Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=2)[CH:6]=1.[C:19]([C:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20].CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[C:19]([C:22]1[CH:26]=[C:25]([C:27]([NH:2][CH2:3][CH2:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([Cl:18])[CH:11]=3)[CH:6]=2)=[O:28])[NH:24][N:23]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: N#Cc1ccc(-c2cc(CCN)on2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)c1cc(C(=O)NCCc2cc(-c3ccc(C#N)c(Cl)c3)no2)[nH]n1
Yield: 12 %

Procedure:
The title compound was prepared from 4-(5-(2-aminoethyl)isoxazol-3-yl)-2-chlorobenzonitrile hydrochloride (0.080 g, 0.282 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.043 g, 0.282 mmol), DIPEA (0.196 ml, 1.126 mmol 1), HOBt hydrate (0.065 g, 0.422 mmol) and EDCI (0.081 g, 0.422 mmol) using the method of Example 274 affording 0.013 g of the title compound after preparative HPLC purification. 1H-NMR (400 MHz; d6-DMSO): δ 2.53 (s, 3H), 3.20 (t, 2H), 3.83 (m, 2H), 6.54 (s, 1H), 7.33 (bs, 1H), 7.63 (bs, 1H), 7.79 (m, 1H), 7.97 (bs, 1H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:29]([CH3:30])=[C:28]([C:31]([NH2:33])=O)[N:27]([CH3:34])[N:26]=4)=[CH:21][C:20]=3[CH3:35])=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.N1C=CC=CC=1.P(Cl)(Cl)(Cl)=O>O>[CH:1]1([C:4]2[C:5]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:29]([CH3:30])=[C:28]([C:31]#[N:33])[N:27]([CH3:34])[N:26]=4)=[CH:21][C:20]=3[CH3:35])=[C:6]([N:10]3[C:14](=[O:15])[N:13]([CH3:16])[N:12]=[N:11]3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2nn(C)c(C(N)=O)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(-c2nn(C)c(C#N)c2C)ccc1OCc1c(C2CC2)cccc1-n1nnn(C)c1=O
Reaction time: 2 h

Procedure:
At room temperature, to the mixture of 1-{3-cyclopropyl-2-[2-methyl-4-(5-aminocarbonyl-1,4-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (Present compound 49) 0.8 g and pyridine 10 ml was added phosphorus oxychloride 0.58 g and was stirred for two hours. To the resulting mixture was added water 40 ml and precipitates were filtrated. The precipitates were washed with water and dried under reduced pressure to give 1-{3-cyclopropyl-2-[2-methyl-4-(5-cyano-1,4-dimethyl-1H-pyrazol-3-yl)-phenoxymethyl]-phenyl}-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Present compound 50”) 0.6 g.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH:16]1[C:20]([Br:21])=[C:19]([Br:22])[NH:18][C:17]=1[C:23]([OH:25])=[O:24].[NH2:26][C@H:27]([C:35]([NH:37]N)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.N[C@@H:40]([C:48]([NH:50][C@H:51]([C:56]([NH:58][C@H:59]([C:64]([NH2:66])=[O:65])[CH2:60][CH2:61][S:62][CH3:63])=[O:57])[CH2:52][CH:53]([CH3:55])[CH3:54])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH:16]1[C:20]([Br:21])=[C:19]([Br:22])[NH:18][C:17]=1[C:23]([OH:25])=[O:24].[NH2:26][C@H:27]([C:35]([NH:37][C@@H:40]([C:48]([NH:50][C@H:51]([C:56]([NH:58][C@H:59]([C:64]([NH2:66])=[O:65])[CH2:60][CH2:61][S:62][CH3:63])=[O:57])[CH2:52][CH:53]([CH3:54])[CH3:55])=[O:49])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1ccccc1)C(N)=O
Reactant: NNC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: O=C(O)c1cc(Br)c(Br)[nH]1
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H](N)Cc1ccccc1)C(N)=O
Yield: 51 %

Procedure:
Condensation of each of BocPro-LBpa-PheNHNH2 (1.20 g.) and BocPro-DBpa-PheNHNH2 (0.450 g.) with HDPhe-Leu-MetNH2 hydrochloride salt (Example 23, 1.02 g., 0.445 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-LBpa-Phe-DPhe-Leu-MetNH2 in 51% yield and BocPro-DBpa-Phe-DPhe-Leu-MetNH2 in 44% yield. De-t-butoxycarbonylation of BocPro-LBpa-Phe-DPhe-Leu-MetNH2 (0.500 g.) and BocPro-DBpa-Phe-DPhe-Leu-MetNH2 (0.250 g.) using hydrogen chloride in dioxane gave HPro-LBpa-Phe-DPhe-Leu-MetHN2, which was isolated as the amorphous white solid dihydrochloride salt hydrate (2:9) in 53% yield, and HPro-DBpa-Phe-DPhe-Leu-MetNH2, which was isolated as the dihydrochloride salt hexahydrate in 59% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[F:13][C:14]([F:24])([F:23])[C:15](=O)[CH2:16][C:17]([O:19][CH2:20]C)=[O:18].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:12][O:11][C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:15]([C:14]([F:24])([F:23])[F:13])=[CH:16][C:17]([O:19][CH3:20])=[O:18])=[CH:7][CH:6]=1)=[O:10]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: COC(=O)C=C(Nc1ccc(CC(=O)OC)cc1)C(F)(F)F
Yield: 53.4 %

Procedure:
Methyl p-aminophenylacetate (7 g), ethyl trifluoroacetoacetate (8.19 g) and p-toluenesulfonic acid (500 mg) were dissolved into benzene (100 ml) and, providing Dean Stalk dehydrating apparatus placed molecular sieve (MS 4 angstroms) therein, the solution was refluxed for 10 hours under heat. Solvent was distilled off under reduced pressure and the residue was purified by means of silica gel column chromatography (development solvent: ethyl acetate:hexane=1:4) to obtain methyl 3-(4-methoxycarbonylmethylphenylamino)-3-trifluoromethylacrylate (7.18 g) as colorless prismatic crystals. Melting point: 50°-51° C. (recrystallization solvent: ethyl acetate-n-hexane)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](Cl)=[O:19])([CH3:14])([CH3:13])[CH3:12]>COCCOC>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[C:17]2[CH:21]=[C:22]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:23]([OH:24])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:16]=2)[CH:10]=[CH:9][CH:8]=1)([OH:7])=[O:6]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: Nc1cccc(C(=O)O)c1
Solvent: COCCOC
Product: CC(C)(C)c1cc(C(=O)Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Temperature: 24 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
A solution of 8.6 g (0.063 mole) of a m-aninobenzoic acid in 200 ml of 1,2-dimethoxyethane was mixed with a suspension of 8.0 g (0.0298 mole) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in 100 ml of 1,2-dimethoxyethane, and the mixture was stirred at 24° C. for one hour. The reaction mixture was then filtered. The filtrate was thereafter diluted with 300 ml of water and cooled to give the crude product as a white solid. This material was recrystallized from a mixture of ethanol and water to give 5.6 g of white solid N-(3-carboxyphenyl)-3,5-di-t-butyl-4-hydroxybenzamide, m.p. 279°-280° C. Analysis: Calculated for C22H27NO4 : %C, 71.5; %H, 7.4; %N, 3.8; Found: %C, 72.0; %H, 7.3; %N, 3.7.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][C:5]([CH3:7])=O.[F:8][C:9]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[CH:23][C:10]=1[C:11]([C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12].C(=O)=O.CC(C)=O>C(O)C>[F:8][C:9]1[C:26]([F:27])=[C:25]([F:28])[C:24]([F:29])=[CH:23][C:10]=1[C:11]([C:13](=[CH:19][NH:2][N:3]=[CH:4][CH2:5][CH3:7])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:12]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Reactant: NN
Reactant: CC(C)=O
Agent: O=C=O
Solvent: O
Solvent: CCO
Product: CCC=NNC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Yield: 72.2 %

Procedure:
First 2.8 g of hydrazine hydrate and, 30 minutes later, 12.8 g of acetone are added dropwise to a solution of 16 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-ethoxyacrylate in 70 ml of ethanol, while cooling with dry ice/acetone at -25° C. to -30° C. The mixture is allowed to come slowly to room temperature and is then stirred at 20° C. to 25° C. for a further hour. The solvent is then distilled off in vacuo and the orange-colored residue is recrystallized from cyclohexane/light petrol. 12.5 g of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-3-(2-propylidenehydrazino)acrylate of melting point 86° C. are obtained.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]2)[C:6]=1[C:7]#[N:8])([O-:4])=[O:3].C(N(CC)CC)C.[CH2:28]([N:31]=[C:32]=[O:33])[CH2:29][CH3:30]>C1COCC1>[C:7]([C:6]1[C:5]([N+:2]([O-:4])=[O:3])=[CH:12][CH:11]=[CH:10][C:9]=1[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][N:17]([C:32]([NH:31][CH2:28][CH2:29][CH3:30])=[O:33])[CH2:16]1)#[N:8]
Reactant: N#Cc1c(OCC2CCCNC2)cccc1[N+](=O)[O-]
Reactant: CCCN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCNC(=O)N1CCCC(COc2cccc([N+](=O)[O-])c2C#N)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 110.4 %

Procedure:
To a solution of 2-nitro-6-(piperidin-3-ylmethoxy)benzonitrile hydrochloride (Example 262d) (0.10 g, 0.34 mmol) in THF (6 mL) were added triethylamine (0.10 mL, 0.76 mmol) and propylisocyanate (0.05 mL, 0.52 mmol) and the reaction mixture was stirred at r.t. under nitrogen for 3 hour then filtered and evaporated, to give 3-((2-cyano-3-nitrophenoxy)methyl)-N-propylpiperidine-1-carboxamide (0.13 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ 0.81 (t, J=7.2 Hz, 3H), 1.34-1.41 (m, 4H), 1.62-1.64 (bm, 1H), 1.87-1.95 (bm, 2H), 2.64-2.77 (m, 2H), 2.93-2.98 (m, 2H), 3.77 (bd, J=12.8 Hz, 1H), 3.98 (bd, J=12.8 Hz, 1H), 4.09-4.13 (m, 1H), 4.17-4.20 (m, 1H), 6.38 (d, J=5.6 Hz, NH), 7.74 (bdd, J=1.6 Hz, J=8.0 Hz, 1H), 7.88-7.94 (m, 2H). MS 347 (MH+).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH3:12][S:13]([N:16]1[CH2:33][CH2:32][CH2:31][N:19]2[C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][C:21]=3[N:30]=[C:18]2[CH2:17]1)(=[O:15])=[O:14].[OH-].[NH4+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[CH3:12][S:13]([N:16]1[CH2:33][CH2:32][CH2:31][N:19]2[C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N+:23]([O-:9])=[CH:22][C:21]=3[N:30]=[C:18]2[CH2:17]1)(=[O:15])=[O:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CS(=O)(=O)N1CCCn2c(nc3cnc4ccccc4c32)C1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCCn2c(nc3c[n+]([O-])c4ccccc4c32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
mCPBA (2.55 g of 77%, 11.38 mmol) was added to a suspension of 9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline (3.0 g, 9.5 mmol) in chloroform, and the reaction was stirred for 30 minutes at ambient temperature. The reaction was incomplete as determined by LC/MS analysis. Additional mCPBA (approximately 0.5 equivalent) was added twice, and the reaction was stirred overnight. The solvent was removed under reduced pressure, and a solution of potassium hydroxide in methanol was added to adjust to pH 7.5. The methanol was removed under reduced pressure, and residue was dissolved in chloroform. Additional mCPBA (1.2 equivalents) was added, and the reaction was stirred for two hours. Additional mCPBA was added, and the reaction was stirred overnight at ambient temperature. Ammonium hydroxide (15 mL) and p-toluenesulfonyl chloride (1.99 g, 10.4 mmol) were added, and the reaction was stirred at ambient temperature for two hours. The organic layer was separated, concentrated under reduced pressure, and purified by normal phase preparative HPLC on silica gel (eluting with 2 N ammonia in methanol/chloroform in a 42-minute gradient from 0:100 to 25:75). The resulting solid was recrystallized from 5:2:1 acetonitrile/ethanol/methanol to provide 9-(methylsulfonyl)-5-oxido-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline, which was dissolved in chloroform, treated with ammonium hydroxide and p-toluenesulfonyl chloride, and purified by chromatography and recrystallization again as described above to provide 161 mg of 9-(methylsulfonyl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinolin-6-amine as a white powder, mp 280° C.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[NH:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)[N:19]=2)=[CH:10][C:3]=1[O:4][CH2:5][C:6](OC)=[O:7].[NH4+:37].[OH-]>O>[F:1][C:2]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]2[NH:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH3:36])[N:31]=3)=[C:18]([C:20]3[CH:21]=[C:22]4[C:27](=[CH:28][CH:29]=3)[N:26]=[CH:25][CH:24]=[CH:23]4)[N:19]=2)=[CH:10][C:3]=1[O:4][CH2:5][C:6]([NH2:37])=[O:7]
Reactant: COC(=O)COc1cc(Cc2nc(-c3ccc4ncccc4c3)c(-c3cccc(C)n3)[nH]2)ccc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(OCC(N)=O)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Methyl 2-(2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)phenoxy)acetate (Example 93) (32.5 mg, 0.067 mmol) was treated with aqueous NH4OH (28-30%, 1 mL). The suspension was stirred at room temperature. After 2 hours, the reaction mixture was diluted with H2O (3 mL) and stirred for 30 min. The precipitate was filtered, washed with water, and dried under vacuum for overnight to afford the title compound (26.8 mg, 86%). (300 MHz, CDCl3) δ 2.49 (3H, s), 4.15 (2H, s), 4.51 (2H, s), 5.80 (N—H, 1H, bs), 6.71 (N—H, 1H, bs), 6.63-7.06 (4H, m), 7.25-7.28 (1H, m), 7.37-7.44 (2H, m), 7.94 (1H, dd), 8.10 (1H, d), 8.16-8.18 (2H, m), 8.91 (1H, dd), 11.00 (1H, bs). MS (ESI) m/z 468 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[NH:5]2.[C:16](Cl)(=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH3:15])[N:5]2[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: CC1Nc2cc(Br)ccc2-n2cccc21
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(C(=O)N2c3cc(Br)ccc3-n3cccc3C2C)cc1

Procedure:
7-Bromo-5-(4-methoxybenzoyl)-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from 7-bromo-4-methyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (see Example 106, Step 1) and p-anisoyl chloride according to the procedure of Example 106, Step 2 and purified via Biotage Horizon® (25S, silica, gradient from 5% EtOAc/hexane to 40% EtOAc/hexane). MS (ESI) m/z 397/399 ([M+H]+); HRMS: calcd for C20H17BrN2O2, 396.0473; found (ESI+), 396.04740.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.OC1C2N=NNC=2C=CC=1.[CH2:39]([S:46][CH:47]1[N:50]([CH2:51][C:52](O)=[O:53])[C:49](=[O:55])[CH2:48]1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:52](=[O:53])[CH2:51][N:50]2[CH:47]([S:46][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH2:48][C:49]2=[O:55])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CN1C(=O)CC1SCc1ccccc1
Reactant: NCCCCCCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)CC1SCc1ccccc1)NCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of 6-phenylhexylamine (Morse M. A. et al., Cancer Research, 1991, 1846), (7.0 g, 40 mmol) in DMF (20 ml) was added to DCC (8.2 g, 40 mmol), hydroxybenzotriazole (5.3 g, 39 mmol) and (4-benzylthio-2-oxoazetidin-1-yl)acetic acid (10 g, 39 mmol) and the mixture stirred for 2 hours at room temperature. Ethyl acetate (250 ml) was added, the precipitate filtered, the filtrate washed with dil NaHCO3, water (×2), dried (MgSO4) and evaporated to an oil which was purified by flash chromatography on silica gel using hexane/ethyl acetate (1:1). Evaporation of the appropriate fractions followed by treatment with hexane gave a white solid (11.2 g, 70%), mp 65-70° C.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[C:15]([C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][NH:23][CH2:24]4)=[CH:19][CH:18]=3)[N:14]=[C:13]([NH2:27])[N:12]=2)[CH2:7][CH2:6]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[N:62]1([C:67]2[N:72]=[CH:71][C:70]([CH2:73][C:74](O)=[O:75])=[CH:69][CH:68]=2)[CH2:66][CH2:65][CH2:64][CH2:63]1>>[CH3:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:16]=[C:15]([C:17]3[CH:26]=[C:25]4[C:20]([CH2:21][CH2:22][N:23]([C:74](=[O:75])[CH2:73][C:70]5[CH:71]=[N:72][C:67]([N:62]6[CH2:63][CH2:64][CH2:65][CH2:66]6)=[CH:68][CH:69]=5)[CH2:24]4)=[CH:19][CH:18]=3)[N:14]=[C:13]([NH2:27])[N:12]=2)[CH2:9][CH2:10]1
Reactant: O=C(O)Cc1ccc(N2CCCC2)nc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Cc3ccc(N5CCCC5)nc3)CC4)nc(N)n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine trihydrochloride (180 mg, 0.43 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (190 mg, 0.43 mmol) and triethylamine (0.30 mL, 2.1 mmol) were added to 2-(6-(pyrrolidin-1-yl)pyridin-3-yl)acetic acid (0.4 mmol, from the above step) in N,N-dimethylformate (5 mL). The reaction mixture was stirred at r.t. for 2 h. The mixture was purified by Prep-LCMS (pH=10) to afford the desired product. Analytic LCMS (M+H)+: m/z=513.2.
Reaction SMILES: [CH2:1]([C:4](=[CH2:8])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](I)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(N(CC)CC)C>ClCCl>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](/[CH:8]=[C:4](\[CH2:1][CH2:2][CH3:3])/[C:5]([OH:7])=[O:6])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: C=C(CCC)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)I)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC/C(=C\S(=O)(=O)c1ccc(C)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
2-Propylacrylic acid (5.0 g, 43.80 mmol) was added to a solution of toluene-4-sulfonyl iodide (14.32 g, 65.70 mmol) in dichloromethane (100 ml). The solution was stirred overnight at room temperature and then cooled to 0° C. Triethylamine (12.2 ml, 87.6 mmol) was added and the solution was stirred for 1 hour then allowed to warm to room temperature over 2 hours. The organic solution was washed with water (100 ml), 1N hydrochloric acid ((100 ml) 10% aqueous sodium bisulfite (50 ml), then extracted with sodium hydroxide (5 g) in water (100 ml). The aqueous layer was washed with ethyl acetate (20 ml) and then acidifed with conc. sulfuric acid (3 ml). The product was extracted into ethyl acetate (2×50 ml) and the combined organic layers were washed with brine (20 ml), dried over magnesium sulfate, filtered and evaporated to give the title compound in 85% yield. This yellow solid was dissolved in methanol (100 ml ) and stirred with activated charcoal (1 g). Filtration and evaporation gave a pale yellow solid which was slurried in dichloromethane:heptane 20:80. Filtration gave the title compound as white crystals (8.3 g, 70%).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:10]2CCC[N:12](C(=O)C(F)(F)F)[CH2:11]2)[CH:5]=[CH:6][C:7]=1OC.CCC([O:26]CC)=S.ClOC(C)(C)C.Cl>C(N(CC)CC)C.C(Cl)Cl>[N:12]1[C:11](=[O:26])[CH:10]=[C:4]2[C:5]=1[CH:6]=[CH:7][CH:2]=[CH:3]2
Reactant: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1N
Reactant: CCOC(=S)CC
Agent: CC(C)(C)OCl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C=c2ccccc2=N1
Temperature: -65 °C

Procedure:
604 mg of 3-(3-amino-4-methoxyphenyl)-1-trifluoroacetyl piperidine were added with stirring under an inert atmosphere to 20 ml of methylene chloride and 0.26 ml of ethyl methylthioacetate cooled to -65° C., and then 0.24 ml of tert-butyl hypochlorite were added over 5 minutes. After stirring for an hour, 0.29 ml of triethylamine were added dropwise and the temperature was allowed to return to ambient. 5 ml of aqueous 2N hydrochloric acid were added and the mixture was stirred for an hour. The decanted organic phases were washed with water, dried and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica (eluent benzene--ethyl acetate 7-3) to obtain 580 mg of 1,3-dihydro-7-methoxy-3-methylthio-4-[1-trifluoroacetyl)-3-piperidinyl]-2H-indol-2-one which after crystallization from ethanol melted at ≈189° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[F:21])[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccccc3F)CC2)cc1-c1ccc(F)cc1

Procedure:
142 mg (82%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(2-fluorophenyl)piperazine (66 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[CH3:21])[CH2:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][NH:7]1
Reactant: Cc1ccc(C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(C[C@@H]2CCCN2)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
A solution of tert-butyl (2S)-2-(3-fluoro-4-methylbenzyl)pyrrolidine-1-carboxylate (0.95 g, 3.24 mmol), which had been obtained in Example 1 (1d), in methylene chloride (9 mL) was added with trifluoroacetic acid (2.40 mL, 32.3 mmol), and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was added with saturated aqueous sodium hydrogen carbonate solution (20 mL) and extracted with methylene chloride (20 mL×3). After that, the organic layers were dried over sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound as a yellow oily substance (0.44 g, yield 71%).