Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([OH:24])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[K+].[C:30]([O:36][CH2:37]Cl)(=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].CN(C)C=O>CCOCC>[C:1]([N:9]1[C:21]2[CH2:20][CH2:19][CH:18]([C:22]([O:24][CH2:37][O:36][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[O:23])[CH2:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCOC(=O)C1CCc2c(c3ccccc3n2C(=O)c2ccccc2)C1

Procedure:
A mixture of 12.8 g. of 9-benzoyl-1,2,3,4-tetrahydrocarbazole-3-carboxylic acid, 20 g. of potassium bicarbonate, 12 ml. of chloromethyl pivalate in 50 ml. of dry dimethylformamide was stirred and heated on a steambath for two hours. The mixture was cooled and diluted with ether, the ether mixture was washed several times with water, dried over magnesium sulfate, and evaporated under reduced pressure to dryness to give 10.6 g. of the title compound; m.p. 75°-77°C. (methyl alcohol).
Reaction SMILES: [OH:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][CH2:4][C:5]([NH:7][CH3:8])=[O:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:8][NH:7][C:5](=[O:6])[CH2:4][CH2:3][C:2](=[O:1])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CNC(=O)CCC(O)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CNC(=O)CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.9 %

Procedure:
A mixture of 4-hydroxy-N-methyl-4-phenyl-butyramide (4.50 g, 23.3 mmol), prepared in the previous step, and pyridinium chlorochromate (7.54 g, 35.0 mmol) in 200 ml of methylene chloride was stirred at room temperature for 2.5 hours. The reaction was poured onto 4 g of silica gel (230-400 mesh) and the material eluted with ethyl acetate-methylene chloride and then ethyl acetate. Isolation of the major component gave N-methyl-4-oxo-4-phenyl-butyramide (3.65 g, 82%) as an off-white solid, mp 80-82° C.
Reaction SMILES: [CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)[O:8][CH:7]([CH3:9])[CH2:6][N:5]([CH3:10])[CH2:4]1)[CH3:2].[BrH:19]>>[CH2:1]([C:3]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[O:8][CH:7]([CH3:9])[CH2:6][N:5]([CH3:10])[CH2:4]1)[CH3:2].[BrH:19]
Reactant: CCC1(c2cccc(OC)c2)CN(C)CC(C)O1
Agent: Br
Product: CCC1(c2cccc(O)c2)CN(C)CC(C)O1

Procedure:
2-Ethyl-2-(3-methoxyphenyl)-4,6-dimethylmorpholine (7.0 g) was refluxed for 2.5 hours with aqueous 48% hydrobromic acid (50 ml). After removal of the solvent under reduced pressure the residue was re-evaporated using isopropyl alcohol to remove last traces of HBr and water. Fractional crystallisation of the residue (10.5 g) from isopropyl alcohol/ether gave 1.53 g of 95% stereochemically pure title compound isomer A hydrobromide (m.p. 241°-5° C.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[N+:23]([C:20]1[CH:21]=[CH:22][C:17]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:18][CH:19]=1)([O-:25])=[O:24]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 82.9 %

Procedure:
To a solution of 4-hydroxybenzaldehyde (366 mg, 3 mmol) in anhydrous DMF (7 ml), under nitrogen atmosphere, K2CO3 (829 mg, 6 mmol), and, after 10 minutes, 4-bromonitrobenzene (726 mg, 3.6 mmol) were added. The mixture was heated to reflux for 3 hours, then water was added and the product was extracted with CH2Cl2. The organic layers were washed with water and with NaCl saturated solution and dried with Na2SO4. After evaporation of the solvent the crude product was purified by chromatography on silica gel (Petroleum ether/Ethyl acetate 5/1); 605 mg (yield 82%) of pure title product were obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([O:24]C)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+].Cl>CO.O1CCCC1>[Br:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[C:22]([OH:24])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1cccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
Methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (from step 3) (10.0 g, 21.539 mmol) was dissolved in methanol (36 mL) and tetrahydrofuran (14 mL). 4N NaOH (13.5 mL, 53.847 mmol) was added. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction was acidified (pH 2) with 4N HCl. The precipitate was collected by filtration to afford an off white solid (7.83 g, 81%) 1H NMR (400 MHz, DMSO-d6) δ 8.01 (dt, J=1.41, 7.65 Hz, 1H), 7.76 (app t, J=1.78 Hz, 1H), 7.76-7.15 (m, 5H), 6.66 (s, 1H), 5.32 (s, 2H), 1.92 (s, 3H) ES-HRMS m/z 450.0134 (M+H C20H14BrF2NO4 requires 450.0147).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:43]I.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][O:14][CH3:43])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:37][CH2:38][CH2:39][CH3:40])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CO)cc1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2COC)cc1-c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h

Procedure:
To a stirred solution of (±)-trans-3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-4-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (Example 6, 1.0 mmol, 547 mg) in THF (4.0 mL) at 0° C., NaH (60% dispersion in mineral oil, 1.5 mmol, 60 mg) was added and stirring continued for 10 min at room temperature, then methyl iodide (1.5 mmol, 94 μL) was added. The resulting mixture was stirred at room temperature for 2 hour, poured into water, and extracted with ethyl acetate. The organic layers were combined and concentrated under reduced pressure. The product was purified by column chromatography using 50% ethyl acetate in hexanes to give (±)-trans-3-[5-(4-benzyloxy-phenyl)-6-butyl-pyridazin-3-yloxymethyl]-4-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester, which was dissolved in dichloromethane (1.0 mL), added 4.0 M HCl in dioxane (1.0 mL) and stirred at room temperature for 1 hour. Solvents were evaporated to give (±)-trans-4-(4-benzyloxy-phenyl)-3-butyl-6-(4-methoxymethyl-pyrrolidin-3-ylmethoxy)-pyridazine dihydrochloride.
Reaction SMILES: [CH2:1](C([Sn])=C(CCCC)CCCC)[CH2:2]CC.Cl[C:17]1[N:22]=[C:21]([C:23]2[C:24]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=[CH:33][CH:32]=3)=[C:25]3[CH2:30][CH2:29][CH2:28][N:26]3[N:27]=2)[CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([C:17]1[N:22]=[C:21]([C:23]2[C:24]([C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=4)[N:34]=[CH:33][CH:32]=3)=[C:25]3[CH2:30][CH2:29][CH2:28][N:26]3[N:27]=2)[CH:20]=[CH:19][CH:18]=1)=[CH2:2]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: Clc1cccc(-c2nn3c(c2-c2ccnc4ccccc24)CCC3)n1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1cccc(-c2nn3c(c2-c2ccnc4ccccc24)CCC3)n1
Reaction time: 0.08 h
Yield: 62 %

Procedure:
Add tributylvinyltin (0.059 mL, 0.19 mmol) to a solution of 4-[2-(6-chloro-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline, EXAMPLE 101, (59 mg, 0.17 mmol) in toluene (0.7 mL) at RT. Bubble nitrogen into the reaction mixture for 5 min and add tetrakis-(triphenylphosphine) palladium (0) (10 mg, 0.0085 mmol). Bubble nitrogen into the solution for an additional 2 min and heat the reaction to 110° C. for 18 h. Concentrate the reaction in vacuo and purify by flash column chromatography (SiO2, 20-40% acetone/hexanes) to provide the title compound (35 mg, 62%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH:12]=O)[N:11]=1.[S:19]1[CH2:25][C:23](=[O:24])[N:22]([CH2:26][C:27]([OH:29])=[O:28])[C:20]1=[S:21].[Cl-].[NH4+].N>C(O)C>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[NH:6][C:7]1[S:8][CH:9]=[C:10]([CH:12]=[C:25]2[S:19][C:20](=[S:21])[N:22]([CH2:26][C:27]([OH:29])=[O:28])[C:23]2=[O:24])[N:11]=1
Reactant: O=Cc1csc(Nc2cccc(C(F)(F)F)c2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(Nc3cccc(C(F)(F)F)c3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 1 g of 2-(m-trifluoromethylanilino)thiazole-4-carbaldehyde, 0.7 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia, and 10 ml of ethanol, giving the title compound as yellowish-orange prisms.
Reaction SMILES: C(OC(=O)[C:5]1[C:6](=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=1Cl)[N:7]([CH3:9])[CH3:8])C.[OH-:17].[K+]>O>[CH3:8][N:7]([CH3:9])[C:6]1[CH:5]=[C:13]([OH:17])[CH:12]=[C:11]([CH3:15])[CH:10]=1
Reactant: CCOC(=O)c1c(Cl)cc(C)cc1N(C)C
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: Cc1cc(O)cc(N(C)C)c1

Procedure:
Ethyl-6-chloro-4,N,N-trimethylanthranilate (2.4 g) and KOH (powdered, 1.5 g) were heated together in a test-tube with a free flame. After the initial reaction (temp 200°-220°) had subsided, the temperature was raised to 240°-260°, whereupon a second vigorous reaction ensued and the mixture became dark. On cooling, the mixture was dissolved in water, extracted with ether to remove tarry byproducts, and acidified (pH 5) with acetic acid. The crude product was extracted into chloroform and after removal of solvent, was purified by sublimation at 0.1 mm. 3-Dimethylamino-5-methylphenol was obtained as a pale yellow solid, mp 67°-68°.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH:5]([NH:18]C(=O)OC(C)(C)C)[CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2].Cl>>[NH2:18][CH:5]([CH2:4][O:3][CH2:1][CH3:2])[CH2:6][NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOCC(CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Product: CCOCC(N)CNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of benzyl tert-butyl (3-ethoxypropane-1,2-diyl)biscarbamate (3.0 g, 8.5 mmol) in hydrochloric acid (4.0 M in methanol, 20 mL, 80 mmol) was stirred at ambient temperature. After 2 hours, the reaction mixture was concentrated under reduced pressure to give benzyl (2-amino-3-ethoxypropyl)carbamate. MS ESI calc'd. for C13H21N2O3 [M+H]+ 253. found 253. 1H NMR (400 MHz, CD3OD) δ 7.45-7.26 (m, 5H), 5.13 (s, 2H), 3.67-3.51 (m, 4H), 3.45-3.39 (m, 3H), 1.24 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][N:15]2[C@H:10]([CH2:11][O:12][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[C:20]=3[CH3:28])(O)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][N:15]2[C@H:10]([CH2:11][O:12][C:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]#[N:27])[C:20]=3[CH3:28])=[CH:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c([C@]2(O)CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(C2=CN3CCN(C(=O)OC(C)(C)C)C[C@H]3CO2)ccc(F)c1C#N
Temperature: 25 °C

Procedure:
Mesyl-Cl (17.2 mL, 221 mmol) was added dropwise to a stirred, <5° C. internal temperature mixture of (3R,9aS)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-3-hydroxy-hexahydro-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester (66.6 g, 170 mmol) and triethylamine (71.1 mL, 510 mmol) in CH2Cl2 (1000 mL) (exotherm occurs, so must keep addition slow), and the reaction was allowed to warm to room temperature for 30 minutes, by which time reaction was complete. The solution was washed with 500 mL 10% w/w NaHCO3 aqueous solution. The organics were dried over MgSO4, filtered and concentrated. The resulting material was taken up in a minimal amount of EtOAc (125 mL) with some heating (solution kept<50° C.) until all solids dissolved. The solution was allowed to cool with stirring, then dropwise overnight 350 mL hexanes was added. By the next morning the solution had clarified and there was considerable powder. The solids were collected by filtration and washed with 20% EtOAc/Hexanes, providing product. The mother liquors were concentrated until precipitate appeared, which was filtered to give additional (S)-3-(3-Cyano-4-fluoro-2-methyl-phenyl)-6,7,9,9a-tetrahydro-1H-pyrazino[2,1-c][1,4]oxazine-8-carboxylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH2:12])[CH:3]=1.CN(C=O)C.[Br:18][CH2:19][C:20](Br)=[O:21].[Br-]>O1CCOCC1>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([NH:12][C:20](=[O:21])[CH2:19][Br:18])[CH:3]=1
Reactant: O=C(Br)CBr
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(CBr)Nc1cc(F)c(F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution of 4,5-difluoro-2-aminobenzoic acid (20.0 g, 115.5 mmol) in a mixture of anhydrous DMF (50 mL) and anhydrous dioxane (50 mL) was cooled to 0° C. under N2 using an ice-bath. Bromoacetyl bromide (23.3 g, 10.1 mL, 115.5 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 3/4 h period. After the addition of bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 200 mL of ice-water. The resulting precipitate was filtered, washed with water, and then dried in a vacuum desiccator overnight to afford 31.24 g (92%) of the title compound as a white solid, mp 177°-180° C.: 1H NMR (DMSO-d6) δ14.17 (bs, 1H), 11.66 (s, 1H), 8.47 (dd, J=13.6, J=7.6, 1H), 7.97 (dd, J=11.2, J=9.2, 1H), 4.28 (s, 2H); 13C NMR (DMSO-d6) δ167.55, 165.45, 151.99 (dd, J=249, J=12.9), 144.53 (dd, J=242, J=12.9), 137.58 (dd, J=7.5, 1=3), 119.75 (d, J=18.9), 114.18 (t, J=3), 108.96 (d, J=23.5), 30.43; MS (EI m/z) 293 (M+).
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][NH2:13])(=O)=O)=CC=1.N1C=CC=CC=1.Cl[P:22]1(=[O:27])[O:26][CH2:25][CH2:24][O:23]1>C(#N)C>[NH2:13][CH2:12][CH2:11][O:10][P:22]1(=[O:27])[O:26][CH2:25][CH2:24][O:23]1
Reactant: Cc1ccc(S(=O)(=O)OCCN)cc1
Reactant: O=P1(Cl)OCCO1
Solvent: c1ccncc1
Solvent: CC#N
Product: NCCOP1(=O)OCCO1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethanolamine p-toluenesulphonate (10.0 g, 39.8 mmol was dissolved in dry acetonitrile (500 ml) at 60° C. The solution was cooled to 30° C. when pyridine (3.15 g, 39.8 mmol) was added. A solution of 2-chloro-2-oxo-1,3,2-dioxaphospholane (5.68 g, 39.8 mmol) in dry acetonitrile (5 ml) was then added over 10 minutes. The mixture was stirred at ambient temperature for 4 hours and then the acetonitrile evaporated in vacuo to give 2-(2-aminoethoxy)-2-oxo-1,3,2-dioxaphospholane as a viscous oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([CH:30]([CH3:32])[CH3:31])[C:17]=1OC1N(C2C=CC=CC=2)N=NN=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])([CH3:3])[CH3:2]>C1C=CC=CC=1.[Pd]>[CH:1]([C:4]1[CH:5]=[C:6]([CH:15]=[C:16]([CH:30]([CH3:32])[CH3:31])[CH:17]=1)[C:7]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:8])([CH3:3])[CH3:2]
Reactant: COC(=O)CCC(=O)c1cc(C(C)C)c(Oc2nnnn2-c2ccccc2)c(C(C)C)c1
Agent: [Pd]
Solvent: c1ccccc1
Product: COC(=O)CCC(=O)c1cc(C(C)C)cc(C(C)C)c1
Reaction time: 14 h
Yield: 71.7 %

Procedure:
14.1 g of Methyl 3-[3,5-diisopropyl-4-(1-phenyltetrazol-5-yloxy)benzoyl]propionate was dissolved in 100 ml of benzene, followed by the addition of 10 g of 10% palladium/carbon. The obtained mixture was subjected to hydrogenation under a pressure of 3 kg/cm2, at room temperature for 14 hours. The reaction mixture thus obtained was filtered to remove the catalyst. The filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (developer: 3% ethyl acetate/n-hexane) to give 6.4 g of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
35 G. of p-chlorobenzoyl chloride are added dropwise to a solution of 26 g. of N-(2-aminoethyl)-morpholine in 200 ml. of pyridine, while stirring and cooling with ice-water. Thereafter, the mixture is stirred overnight at room temperature and subsequently evaporated to dryness. Then, the residue is evaporated twice more with 200 ml. of toluene each time. The solid residue is taken up in 300 ml. of ice-water and 300 ml. of methylene chloride and rendered basic with 3-N sodium hydroxide solution. The phases are separated and the methylene chloride extract is washed with water, dried over sodium sulfate and evaporated to dryness. The residue is recrystallized from isopropanol and 41.5 g. of p-chloro-N-(2-morpholinoethyl)-benzamide, melting point 137° C., are obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29](Cl)=[O:30].N1C=CC=CC=1>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=2)=[O:30])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccccn1
Yield: 64.3 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (40 ml), picolinoyl chloride hydrochloride (1.41 g) and pyridine (1.28 ml) were added, and the mixture was refluxed for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (150 ml), successively washed with water and saturated aqueous sodium bicarbonate, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, diethyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 1.75 g of the titled compound.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].Cl.CCOCC.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]([O:5][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:4])[CH2:2][OH:3]
Reactant: O=C(O)CO
Reactant: OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: O=C(CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
Into a solution of glycolic acid (35 gm, 46 mmol) in benzyl alcohol (200 mL) was bubbled anhydrous hydrogen chloride for 1 hr at 0° C. The reaction was then stirred for an additional 4 hrs at 0° C. before it was poured into a mixture of ice water and ether. The layers were separated and the aqueous layer was reextracted with ether. The ether layers were sequentially washed with sodium bicarbonate and brine, combined, dried over sodium sulfate and evaporated. Distillation of the residue at 103°-110° C. 0.5 mm afforded 59 gm (77%) of benzyl glycolate as a clear liquid.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][O:12][CH:11]([CH:15]([OH:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:10]1)C1C=CC=CC=1>CCO>[ClH:1].[OH:21][CH:15]([CH:11]1[O:12][CH2:13][CH2:14][NH:9][CH2:10]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(O)C1CN(Cc2ccccc2)CCO1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(O)C1CNCCO1
Yield: 101.1 %

Procedure:
According to the Step 33-1 in synthetic method for EXAMPLE 33, compound 115-2 (0.9 g) with EtOH was used instead of EXAMPLE 32 to obtain compound 115-3 (0.65 g) as pale yellow amorphous solid.
Reaction SMILES: N1C2C(=CC=CC=2)C([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=C1.[NH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:18](C)=[CH:17]1>>[NH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:18]=[C:17]1[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: Cc1c[nH]c2ccccc12
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Product: O=C(O)CCCc1cc2ccccc2[nH]1
Reaction time: 3 h

Procedure:
Microtiter plates (Nunc, Sweden) coated with anti-indoleacetic acid polyclonal antibodies (described above) were used. A mixture of 100 μl of the enzyme conjugate (Indole-3-butyric acid-AP conjugate, prepared as described above, and diluted 1:10,000 in TBS) and 100 μl of skatole solution (either in TBS or in 10% porcine serum solution) of a number of dilutions was added to wells in duplicate. The mixture was incubated for 3 hrs. at 4° C. and then washed with saline-Tween solution 3 times (200 μl volume). 200 μl of the substrate solution (1mg/ml in TBS) was added per well and incubated at 37° C. for an hour. The wells were then treated with approximately 50.0 μl of 1N NaOH/well to stop the reaction. Final absorbances were measured.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18]C)=[O:17])=[C:8]2[C:20]([O:22]C)=[O:21])=[CH:4][CH:3]=1.[OH-].[K+].Cl>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[C:8]2[C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1
Reactant: COC(=O)c1c(C(=O)OC)n(Cc2ccc(F)cc2)c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1c(C(=O)O)n(Cc2ccc(F)cc2)c2ccccc12
Temperature: 95 °C
Reaction time: 18 h
Yield: 86.3 %

Procedure:
A rbf charged with dimethyl 1-(4-fluorobenzyl)-1H-indole-2,3-dicarboxylate (3.79 g, 11.10 mmol) was treated with a solution of KOH (7.48 g, 133 mmol) in Ethanol (13.88 ml) (0.5 M solution) and heated to reflux (95° C. bath temp). After 18 h, the reaction mixture was cooled to ambient temperature, and acidified to pH 1 with 4M HCl and extracted with EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated to afford 1-(4-fluorobenzyl)-1H-indole-2,3-dicarboxylic acid (3.0 g, 9.58 mmol, 86% yield) as a yellowish solid. LCMS (m/z) ES+=314 (M+1).