Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.O.N1(O)C2C=CC=CC=2N=N1.Cl.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][CH:36]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:37]([OH:39])=[O:38].[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48](O)[CH2:47]2>C1COCC1>[N:46]12[CH2:53][CH2:52][CH:49]([CH2:50][CH2:51]1)[C@@H:48]([O:38][C:37](=[O:39])[CH:36]([NH:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[F:28])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:47]2
Reactant: O=C(O)C(Nc1ccccc1F)c1ccccc1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccccc1F)c1ccccc1
Yield: 16.3 %

Procedure:
A solution of DCC (534 mg, 0.71 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (217 mg, 1:42 mmol), (2-fluoro-phenylamino)-phenyl-acetic acid hydrochloride (I247) (200 mg, 0.71 mmol) and (R)-quinuclidin-3-ol (271 mg, 2.13 mmol) in THF (10 mL) is stirred at RT for 2 days. The solvent is evaporated and the residue is taken up with EtOAc, washed with sat NaHCO3, water and brine. The organic layer is collected, dried over Na2SO4, filtered and evaporated to dryness. The residue is purified by preparative HPLC. The organic solvent is evaporated and the acid aqueous phase is basified with Na2CO3 and extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and evaporated to afford the title compound as yellow oil (41 mg, 16% yield).
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[S:22][C:23]([CH3:26])=[CH:24][N:25]=1>>[CH3:26][C:23]1[S:22][C:21]([NH:20][C:4]([C:6]2[C:11]([NH:12][C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:25][CH:24]=1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1cccnc1
Reactant: Cc1cnc(N)s1
Product: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2ncc(C)s2)n1

Procedure:
The title compound, was prepared from 6-Methyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-5-methylthiazole in accordance with the general method of example 78, step 2 to yield the final compound as a yellow crystalline solid, MS (ISP): m/e=326.1 (M+H+).
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:23]5[CH:31]=[C:30](F)[N:29]=[CH:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:17][C:16]=3[CH3:33])[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.CCN(CC)CC>CS(C)=O>[CH:1]1([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:23]5[CH:31]=[C:30]([N:34]6[CH2:38][CH2:37][CH2:36][CH2:35]6)[N:29]=[CH:28][C:24]=5[N:25]=[CH:26][N:27]=4)=[CH:17][C:16]=3[CH3:33])[CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: Cc1cc(Nc2ncnc3cnc(F)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1cc(Nc2ncnc3cnc(N4CCCC4)cc23)ccc1OC1CCN(C(=O)C2CCCC2)CC1
Yield: 39.9 %

Procedure:
A solution of Cyclopentyl-{4-[4-(6-fluoro-pyrido[3,4-d]pyrimidin-4-ylamino)-2-methyl-phenoxy]-piperidin-1-yl}-methanone (50 mg, 0.11 mmol), pyrrolodine (15.8 mg, 0.222 mmol), and NEt3 (33.7 mg, 0.333 mmol) in DMSO (1 mL) was heated to 120° C. for 12 h. The reaction was concentrated and purified by preparative HPLC to give the title compound as a yellow solid (22 mg, 40%). MS: 501.4 (MH+); 1H NMR (DMSO-d6, 400 MHz): δ 8.84 (s, 1H), δ 8.30 (s, 1H), δ 7.50-7.54 (m, 2H), δ 7.24 (s, 1H), δ 6.08 (d, J=8.72 Hz, 1H), δ 6.55 (s, 1H), δ 4.52 (m, 1H), δ 3.70 (m, 3H), δ 3.48-3.65 (m, 4H) δ 2.86-2.94 (m, 1H), δ 2.22 (s, 3H), 1.53-2.00 (m, 17H)
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]([C@:11]([NH2:18])(CBr)[C:12](OC)=O)([O:6][C:7](C)(C)C)=[O:5]>C1COCC1>[NH2:18][C@@H:11]([CH2:12][N:2]([CH3:3])[CH3:1])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)[C@@](N)(CBr)C(=O)OC(C)(C)C
Reactant: CNC
Solvent: C1CCOC1
Product: COC(=O)[C@@H](N)CN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 2M solution of dimethylamine in THF (2.5 mL) is added dropwise to a stirred solution of methyl (S) 2-BOC-amino-3-bromo-propionate (0.45 g; 1.42 mmol) (Weiss R. G. et al., J. Org. Chem, 36, 403, 1971; Kang M. et al., ibidem, 61, 5528, 1996) in anhydrous THF (10 mL) at 25° C. The mixture is stirred overnight at r.t. and evaporated to dryness in vacuum. The residue is partitioned between Et2O (30 mL) and aqueous 0.5 N NaOH (2×5 mL); the ethereal extracts are combined, washed with brine, dried over Na2SO4 and evaporated to dryness to obtain 0.34 g (1.22 mmol) of methyl (S)-2-amino-3-dimethylamino-propionate as a pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:20]2[C:21](=[O:33])[N:22]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([Cl:26])=[CH:24][N:25]=2)[CH2:9]1)=O)(C)(C)C.CCN(C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:43][S:44]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:20]2[C:21](=[O:33])[N:22]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([Cl:26])=[CH:24][N:25]=2)[CH2:9]1)(=[O:46])=[O:45]
Reactant: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccccn2)c1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1c(Cl)cnc(N[C@@H]2CN(S(C)(=O)=O)C[C@H]2c2ccccn2)c1=O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred solution of the hydrochloride salt of 3-(trans-4-(2-pyridyl)-pyrrolidin-3-ylamino)-6-chloro-1-ethoxycarbonylmethylpyrazinone from step 9 above (0.2 g, 0.48 mmol) in CH2Cl2 (20 mL) at 0° C. was added DIEA (0.30 mL, 1.7 mmol) and methanesulfonyl chloride (63 mg, 0.55 mmol). The resulting solution was stirred at 0° C. for 6 h and then at ambient temperature for 12 h. The mixture was diluted with CH2Cl2 and aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography using a gradient elution of 2-4% MeOH:CH2Cl2 (0.20 g, TLC Rf=0.5, 95:5 CH2Cl2:MeOH; HPLC RT=5.47 min, method A).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)=[O:4]>Cl.O1CCOCC1>[ClH:24].[CH3:1][O:2][C:3]([C:5]1([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[CH2:6][CH2:7][NH:8][CH2:9][CH2:10]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A 660 mg sample of crude 4-(4-chloro-phenyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (1.87 mmol, 1 equiv) was dissolved in 10 mL of 4 M HCl in p-dioxane and stirred at room temperature for 4 h. The resultant slurry was dried under vacuum to yield 4-(4-chloro-phenyl)-piperidine-4-carboxylic acid methyl ester hydrochloride: MS (ES) M+H expected=254.7, found=254.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[CH2:13][C:12]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][NH2:25])=[CH:16][CH:15]=3)=[N:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:29])[F:27])[CH2:13][C:12]([C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([CH2:24][NH:25][C:30](=[O:32])[CH3:31])=[CH:16][CH:15]=3)=[N:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
1-{4-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]naphthalen-1-yl}methanamine (0.1 g) was dissolved in THF (10 ml), and was added acetic anhydride (0.04 g) thereto. The mixture was stirred for 4 hours at room temperature. The mixture was concentrated under reduced pressure to give residual material which was purified by silica gel chromatography, to obtain the desired compound (63 mg) in a yield of 58%.
Reaction SMILES: [CH3:1][N:2]([CH3:40])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH:12][C:13]2[N:18]=[C:17]([C:19]3[N:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]4=[N:21][C:20]=3[C:28]3[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([CH:37]=3)[C:33](OC)=[O:34])[CH:16]=[CH:15][N:14]=2)[CH:9]=[CH:10][CH:11]=1.[F:41][C:42]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:43]=1[NH2:44].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[F:41][C:42]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[C:43]=1[NH:44][C:33](=[O:34])[C:32]1[CH:37]=[C:28]([C:20]2[N:21]=[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]3[C:19]=2[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([NH:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:40])[CH3:1])[CH:7]=3)[N:18]=2)[CH:29]=[CH:30][C:31]=1[O:38][CH3:39]
Reactant: Nc1c(F)cccc1F
Reactant: COC(=O)c1cc(-c2nc3ccccn3c2-c2ccnc(Nc3cccc(OCCN(C)C)c3)n2)ccc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cccc(OCCN(C)C)c3)n2)cc1C(=O)Nc1c(F)cccc1F
Yield: 74.1 %

Procedure:
To methyl 5-(3-{2-[(3-{[2-(dimethylamino)ethyl]oxy}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(methyloxy)benzoate (2.35 g, 4.36 mmol) and 2,6-difluoroaniline (2.35 mL, 21.8 mmol) in THF (30 mL) was added sodium bis(trimethylsilyl)amide (26.0 mL, 1M in THF, 26.0 mmol) in one portion. Upon completion by MS, the reaction was poured into half saturated NaHCO3, extracted with DCM and EtOAc, dried (MgSO4) and concentrated. Purification by flash chromatography and trituration with diethyl ether provided the title compound (2.05 g, 3.23 mmol, 74%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.16 (s, 6H), 2.56 (br. s., 2H), 3.98 (br. s., 5H), 6.55 (d, J=7.7 Hz, 1H), 6.69 (d, J=4.4 Hz, 1H), 7.01-7.11 (m, 1H), 7.17 (d, J=7.3 Hz, 3H), 7.27 (s, 2H), 7.32-7.42 (m, 1H), 7.42-7.54 (m, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.81 (d, J=8.1 Hz, 1H), 8.15 (s, 1H), 8.37 (d, J=4.4 Hz, 1H), 9.49 (br. s., 1H), 9.78 (d, J=12.5 Hz, 2H). MS (M+H, ES+) 636.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N+:11]([O-])=O.C(O)(C)(C)C.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:4]([NH2:11])=[C:3]([NH:2][CH3:1])[CH:8]=1
Reactant: CNc1cc(OC)ccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CNc1cc(OC)ccc1N
Temperature: 60 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
346 g of stannous chloride were added to a mixture of 35 g of N-methyl-5-methoxy-2-nitroaniline (prepared as described in Preparation 8), 900 ml of t-butanol and 100 ml of ethyl acetate at room temperature, and the resulting mixture was stirred at 60° C. for 2 hours, after which 11 g of sodium borohydride were added in portions at 60° C. over a period of about 1 hour. The reaction mixture was then stirred at 60° C. for 3 hours, after which it was allowed to stand at room temperature for 2 days. It was then poured into ice-water and the aqueous mixture was neutralized by the addition of sodium hydrogencarbonate. The mixture was extracted with ethyl acetate, and the extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed from the mixture by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel using a 3:2 by volume mixture of ethyl acetate and hexane as the eluent, to give 21.9 g of the title compound having an Rf value=0.18 (on thin layer chromatography on silica gel; developing solvent: a 1:1 by volume mixture of ethyl acetate and hexane).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([O:17][CH3:18])[CH:11]=1.[C:19](Cl)(Cl)=[O:20]>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[CH:5][C:6]([C:8]#[N:9])=[CH:7][C:2]=2[N:1]=[C:19]=[O:20])=[CH:11][C:12]=1[O:17][CH3:18]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(-c2ccc(C#N)cc2N)ccc1Br
Product: COc1cc(-c2ccc(C#N)cc2N=C=O)ccc1Br
Yield: 100 %

Procedure:
To the product from Step 2 (363 mg, 1.2 mmol) was added phosgene (20% solution in PhMe, 5.9 g, 11.97 mmol), and the mixture was heated to reflux for 2 hours. The solvent was then removed in vacuo to give crude 4′-bromo-2-isocyanato-3′-methoxybiphenyl-4-carbonitrile (394 mg, 1.2 mmol), which was then taken up in chlorobenzene (4 mL). To this mixture, AlCl3 (319 mg, 2.4 mmol) was added at RT. 1 N HCl (30 mL) was then added, which caused a grey precipitate to form. This was isolated by filtration and washed with DCM and MeOH to give the title compound. LRMS (M+H)+=329.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:16][CH3:17])[CH:10]=[CH:11][C:12]=2[CH3:13])=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Cc1cc[nH]c1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(C)c1-c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
A solution of 2-(4-chlorophenyl)-3-methyl-1H-pyrrole (prepared according to the procedure given in Tetrahedron Letters 46 (2005) 4539-4542, 1.0 g, 5.22 mmol) in DMF (10 ml) was added dropwise to a stirred suspension of Sodium hydride (0.23 g, 5.74 mmol, 60% dispersion in mineral oil) in 20 ml DMF at 0° C. under a nitrogen atmosphere. The reaction mixture was then stirred at about 0° C. for 30 min. Ethyl iodide (0.89 g, 0.47 ml, 5.74 mmol) was then added to the reaction mixture maintaining the temperature at 0° C. The reaction mixture was then stirred at 25° C. for 3 hrs. The progress of the reaction was monitored by TLC. The reaction mixture was slowly quenched with cold water (30 ml) and the resulting mixture was then extracted with ethyl acetate (2×30 ml). The combined organic layer was then washed with brine (1× 30 ml) and dried over sodium sulfate. The dried organic layer was then concentrated under reduced pressure to obtain crude product as semi-solid mass (0.8 g), which was then purified by flash column chromatography using 5% ethyl acetate in hexanes as an eluent to obtain the title compound (0.6 g, 52.3%).
Reaction SMILES: [CH2:1](OC(=O)C(C1C=CC(C)=CC=1)=CN(C)C)C.[CH2:18]([O:20][C:21](=[O:35])[C:22]([C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[CH:23][N:24](C)C)[CH3:19]>>[CH2:18]([O:20][C:21]([C:22]1[CH:23]=[N:24][O:34][C:27]=1[C:28]1[CH:33]=[CH:32][C:31]([CH3:1])=[CH:30][CH:29]=1)=[O:35])[CH3:19]
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1ccccc1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C)cc1
Product: CCOC(=O)c1cnoc1-c1ccc(C)cc1
Yield: 59 %

Procedure:
The procedure of Example 15 was employed utilizing ethyl-2-(4-toluyl)-3-dimethylaminopropenoate in lieu of ethyl-2-benzoyl-3-dimethylaminopropenoate to yield ethyl-5-(4'-methylphenyl)-4-isoxazolecarboxylate (2.03 g.; 59% yield) having a melting point of 42°-44° C. and the following analysis:
Reaction SMILES: Br[CH:2]1[CH2:6][C:5](=[O:7])[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:3]1.CC(C)=[O:19].O>[B-](F)(F)(F)F.[Ag+].CO>[C:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:4]1[C:5](=[O:7])[CH2:6][CH:2]([OH:19])[CH:3]=1)([OH:16])=[O:15]
Reactant: O=C(O)CCCCCCC1=CC(Br)CC1=O
Reactant: CC(C)=O
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CO
Product: O=C(O)CCCCCCC1=CC(O)CC1=O
Reaction time: 1.5 h

Procedure:
To a stirred solution of 10.6 g. (ca. 34 moles) of crude 4-bromo-2-(6-carboxyhexyl)cyclopent-2-en-1 -one (Example 93) in 100 ml. of acetone and 65 ml. of water is added 8.80 g. (45.2 mmoles) of silver fluoborate during 2 minutes. The temperature is maintained at 25°-30° C. by external cooling. The mixture is stirred for 90 minutes, filtered, saturated with sodium chloride, and extracted with ether. The extract is extracted with half saturated sodium bicarbonate solutions. The basic solutions is reacidified with dilute hydrochloric acid, saturated with sodium chloride, and extracted with ether. The extract is washed with water and saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The crude product is purified by partition chromatography on Celite to give an oil; λmax.MeOH =233 mμ. (7360); νmax.=3380 (hydroxyl groups), 1710 (carbonyl groups), and 1632 cm-1 (olefin group).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[C:11]([CH2:16][CH2:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>C(O)C>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([NH:20][NH2:21])[CH:12]=[C:11]([CH2:16][CH2:17][CH3:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCCc1cc(Cl)nc(SCc2ccccc2)n1
Solvent: O
Solvent: CCO
Product: CCCc1cc(NN)nc(SCc2ccccc2)n1

Procedure:
A mixture of 40 g (0.014 mole) of 2-benzylthio-4-chloro-6-n-propylpyrimidine (from Part B) and 15 g (0.3 mole) of hydrazine hydrate in 300 ml of ethanol was heated at reflux for 2 hours, cooled and evaporated. Water was added to the residue. The white solid was collected by filtration and dried to provide 2-benzylthio-4-hydrazino-6-n-propylpyrimidine. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:5]=1[NH:14][CH2:15][CH2:16][OH:17])([O-:3])=[O:2].[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C.C(OCC)(=O)C>[Si:22]([O:17][CH2:16][CH2:15][NH:14][C:5]1[CH:6]=[CH:7][C:8]([C:10]([F:11])([F:12])[F:13])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1NCCO
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of the product of Step A (2.4 g, 9.6 mmol) and TBSCl (1.73 g, 11.5 mmol) in DMF (15 mL) was added imidazole (1.3 g, 19.2 mmol) at room temperature. The mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate (100 mL), and washed with brine (30 mL×3) and dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel chromatography (eluted with PE) to obtain the title compound (3.5 g, 100%) as yellow solid. 1H NMR (600 MHz, CDCl3) δ 8.56 (s, 1H), 8.50 (d, J=1.2 Hz, 1H), 7.63 (dd, J=9.0, 2.2 Hz, 1H), 7.00 (d, J=9.0 Hz, 1H), 4.02-3.87 (m, 2H), 3.52-3.48 (m, 2H), 0.94 (s, 9H), 0.13 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH:15]([CH3:18])[CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O.S([O-])([O-])(=O)=O.[Mg+2].[H][H]>C(OCC)(=O)C.[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH:15]([CH3:18])[CH2:16][OH:17])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: [H][H]
Reactant: CC(CO)Nc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Product: CC(CO)Nc1c(N)cnc2ccccc12

Procedure:
A mixture of 27.9 g (0.113 mole) of 2-[(3-nitro-4-quinolinyl)amino]-1-propanol in 1.2 l of ethyl acetate, 28 g of magnesium sulfate and 2.0 g of 5% platinum on charcoal was hydrogenated on a Paar apparatus until hydrogen uptake was completed. The catalyst and solid residue were removed by filtration and the filtrate was concentrated by evaporation to provide 2-[(3-amino-4-quinolinyl)amino]-1-propanol as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].CO>O.[C].[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH:10]=[CH:11][C:12]=1[O:13][CH3:14]
Reactant: COc1ccc(C=CC(=O)O)cc1O
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COc1ccc(CCC(=O)O)cc1O
Temperature: 50 °C
Reaction time: 5 h
Yield: 99.3 %

Procedure:
3-Hydroxy-4-methoxycinnamic acid (15.0 g, 77.2 mmo) and 10% palladium carbon in the water content of 50% (2.26 g) were added to a mixed solvent (330 ml) of methanol and water (mixing ratio of 10:1 v/v), and the mixture was stirred under hydrogen atmosphere of normal pressure (0.1 MPa) at 50° C. for 5 hours for reaction. The reaction solution was filtrated to remove the catalyst, and the filtrate was concentrated under reduced pressure to solidification to obtain 3-(3-hydroxy-4-methoxyphenyl) propionic acid (15.1 g, 76.7 mmol, yield: 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]1[C:12]2[C:13]([N+:17]([O-])=O)=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:23])[CH2:7][N:8]1[C:12]2[C:13]([NH2:17])=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:20][CH2:21][CH3:22])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1nc2cccc([N+](=O)[O-])c2n1CC(=O)OC(C)(C)C
Agent: [Pd]
Product: CCCc1nc2cccc(N)c2n1CC(=O)OC(C)(C)C

Procedure:
The sub-title compound was prepared by the method of example 1, step c.) using (7-nitro-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester from example 34, step b.) (regioisomer 1) and 10% Pd/C and was used in crude form without purification.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](=[O:7])[CH2:4][CH:5]=O.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[Cl:18]/[CH:5]=[CH:4]/[C:3](=[O:7])[C:2]([CH3:15])([CH3:1])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(Cc1ccccc1)C(=O)CC=O
Solvent: c1ccccc1
Product: CC(C)(Cc1ccccc1)C(=O)/C=C/Cl

Procedure:
A solution of 6.6 g. of 4,4-dimethyl-3-oxo-5-phenylpentanal in 25 ml. of dry benzene was treated with 4.7 g. of thionyl chloride and refluxed for 21/2 hours. Solvent was evaporated and the residue was distilled under reduced pressure to afford 5.8 g. of the title product as a colorless oil, B.P. 86°-90°/0.1 mm. λmaxfilm 3.45, 5.92, 6.32, 6.70, 6.82, 9.30, 9.48, 10.65, 11.95, 12.50, 13.0, 13.54 and 14.23 μ.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[S:17][N:16]=[C:15](Cl)[C:14]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[NH2:20][CH2:21][CH2:22][CH2:23][NH2:24]>>[NH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:15]1[C:14]2=[C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])[CH:10]=[CH:11][CH:12]=[C:13]2[S:17][N:16]=1
Reactant: NCCCN
Reactant: CC(C)(C)NS(=O)(=O)c1cccc2snc(Cl)c12
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cccc2snc(NCCCN)c12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of N-tert-butyl-3-chlorobenzo[d]isothiazole-4-sulfonamide (280 mg, 0.92 mmol) in 1,3-diaminopropane (1 mL) was allowed to stir at room temperature for 2.5 h. The reaction mixture was then poured over water (10 mL), extracted with ethyl acetate and the combined organic layers was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give, upon trituration with ethyl ether, 3-(3-aminopropylamino)-N-tert-butylbenzo[d]isothiazole-4-sulfonamide (257 mg) as an off-white solid. 1H NMR (300 MHz, CD3OD): 8.02 (d, 1H), 7.85 (d, 1H), 7.70 (t, 1H), 3.74 (t, 2H), 3.02 (t, 2H), 1.87-1.95 (m, 2H), 1.24 ppm (s, 9H). MW=342 confirmed by LC-MS, tr=8.22 min (Method Y) MH+=343.