Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH3:28])[N:15]([C:18]3[CH:27]=[N:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[C:16](=[O:17])[C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:29]>CO>[ClH:29].[CH3:28][N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[C:16](=[O:17])[N:15]1[C:18]1[CH:27]=[N:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]=1
Reactant: Cn1c2c(c(=O)n1-c1cnc3ccccc3n1)CN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CO
Product: Cn1c2c(c(=O)n1-c1cnc3ccccc3n1)CNCC2
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of 1-methyl-3-oxo-2-quinoxalin-2-yl-1,2,3,4,6,7-hexahydro-pyrazolo[4,3-c]pyridine-5-carboxylic acid tert-butyl ester (prepared according to the method of Example 75, Step B, 279 mg, 0.73 mmol) in methanol (6 mL) was added hydrogen chloride (5.85 M in methanol, 1.25 mL, 7.3 mmol). This mixture was heated at 60° C. for 30 min, cooled to room temperature, and concentrated to give 249 mg (>100%) of the title compound of Example 75, Step C as a dark red solid. 1H NMR (CD3OD, 250 MHz) δ 9.45 (s, 1H), 8.13 (dd, 1H), 8.05 (m, 1H), 7.91-7.83 (c, 2H), 4.05 (s, 2H), 3.64 (t, 2H), 3.56 (s, 3H), 3.12 (t, 2H), MS (APCI) 282 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[O:18][C:19]1[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH3:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][C:17]1[CH:16]=[C:15]([CH:29]=[CH:28][CH:27]=1)[CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: Cc1cccc(Oc2cccc(CO)c2)c1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(OCc2cccc(Oc3cccc(C)c3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
A solution of methyl 3-(4-hydroxyphenyl)propanoate (0.396 g, 2.20 mmol), [3-(3-methylphenoxy)phenyl]methanol (0.429 g, 2.00 mmol) and tributylphosphine (0.747 mL, 3.00 mmol) in toluene (30 mL) was stirred under ice-cooling, 1,1′-(azodicarbonyl)dipiperidine (0.757 g, 3.00 mmol) was added by small portions, the temperature was raised to room temperature and the mixture was stirred for 18 hrs. Hexane (15 mL) was added to the reaction mixture, the precipitated insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane-20% ethyl acetate/hexane) and preparative HPLC (10-95% acetonitrile/water, containing 0.1% trifluoroacetic acid) to give the title compound (0.414 g, yield 55%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1.[Br:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35]Br>>[Br:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][N:11]([CH2:12][C:13]1[CH:31]=[CH:30][C:16]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: BrCc1ccccc1Br
Reactant: COC(=O)CCc1ccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)cc1
Product: COC(=O)CCc1ccc(Oc2ccc(CN(Cc3ccccc3Br)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 76C and 2-bromobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [C:1]([NH:4][C:5](=[CH2:9])[C:6]([OH:8])=[O:7])(=[O:3])[CH3:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>C(O)C>[C:1]([NH:4][C@H:5]([C:6]([OH:8])=[O:7])[CH2:9][S:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH2:10])(=[O:3])[CH3:2]
Reactant: Nc1ccccc1S
Reactant: C=C(NC(C)=O)C(=O)O
Solvent: CCO
Product: CC(=O)N[C@@H](CSc1ccccc1N)C(=O)O
Yield: 52.5 %

Procedure:
A mixture consisting of 8.6 g of α-acetylaminoacrylic acid, 20 g of 2-aminobenzenethiol and 50 ml of ethanol was heated for an hour. After the ethanol was distilled off, ether was added to the residue so as to cause crystallization. Upon recrystallization from ethanol, there was obtained 8.9 g of the desired product. Its melting point (m.p.) was 143°-144° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][C:18]2=[O:19])[CH2:13][CH2:12]1)=[O:10])=O)C.[NH3:31].[Cl-].[NH4+]>C(O)C>[C:4]([C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH2:20][C:18]2=[O:19])[CH2:13][CH2:12]1)=[O:10])(=[O:3])[NH2:31]
Reactant: CCOC(=O)c1cccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)c1
Reactant: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: NC(=O)c1cccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)c1
Reaction time: 10 h

Procedure:
1-[1-(3-Ethoxycarbonylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.5 g), aqueous ammonia (10 ml) and ammonium chloride (the affective amount as a catalyst) are dissolved in ethanol (10 ml) and the mixture is stirred at 110°-130° C. for 10 hours in an autoclave. Ethanol is distilled off under reduced pressure and the residue is extracted with methylene chloride. The organic layer is washed with water and saturated saline solution, dried with sodium sulfate and concentrated. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (solvent: methylene chloride:methanol=10:1) to give 1-[1-(3-carbamoylbenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.15 g).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[Mg].[CH2:11]([O:17][C:18](=[O:28])[C:19](OCC/C=C\CC)=[O:20])[CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16].[NH4+].[Cl-]>C1COCC1>[O:20]=[C:19]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)[C:18]([O:17][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16])=[O:28]
Reactant: C=Cc1ccc(Br)cc1
Reactant: CC/C=C\CCOC(=O)C(=O)OCC/C=C\CC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)C(=O)OCC/C=C\CC)cc1
Temperature: 25 °C
Yield: 37.8 %

Procedure:
A Grignard reagent prepared from 4-bromostyrene (6.95 g, 38.0 mmol) and magnesium (0.97 g, 39.9 mmol) in THF (100 mL) was added dropwise (during a period of 20 min) to a stirred solution of bis[(Z)-3-hexenyl]oxalate (9.20 g, 36.2 mmol) in THF (35 mL) at −60° C. The mixture was left warming to room temperature and poured into a mixture of ice (100 g) and a saturated solution of NH4Cl (100 mL). Extraction with diethyl ether (200 mL, 2×), washing with a saturated solution of NaCl (50 mL, 4×, pH 7), drying (Na2SO4) and concentrating afforded 11.47 g of the crude compound as a brownish oil. Bulb-to-bulb distillation of 8.68 g of the crude product (0.06 mbar, 60° C.) and column chromatography (SiO2, heptane/ether 95:5, then 1:1, then pure ether) gave 3.53 g (50%) of an oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:16])[CH:3]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([F:16])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: O=C1NCCn2c1cc1cc(F)cc(Br)c12
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C1NCCn2c1cc1cc(F)cc(-c3ccc(Cl)cc3)c12

Procedure:
The title compound, light grey solid (75 mg, 95%), MS (ISP) m/z=315.1 [(M+H)+], mp 322° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 1) (70.8 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [CH3:1][CH:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:12][CH:13]=[CH2:14])[S:4](=[O:16])(=[O:15])[NH:3]1.[CH3:17][Mg]Br.O>O1CCCC1>[CH3:1][C:2]1([CH3:17])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]([CH2:12][CH:13]=[CH2:14])[S:4](=[O:16])(=[O:15])[NH:3]1
Reactant: C[Mg]Br
Reactant: C=CCN1c2ccccc2C(C)NS1(=O)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCN1c2ccccc2C(C)(C)NS1(=O)=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Aminoacetophenone(5.6 g, 41.5 mmol)and sulfamide (4 g, 41.5 mm) were added to diglyme (70 ml, dried over 4A molecular sieves) and the solution heated under nitrogen at 150° C. After 1 hour a solid forms but heating was continued for 2 hours in total. After cooling, ether was added followed by 2N sodium hydroxide which dissolved the solid formed. The aqueous phase was collected, diluted with ethanol and (prop-2-en-1-yl) bromide (8 ml) added, stirring being continued overnight. After concentration under vacuo the residue was partitioned between water and ethyl acetate. The organic phase was collected, dried, over magnesium sulfate, filtered and the solvent evaporated under reduced pressure to yield a yellow oil, 3,4-dihydro-4-methyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. 3,4-Dihydro-4-methyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide(2.4 g, 10 mmol) was dissolved in dry tetrahydrofuran (40 ml) under nitrogen and the solution cooled to -78° C. in an acetone/dry ice bath. Methyl magnesium bromide (5 ml, 3M solution in ether) was added at this temperature and kept for 30 minutes when it was allowed to come to room temperature. After stirring for 2 hours, water was added and the solution concentrated. Partitioning between ethyl acetate and dilute HCl(aq) and collection of the organic extracts followed by drying, filtering and removal of solvent gave a product showing 75% conversion to product. Column chromatography eluting with ethyl acetate/hexane gave product, 3,4-dihydro-4,4-dimethyl-1-(prop-2-en-1-yl)-1H-2,1,3-benzothiadiazine-2,2-dioxide. This compound (1.85 g, 7.3 mmol) was dissolved in N-methylpyrrolidine (30 ml) under nitrogen and sodium hydride (350 mg) was added at room temperature resulting in a vigorous effervescence. After the gas evolution had subsided (30 minutes), methyl iodide (300 mg) was added and the solution stirred overnight. The reaction was poured onto water and extracted with ethyl acetate(3×50 ml). Organic phase was washed with water (2×100 ml), dried, filtered and vacced to an oil, 3,4-dihydro-1-(prop-2-en-1-yl)-3,4,4-trimethyl-1H-2,1,3-benzothiadiazine-2,2-dioxide.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[CH2:19]([NH2:21])[CH3:20]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:21][CH2:19][CH3:20])[N:6]=1)[CH:2]=[CH2:3]
Reactant: CCN
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Solvent: O
Product: C=CCNc1nc(NCC)nc2ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.6 %

Procedure:
A mixture of 250 mg (0.95 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 796 mg (15.52 mmol) of a 70% aqueous ethylamine solution was stirred at room temperature for 3 hours. Water. was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 234 mg (yield: 90.6%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]([C@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([O:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]([C@H:16]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CN([C@@H](C)c1ccccc1)[C@H]1CCCC[C@@H]1COS(C)(=O)=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
A solution of 167.4 g of ethyl 2-(((1S,2S)-2-(hydroxymethyl)cyclohexyl)((S)-1-phenylethyl)amino)acetate (13, 0.524 mol, 1.0 equiv. based on HCl salt 10) dissolved in 685 mL of dichloromethane was added to a 2 L reactor, which is equipped with mechanical stirrer and thermocouple under nitrogen atmosphere. To this solution, 63.8 g of triethylamine (0.629 mol, 1.2 equiv.) was added and the mixture was cooled to less than 5° C. temperature. 66 g (0.576 mol, 1.1 equiv.) of methanesulfonyl chloride was added dropwise while maintaining the temperature below 10° C. and after the addition was complete, the mixture was stirred for an additional 30 min and then warmed to approximately 20° C. temperature under nitrogen atmosphere. The reaction mixture was stirred for NLT 1 h and quenched with 261 mL of ice-water at below 25° C. temperature and mixed for NLT 15 min. The lower organic layer was separated and the upper aqueous layer was extracted with 2×135 mL of dichloromethane. The combined organic layers were washed with 3×327 mL of water, dried using anhydrous magnesium sulfate (13.5 g), filtered and concentrated on a rotary evaporator under vacuum at NMT 60° C. temperature. The resulting crude product (viscous oil) was dried over night using a high vacuum pump to afford 204.7 g of ethyl 2-(((1S,2S)-2-((methylsulfonyloxy)methyl)cyclohexyl) ((S)-1-phenylethyl)amino) acetate (14) as a viscous oil, which was carried to the next step without further purification. Analytical HPLC (Daicel Chiralpack AD-RH column, Size: 150×4.6 mm); 0.02 M Ammonium acetate buffer (pH: 7.7-7.8): Acetonitrile/50:50, 0.3 mL/min, Wave length: 220 nm, Column oven temperature: 55° C., Rt: 17.23 min; LC-MS (m/z): 398.2 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH2:12])=[O:11].[NH:16]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:17]([C:26](ON1C(=O)CCC1=O)=[O:27])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=1>CN(C=O)C>[NH:16]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:17]([C:26]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([NH2:12])=[O:11])=[O:27])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([I:25])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)ON1C(=O)CCC1=O
Reactant: NC(=O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)N1CCC[C@H]1C(N)=O
Reaction time: 16 h

Procedure:
Triethylamine (163.8 ml, 1.17 mmol) was added to a solution of H-ProNH2*HCl (118.5 mg, 0.782 mmol) in dry DMF (10 ml). Boc-p-Iodo-Phe-OSu (0.42 g, 0.86 mmol) was added in one portion and the mixture stirred for 16 h under an argon atmosphere. The solvent was evaporated and the residue treated in a standard way, i.e. the residue was partitioned between ethylacetate (60 ml) and 0.3N KHSO4 solution (10 ml). The organic layer was further washed with saturated NaCHO3 solution (10 ml), water (10 ml)and brine (5 ml). The solution was dried and evaporated at reduced pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CNCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 60.2 %

Procedure:
In a 32 mL reaction vial was placed a stir bar and 4-methylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (0.97 g) dissolved in 12.8 mL anhydrous THF. The solution was cooled to 0° C. with an ice-bath. A 65% toluene solution of Red-A1 (3.66 mL) was added dropwise at 0° C. After the addition was completed, the mixture was stirred under N2 at room temperature until all the starting materials were just consumed. The reaction mixture was worked up with H2O at 0° C., extracted with EtOAc (×3). The EtOAc extract was washed with saturated NaCl solution. After drying over Na2SO4, the organic layer was concentrated to give 550 mg of crude product.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]([O:9][C:10]([NH:12][N:13]=[C:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].[OH-].[Na+]>C(O)(=O)C.CO>[C:5]([O:9][C:10]([NH:12][NH:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:11])([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)NN=C1CCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NNC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Sodium cyanoborohydride (6.4 g, 0.101 mol) was added portion-wise to a suspension of 1-cyclopentylidenehydrazine-2-carboxylic acid tert-butyl ester (20 g, 0.101 mol) in a mixture of acetic acid and methanol (288 mL, 1:1). The resulting solution was stirred at RT for 2 h. The reaction mixture was neutralized with 1 N aq NaOH and extracted with CH2Cl2. The organic layer was washed with saturated NaHCO3, dried (Na2SO4) and concentrated under reduced pressure to give 1-cyclopentylhydrazine-2-carboxylic acid tert-butyl ester (18.4 g) as an oil.
Reaction SMILES: Cl.[NH2:2][C:3]1([CH2:8]Cl)[CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:10][C:11]1[CH:12]=[C:13]([N:20]=[C:21]=[S:22])[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]>>[CH3:10][C:11]1[CH:12]=[C:13]([N:20]=[C:21]2[S:22][CH2:8][C:3]3([CH2:7][CH2:6][CH2:5][CH2:4]3)[NH:2]2)[CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1cc(N=C=S)ccc1[N+](=O)[O-]
Reactant: NC1(CCl)CCCC1
Agent: Cl
Product: Cc1cc(N=C2NC3(CCCC3)CS2)ccc1[N+](=O)[O-]

Procedure:
3-Methyl-4-nitroaniline was converted to 3-methyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Amino-1-(hydroxymethyl)cyclopentane was synthesized as described in Method B1c. The 2-hydroxyethylamine was reacted with SOCl2 according to Method B7a to give 1-amino-1-(chloromethyl)cyclopentane HCl salt. The 2-chloroethylamine was reacted with 3-methyl-4-nitrophenyl isothiocyanate according to Method C1a to give 2-(3-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford 1-isobutyl-2-(3-methyl-4-nitrophenylimino)-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7]1[CH:12]=[C:11](F)[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:8]=1[N+:26]([O-:28])=[O:27])[CH3:2].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[C:10]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:8]=1[N+:26]([O-:28])=[O:27])[CH3:2]
Reactant: CCOC(=O)CNc1cc(F)c(Oc2ccc(C(=O)OCC)cc2)cc1[N+](=O)[O-]
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cc(-n2ccnc2)c(Oc2ccc(C(=O)OCC)cc2)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 74.7 %

Procedure:
A mixture of 1.78 g (4.39 mmol) of N-[4-(4-ethoxycarbonylphenoxy)-5-fluoro-2-nitrophenyl]glycine ethyl ester, 896 mg of imidazole and 20 ml of DMF was stirred with heating on an oil bath of 70° C. for 12 hours. After cooling, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate. The resulting solution was washed successively with water and brine, dried over anhydrous sodium sulfate and then, concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (developing solvent: chloroform+0 to 1% methanol) to give 1.49 g (75%) of N-[4-(4-ethoxycarbonylphenoxy)-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester.
Reaction SMILES: [C:1]1([CH:7]([F:15])[C:8](=[O:14])[C:9]([O:11]CC)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)(O)[O-].[Na+]>C(O)(C)C>[C:1]1([CH:7]([F:15])[C:8](=[O:14])[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)C(F)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: O=C(O)C(=O)C(F)c1ccccc1
Reaction time: 15 h
Yield: 68.6 %

Procedure:
To the crude product of ethyl 3-phenyl-3-fluoropyruvate (10.6 g) obtained in Example 1, a 50% aqueous solution of isopropanol (300 ml) is added, and sodium bicarbonate (9.0 g) is added thereto. The mixture is heated gradually while stirring, and hydrolysis is effected at 50° C. for 15 hours. Thereafter, water-insoluble substances are extracted with ethyl acetate (70 ml each for three times). Then, the water layer is admixed with ethyl acetate (200 ml) and made acidic (pH, 1.0-2.0) with 1 N hydrochloric acid under ice cooling. The ethyl acetate layer is dried over magnesium sulfate and distilled under reduced pressure to give 3-phenyl-3-fluoropyruvic acid (6.3 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].N1C=CC=CC=1.[CH3:15][C:16](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:17](Cl)=[O:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:17](=[O:18])[C:16]([CH3:15])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=Cc1ccccc1)C(=O)Cl
Reactant: Nc1cccc(Cl)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=Cc1ccccc1)C(=O)Nc1cccc(Cl)c1
Reaction time: 3 h

Procedure:
To a solution of 3-chloroaniline (0.98 mL, 9.3 mmol) in CH2Cl2 (25 mL) at 0° C. is added pyridine (0.78 mL, 9.5 mmol). To the resulting solution is added dropwise a solution of α-methyl cinnamic acid chloride (1.6 g, 9.3 mmol) in CH2Cl2 (8 mL). After 3 hours, the solution is concentrated. The crude product is purified by column chromatography eluting with 5% EtOAc/hexanes to 10% EtOAc/hexanes. The title compound is obtained as a solid (2.5 g, 9.2 mmol). 1H NMR (CDCl3, 300 MHz) δ7.95 (m, 1H), 7.73 (s, 1H), 7.46 (m, 1H), 7.33 (m, 6H), 7.22 (m, 1H), 7.03 (m, 1H), 2.13 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1(Cl)[N+:14]([O-])=O)[C:6]#[N:7])[CH3:2].CCCCCC.C(Cl)(Cl)[Cl:26]>C(O)(=O)C.[Zn]>[CH2:1]([O:3][C:4]([C:5]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[Cl:26])[NH:14][C:6]=1[NH2:7])=[O:18])[CH3:2]
Reactant: ClC(Cl)Cl
Reactant: CCOC(=O)C(C#N)C1C=CC=CC1(Cl)[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCOC(=O)c1c(N)[nH]c2cccc(Cl)c12
Temperature: 55 °C

Procedure:
4 (18 g, 67 mmol) in 250 mL glacial acetic acid, was treated with a single charge of 18 g of zinc dust. The mixture was heated at 55° C. for 45 minutes. Later 6 g more zinc dust was added. After heating for another 105 minutes, the yellow mixture was filtered through a pad of celite. The pad was washed with acetic acid and the filtrate was concentrated to a residue that was distributed between chloroform and water. The organic phase was washed with NaHCO3 (5%) to provide a pink precipitate which was filtered, dried over P2O5, dissolved in methanol, added silica gel and converted to a silica gel plug by removing the solvent under reduced pressure. The plug was transferred on top of a column packed with silica gel, ten times the weight of plug, eluted with hexane, chloroform, 5% ethylacetate in chloroform and 10% ethylacetate in chloroform. Fractions containing the product 5 (TLC) were pooled and evaporated to give a pink solid. The overall yield from 3 to 5 was 63%. TLC Rf 0.187 (hexane-chloroform 1:1); mp 140-142° C.; 1H NMR (DMSO-d6) δ 1.25-1.28 (t, 3H, CH3); 4.18-4.20 (q, 2H, CH2); 6.85 (bs, 2H, 2-NH2, exch); 6.92-7.09 (m, 3H, phenyl); 10.93 (bs, 1H, 9-NH, exch). Anal. Calculated (C11H11ClN2O2): C, 55.36; H, 4.65; N, 11.74; Cl, 14.85. Found: C, 55.39; H, 4.60; N, 11.65; Cl, 14.96.