Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6].[NH2:24][CH2:25][CH2:26][CH:27]1[O:31][CH2:30][CH2:29][O:28]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:28]1[CH2:29][CH2:30][O:31][CH:27]1[CH2:26][CH2:25][NH:24][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:5]([N:7]([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[O:6]
Reactant: NCCC1OCCO1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCC2OCCO2)c1
Yield: 98 %

Procedure:
A mixture of 3-fluoro-N,N-bis(3-methylbutyl)-4-nitrobenzamide prepared according to Example A1 (1.86 g, 1 eq), 2-(2-aminoethyl)-1,3-dioxolane (0.8 g, 1.2 eq) and potassium carbonate (1.58 g, 2 eq) in acetonitrile (150 ml) is heated under reflux for 3 hours then concentrated under reduced pressure at 40° C. The residue is taken up in dichloromethane (150 ml) and water (60 ml). After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent: heptane/ethyl acetate 8:2 to 7:3) produces the expected compound in the form of an orange-yellow oil (2.4 g; 98% yield).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.Cl.[F:18][C:19]([F:23])([F:22])[CH2:20][NH2:21]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:21][CH2:20][C:19]([F:23])([F:22])[F:18])[N:3]=1
Reactant: NCC(F)(F)F
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Agent: Cl
Solvent: CCN(CC)CC
Product: FC(F)(F)CNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[2,2,2-trifluoroethylamino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2,2,2-trifluoroethylamine hydrochloride, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[CH:12]=[C:11]3[NH:13][C:14](=[O:22])[C:15](C(OCC)=O)([CH3:16])[C:10]3=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3].S(=O)(=O)(O)O.N>>[CH2:1]([C:4]1[NH:5][C:6]2[CH:12]=[C:11]3[NH:13][C:14](=[O:22])[CH:15]([CH3:16])[C:10]3=[CH:9][C:7]=2[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C(=O)OCC
Agent: N
Agent: O=S(=O)(O)O
Product: CCCc1nc2cc3c(cc2[nH]1)NC(=O)C3C

Procedure:
1.50 g. (4.9 mmole) of the compound prepared in Example 10 is stirred in 30 ml. 60% sulphuric acid for 1 hour at 60° C. bath temperature, then poured on to ice, neutralised with 2N aqueous ammonia solution and the precipitated product is filtered off with suction and the residue crystallised from ethyl acetate/methanol. There is obtained 0.70 g. (62% of theory) of the title compound; m.p. 235°-238° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH:22][CH3:23])[CH3:21]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:22]([CH2:20][CH3:21])[CH3:23])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Solvent: CS(C)=O
Product: CCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and N-ethyl-methylamine (2.89 g, 48.8 mmol) in DMSO (35 mL) at RT according to the general procedure C. Obtained as a pale brown solid (3.21 g).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18]C)=[CH:8][CH:7]=1)=[O:5])[CH3:2].B(Br)(Br)Br>ClCCl>[CH2:20]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])=[CH:8][CH:7]=1)=[O:5])[CH3:21]
Reactant: CCN(CC)C(=O)c1ccc(-c2ccccc2OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(-c2ccccc2O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
2-(4-Diethylcarbamoylphenyl)anisole (250 mg) was dissolved in dichloromethane (10 ml), added with boron tribromide (0.42 ml) and stirred at room temperature for 3 hours. After the reaction mixture was slowly poured into ice (20 g) with ice cooling to quench the reaction and the layers were separated, the aqueous layer was extracted with dichloromethane (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=2:1→1:1) to obtain 231 mg of the title compound. Yield: 97%.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH2:35])([CH3:29])([CH3:28])[CH3:27].[OH-].[Na+].OP([O-])(O)=O.[K+]>C1COCC1.CC#N>[C:26]([O:30][C:31](=[O:36])[NH:32][CH2:33][CH2:34][NH:35][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COc1ccc(Nc2nc(NCCNC(=O)OC(C)(C)C)nc(NC3CCCCCC3)n2)cc1Cl
Yield: 81 %

Procedure:
To 133 (2.36 g, 6.2 mmol) dissolved in THF (12 ml), was added a solution of N-(2-aminoethyl)carbamic acid tert-butyl ester (163a, 1 ml, 6.2 mmol) in THF (12 ml) followed by addition of 2.5N NaOH (2.5 ml, 6.2 mmol). The reaction mixture was allowed to reflux overnight under nitrogen. The reaction mixture was extracted 3 times with ethyl acetate; combined organic layers were washed with brine solution and dried over potassium carbonate. The filtered sample was concentrated on the rotary evaporator, and the resulting solid was dried overnight under vacuum. Chromatography [Biotage Horizon HPFC system, silica gel, gradient method 0 to 5% CH3OH in CH2Cl2 (over 600 mL)] yielding a white solid (E65, 2.54 mg, 81% yield), mp 94° C.; HPLC: Intertsil ODS-3V C18, 30:70 [(KH2PO4 (0.01M, pH 3.2): CH3CN], 264 nm, Rt 9.7 min, 99.8% purity; MS (TOF MS ES+), m/z 508 (36.5), 506 (M+H, 100).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([CH3:15])[CH:8]=[C:9]([N+:12]([O-])=O)[CH:10]=2)[CH:5]=[N:4]1)[CH3:2]>[Pd].C(OCC)(=O)C>[CH2:1]([N:3]1[C:11]2[C:6](=[C:7]([CH3:15])[CH:8]=[C:9]([NH2:12])[CH:10]=2)[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(C)cc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCn1ncc2c(C)cc(N)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
10% Palladium on carbon (1.0 g) was added to a solution of 1-ethyl-4-methyl-6-nitro-1H-indazole obtained in the above-described Step 1 (975 mg) in ethyl acetate (10 mL), and the reaction solution was stirred under hydrogen atmosphere at room temperature overnight. The insolubles were filtrated, and the solvent was evaporated under vacuum to obtain 1-ethyl-4-methyl-1H-indazol-6-amine.
Reaction SMILES: [CH2:1]([C:3]([CH2:19][CH3:20])([C:16]([O-:18])=[O:17])[C:4]([O:6]C(C)CCCCCCC)=[O:5])C.[OH-].[K+].[CH2:23](O)[CH3:24]>O>[CH3:1][C:3]([CH2:19][CH2:20][CH2:1][CH2:3][CH2:19][CH2:20][CH2:23][CH3:24])([C:16]([OH:18])=[O:17])[C:4]([OH:6])=[O:5]
Reactant: CCCCCCCC(C)OC(=O)C(CC)(CC)C(=O)[O-]
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCC(C)(C(=O)O)C(=O)O

Procedure:
To a stirring mixture of methyloctyl diethylmalonate (6.8 g, 25 mmol) in water (50 mL) and ethanol (50 mL) was added KOH pellets (15.0 g, 250 mmol). The cloudy mixture was then refluxed overnight where it became clear. The solvent was concentrated in vacuo to a white solid. The solid was dissolved in water and extracted with ether (2×). The water layer was then acidified with concentrated HCl and a solid precipitated out of solution. The white solid was filtered and the resulting mother liquor was extracted with ether in order to isolate any additional product. The combined organic layers were concentrated in vacuo and the resulting white solid was added to the filtered solid and dried in a vacuum oven. This afforded 4.3 g of pure product (75%).
Reaction SMILES: [Cl:1][C:2]1[N:6](COCC[Si](C)(C)C)[CH:5]=[N:4][C:3]=1[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][C:28]2[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[C:30]([Cl:36])[CH:29]=2)[C:20]=1[F:37])=[O:16].C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[N:6]=[CH:5][NH:4][C:3]=1[C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[C:21]([O:27][C:28]2[CH:33]=[C:32]([C:34]#[N:35])[CH:31]=[C:30]([Cl:36])[CH:29]=2)[C:20]=1[F:37])=[O:16]
Reactant: CCc1ccc(CNC(=O)c2ncn(COCC[Si](C)(C)C)c2Cl)c(F)c1Oc1cc(Cl)cc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(CNC(=O)c2[nH]cnc2Cl)c(F)c1Oc1cc(Cl)cc(C#N)c1
Yield: 63.9 %

Procedure:
A solution of 5-chloro-N-({3-[(3-chloro-5-cyanophenyl)oxy]-4-ethyl-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-4-carboxamide (0.12 g, 0.213 mmol) and TFA (1.641 ml, 21.29 mmol) were stirred at RT under an atmosphere of nitrogen for 16 h then the solution was concentrated under vacuum. The material was purified by Reverse Phase HPLC (MeCN/water+0.1% TFA). The desired product was washed with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (50 mL), water (50 mL), dried over MgSO4, filtered and concentrated to give the title compound (0.059 g, 61%) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.73 (s, 1H), 7.50 (s, 1H), 7.31 (t, 1H), 7.15-7.22 (m, 3H), 4.64 (s, 2H), 2.58 (q, 2H), 1.15 (t, 3H). LCMS m/z 434.1 (M+H).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.S[C:8]1[O:9][C:10]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)[CH2:23][CH2:22]1
Reactant: O=[N+]([O-])c1ccc2nc(S)oc2c1
Reactant: CN1CCNCC1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CN1CCN(c2nc3ccc([N+](=O)[O-])cc3o2)CC1
Temperature: 100 °C

Procedure:
Phosphorus pentachloride (764 mg) was dissolved in anhydrous toluene (9 ml), the resulting solution was mixed with 2-mercapto-6-nitrobenzoxazole (600 mg) which has been obtained in the same manner as described in Reference Example 1, and the mixture was then stirred with heating at 100° C. for 3 hours. With cooling in an ice bath, to this was added dropwise N-methylpiperazine (3.4 ml). After 20 minutes of stirring, the thus obtained mixture was extracted with ethyl acetate, and the organic layer was washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order. After drying with magnesium sulfate, the solvent was evaporated under a reduced pressure, and the resulting residue was purified by a silica gel column chromatography (methylene chloride:methanol=20:1) to obtain 2-(4-methyl-1-piperazinyl)-6-nitrobenzoxazole (668.9 mg) in the form of yellow crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]([NH:9][NH:10][C:11](=O)[CH2:12][C:13]2[CH:26]=[CH:25][C:16]3[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:19][C:15]=3[CH:14]=2)=[O:8])=[CH:5][CH:4]=1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([C:7]2[O:8][C:11]([CH2:12][C:13]3[CH:26]=[CH:25][C:16]4[CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[S:19][C:15]=4[CH:14]=3)=[N:10][N:9]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1cc2ccc(CC(=O)NNC(=O)c3ccc(OC)cc3)cc2s1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(Cc3nnc(-c4ccc(OC)cc4)o3)cc2s1
Yield: 93.4 %

Procedure:
A solution of ethyl 6-{2-[2-(4-methoxybenzoyl)hydrazino]-2-oxoethyl}-1-benzothiophene-2-carboxylate (78 mg, 0.19 mmol) and (methoxycarbonylsulfamoyl)-triethylammonium hydroxide, inner salt (113 mg, 0.47 mmol) in THF was heated to 100° C. in the microwave for 10 minutes. The reaction was filtered through a pad of silica and washed with ethyl acetate. The organics were evaporated to dryness to give 70 mg (94%) of the title compound as a clear oil. LC/MS (EI): cal'd 395.1 (MW), exp 395.1 (MW).
Reaction SMILES: COC([C:5]1[N:6]([NH:14][C:15]([NH:17][C:18](=[O:25])C2C=CC=CC=2)=[S:16])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=O.[OH-].[Na+].O.C(O)(=O)C>>[S:16]=[C:15]1[NH:17][C:18](=[O:25])[C:5]2=[CH:13][C:12]3[C:7]([N:6]2[NH:14]1)=[CH:8][CH:9]=[CH:10][CH:11]=3
Reactant: COC(=O)c1cc2ccccc2n1NC(=S)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c(=S)[nH]n2c1cc1ccccc12
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
Into a 1 L beaker, 1-(3-benzoyl-thioureido)-1H-indole-2-carboxylic acid methyl ester (24.27 g, 0.07 mol) and a 2 M solution of sodium hydroxide in water (140 mL, 0.28 mol) were added. The mixture was heated at 85° C. for 75 minutes. The reaction was cooled to room temperature. Acetic acid (16.7 mL, 0.29 mol) was added at 0° C. and the mixture was stirred for 30 minutes. The solid was filtered and dried on filter overnight to afford a white solid, which was further dried under vacuum overnight. NMR indicated about 1:1 molar ratio of product to benzoic acid. Trituration and filtration from hot benzene removed the benzoic acid and afforded 2-thioxo-2,3-dihydro-1H-[1,2,4]triazino[1,6-a]indol-4-one (14.50 g, 96%), which was used in the next step without further purification. 1H-NMR (DMSO-d6) δ 10.29 (br s, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.3 (br s, 1H), 7.27 (m, 1H), 7.12 (m, 1H), 6.88 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:22](=[O:23])[O:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[CH:16][CH:15]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(N)cc2)C1
Solvent: ClCCl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenamine (intermediate 30.7) (300 mg, 0.98 mmol, 1.00 equiv) in dichloromethane (10 mL). This was followed by the addition of 4-nitrophenyl chloroformate (230 mg, 1.14 mmol, 1.20 equiv) in several batches at room temperature. The resulting solution was stirred for 3 h at room temperature. The solids were collected by filtration. This resulted in 0.3 g (65%) of 4-nitrophenyl 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylcarbamate as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][CH:9]([C:22]([O-:24])=[O:23])[C@@H:10]([C:19]([O-:21])=[O:20])[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[CH2:1]([O:8][CH:9]([C:22]([OH:24])=[O:23])[C@@H:10]([C:19]([OH:21])=[O:20])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)[O-])C(OCc1ccccc1)C(=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H](C(=O)O)C(OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 68.7 %

Procedure:
To a solution of 65 mg (0.14 mmol) of the compound (14) in chloroform (2 ml) was added 2 ml of trifluoroacetic acid, and then the mixture was stirred at room temperature for 20 hours. The solvent was distilled off and the residue was subjected to column chromatography on ion exchange resin (Dowex 50Wx4) and washed with water, then eluted with 1N aqueous ammonia to give 23 mg of the title compound (15) (yield 65%).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14](O)=[O:15])[CH2:9]2)=[N:4][N:5]([CH3:7])[CH:6]=1.B.C1COCC1>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([N:8]2[CH2:9][CH:10]([CH2:14][OH:15])[CH2:11][C:12]2=[O:13])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: Cn1cc(Br)c(N2CC(C(=O)O)CC2=O)n1
Agent: B
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cn1cc(Br)c(N2CC(CO)CC2=O)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 17.3 %

Procedure:
To a solution of 1-(4-bromo-1-methyl-1H-pyrazol-3-yl)-5-oxopyrrolidine-3-carboxylic acid (511 mg) obtained in Step A of Example 7 in THF (3.0 mL) was added 1.1M borane-THF complex THF solution (5.0 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 20 hr, and diluted with ethyl acetate. The diluted solution was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and (methanol/ethyl acetate) to give the title compound (84 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:35]2[N:36]=[CH:37]C=[CH:39][C:34]=2N=N1.CNCCC>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5]([N:36]([CH3:37])[CH2:35][CH2:34][CH3:39])=[O:7])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CCCNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-iodo-5-(methoxycarbonyl)benzoic acid (1.0 g, 3.3 mmol), prepared as in Example SP-281, step 1, and diisopropylethylamine (1.7 mL, 9.8 mmol) in DMF (10 mL) is added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.5 g, 3.9 mmol) then N-methylpropylamine (503 μL, 4.9 mmol). The solution is stirred at room temperature 2 h. The solution is diluted in ethyl acetate and washed with water, saturated sodium bicarbonate, and brine. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound in crude form. This material is purified by flash chromatography (40% ethyl acetate/hexane) to give the purified title compound. MS (ESI) [M+H+]=362.4.
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2)=C(N2CC3C(=CC=C(O)C=3)C2)C=1.Cl.ClCCN(C(C)C)C(C)C.[CH:42]([N:45]([CH:78]([CH3:80])[CH3:79])[CH2:46][CH2:47][O:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[CH2:54][N:53]([C:58]1[CH:63]=[C:62]([O:64]C)[CH:61]=[CH:60][C:59]=1[CH:66]1[CH2:75][CH2:74][C:73]3[C:68](=[CH:69][CH:70]=[C:71]([O:76]C)[CH:72]=3)[CH2:67]1)[CH2:52]2)([CH3:44])[CH3:43]>>[CH:78]([N:45]([CH:42]([CH3:44])[CH3:43])[CH2:46][CH2:47][O:48][C:49]1[CH:50]=[C:51]2[C:55](=[CH:56][CH:57]=1)[CH2:54][N:53]([C:58]1[CH:63]=[C:62]([OH:64])[CH:61]=[CH:60][C:59]=1[CH:66]1[CH2:75][CH2:74][C:73]3[CH:72]=[C:71]([OH:76])[CH:70]=[CH:69][C:68]=3[CH2:67]1)[CH2:52]2)([CH3:79])[CH3:80]
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N1Cc3ccc(OCCN(C(C)C)C(C)C)cc3C1)C2
Agent: CC(C)N(CCCl)C(C)C
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1N1Cc3ccc(O)cc3C1)C2
Agent: Cl
Product: CC(C)N(CCOc1ccc2c(c1)CN(c1cc(O)ccc1C1CCc3cc(O)ccc3C1)C2)C(C)C
Yield: 52 %

Procedure:
Synthesized from 2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2,3-dihydro-1H-isoindol-5-ol and (2-chloroethyl)diisopropylamine hydrochloride according to an analogous synthetic method to Preparation Example 40, diisopropyl {2-{2-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2,3-dihydro-1H-isoindol-5-yloxy}ethyl}amine (126 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (62 mg).
Reaction SMILES: C([S:8][C:9]([CH2:22][O:23][CH3:24])([CH2:19][O:20][CH3:21])[CH2:10][N:11]([CH2:13][CH2:14][P:15]([CH3:18])([CH3:17])=S)[CH3:12])C1C=CC=CC=1.[Na].[Cl-].[NH4+]>O1CCCC1.C(Cl)(Cl)Cl>[CH3:18][P:15]([CH3:17])[CH2:14][CH2:13][N:11]([CH2:10][C:9]([CH2:19][O:20][CH3:21])([CH2:22][O:23][CH3:24])[SH:8])[CH3:12]
Reactant: COCC(COC)(CN(C)CCP(C)(C)=S)SCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: COCC(S)(COC)CN(C)CCP(C)C
Temperature: -50 °C

Procedure:
A solution of 2-benzylthio-N-(2-dimethylphosphinothioylethyl)-3-methoxy-2-methoxymethyl-N-methylpropylamine (450 mg) in dry tetrahydrofuran (10 cm3) was placed in a flask fitted with a low temperature condenser (-50° C.), drying tube and gas inlet. The flask was flushed with nitrogen, the solution cooled to -50° C., and then dry ammonia (40 cm3) was condensed into the flask. Small pieces of sodium were then added to this mixture until the blue colouration persisted for at least 1 hour. The blue colouration was then discharged by the addition of ammonium chloride, and the mixture allowed to warm to room temperature. As the ammonia evaporated steps were taken to ensure that no air entered the apparatus. [The flask and its contents were then transfered to a glove box containing a nitrogen atmosphere for subsequent operations.] The reaction mixture was then filtered and the solvent removed under reduced pressure to give a yellow oil containing some solid material. The oil was dissolved in chloroform, the solid removed by filtration, and the solvent removed under reduced pressure to give 2-[N-(2-dimethylphosphinoethyl)-N-methylamino]-1,1-bis(methoxymethyl)ethanethiol as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=O.[CH3:13][NH:14][C:15](=[S:18])[NH:16][NH2:17]>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5](=[N:17][NH:16][C:15](=[S:18])[NH:14][CH3:13])[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CNC(=S)NN
Reactant: O=C(CCCCl)c1cccnc1
Solvent: CCO
Product: CNC(=S)NN=C(CCCCl)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.2 %

Procedure:
A mixture of 4-chloro-1-(3-pyridinyl)-1-butanone (4.4 g, 24 mmol) and 4-methylthiosemicarbazide (2.5 g, 24 mmol) in 150 mL of ethanol under a nitrogen atmosphere was warmed to dissolve all the solids and then allowed to stir at room temperature overnight. By TLC the reaction was not complete. The reaction was then heated at 70° C. for 5 hours and overnight at room temperature. The solvent was removed under reduced pressure to give 7.29 g of a yellow oil. Purification of this oil on 700 g of silica gel (230-400 mesh) using 50-70% EtOAc-hexane as the eluent gave 4.14 g (64%) of the title compound as a white solid, mp 100-102° C.