN(Cc3ccccc3)CC12
Temperature: 25 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
To a suspension of TFA (1.02 g) and 1H-Pyrrole-2,5-dione (10.22 g) in CH2Cl2 (250 mL) at −5° C. was added a solution of N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (29.99 g) in CH2Cl2 (20 mL) dropwise over 1 h. The reaction mixture was stirred at room temperature for another 5 h and evaporated in vacuo. The residue was stirred in the mixed solvent (EA: PE=3:7) at −10° C. for 1 h, and the mixture was filtered to afford the title compound as a white solid (10.18 g, 42.00%).