Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[NH:5]/[C:6](/[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Cl:17])=[CH:7]\[C:8]#[N:9])C.[CH3:19][CH:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([NH:30][NH2:31])=O)[CH2:24][CH2:23]1)[CH3:21].O>CN1CCCC1=O>[Cl:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C:6]1[NH:5][C:4](=[O:3])[N:31]2[N:30]=[C:28]([CH:25]3[CH2:26][CH2:27][N:22]([CH:20]([CH3:21])[CH3:19])[CH2:23][CH2:24]3)[N:9]=[C:8]2[CH:7]=1
Reactant: CC(C)N1CCC(C(=O)NN)CC1
Reactant: CCOC(=O)N/C(=C\C#N)c1ccc(F)cc1Cl
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)[nH]c(=O)n3n2)CC1
Temperature: 160 °C
Reaction time: 3 h

Procedure:
1.5 g (5.14 mmol) of ethyl[(Z)-1-(2-chloro-4-fluorophenyl)-2-cyanoethenyl]carbamate (Example 36A) and 952 mg (5.14 mmol) of 1-(propan-2-yl)piperidine-4-carbohydrazide (Example 38A) were dissolved in 27 ml of N-methylpyrrolidone, and the mixture was stirred under argon at an oil bath temperature of 160° C. in a flask with fitted calcium chloride drying tube for 3 h. The reaction mixture was cooled to RT, water (50 ml) was added and the mixture was stirred for 15 min. The resulting precipitate was filtered off, washed with a little water and then dried under high vacuum. This gave 1.25 g (61% of theory) of the product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.Cl[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][N:9]=2)[CH:6]=1
Reactant: Clc1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(-n2cnc(Cl)c2)nc1
Temperature: 80 °C
Yield: 68.3 %

Procedure:
A vial was charged with 4-chloro-1H-imidazole (450 mg, 4.4 mmol), 2-chloro-5-nitropyridine (1.04 g, 6.58 mmol), potassium carbonate (1.21 g, 8.78 mmol), and acetonitrile (10 mL). The vial was capped and heated to 80° C. for 2 hours. The reaction was cooled to room temperature and poured into water (20 mL). The mixture was extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave 2-(4-chloro-1H-imidazol-1-yl)-5-nitropyridine (675 mg, 68%) as a white solid. 1H NMR (400 MHz, CD3OD, δ): 9.35 (d, J=2.4 Hz, 1H), 8.78 (dd, J=9.0, 2.6 Hz, 1H), 8.64 (d, J=1.6 Hz, 1H), 8.05 (d, J=1.6 Hz, 1H), 7.95 (d, J=8.8 Hz, 1H).
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[CH2:19]([NH2:23])[C:20]#[C:21][CH3:22]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:23][CH2:19][C:20]#[C:21][CH3:22])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: CC#CCN
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Solvent: CC#N
Product: CC#CCNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reaction time: 15 h
Yield: 80 %

Procedure:
A mixture of 1-nitro-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene (2.25 g, 7.8 mmole) and 2-butyn-1-amine (2.16 g, 31.2 mmole) in acetonitrile (35 ml) was stirred under a positive pressure of nitrogen at reflux temperature for 7 hours and at room temperature for 15 hours. The solvent was removed by evaporation under reduced pressure, and the residue placed on silica gel and chromatographed by gradient elution using methylene chloride-methanol. The appropriate fractions yielded 1.93 g (80%) of the title product from acetonitrile. Recrystallization from isopropyl alcohol gave the product with mp 147.5°-151°.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12].C(N(C(C)C)CC)(C)C.[CH3:22][O:23][CH2:24][CH2:25][NH2:26]>>[CH3:22][O:23][CH2:24][CH2:25][NH:26][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cccc([N+](=O)[O-])c1Cl
Reactant: COCCN
Solvent: CCN(C(C)C)C(C)C
Product: COCCNc1c(OC)cccc1[N+](=O)[O-]
Temperature: 180 °C
Yield: 85 %

Procedure:
A mixture of 7.5 g (40 mmol) 2-chloro-1-methoxy-3-nitro-benzene, 14 ml diisopropylethylamine and 35 ml 2-methoxyethyl amine is heated (180° C. oil bath temperature) in a closed steel reactor for 25 min. Then the reaction mixture is cooled to room temperature and is concentrated in vacuo (3× coevaporation with toluene) to obtain ca. 20 g (which contains 85% of the title compound) of a red oil which is used without further purification in the next step.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Cc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: Cc1cc(-c2ncnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f40) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:5]1[NH:9][C:8]([C:10]([O:12]C)=[O:11])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl>O.C1COCC1.CO>[C:1]([C:5]1[NH:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1[nH]c(C(C)(C)C)cc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc([N+](=O)[O-])c(C(=O)O)[nH]1
Temperature: 75 °C
Yield: 64.3 %

Procedure:
A solution of LiOH monohydrate (0.083 g, 2.0 mmol) in water (1 mL) was added to a solution of methyl 5-tert-butyl-3-nitro-1H-pyrrole-2-carboxylate (0.150 mL, 0.66 mmol) in THF:MeOH (3:1, 3 mL) and the resulting mixture heated at 75° C. for 5 hours. The reaction was cooled down to room temperature and acidified with 1N aqueous HCl, extracted with ethyl acetate. The combined organic layers were dried, the solvent eliminated under vacuum and the crude product recrystallized from dichloromethane:hexane to afford 90 mg of expected 5-tert-butyl-3-nitro-1H-pyrrole-2-carboxylic acid as a yellow solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:32])([CH3:31])[NH:9][C:10](=[O:30])[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19]C2C=CC3C(=CC=CC=3)N=2)=[CH:14][CH:13]=1)(=O)=O.[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Na+].[Na+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:32][C:8]1([CH3:31])[NH:9][C:10](=[O:30])[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][C:36]3[CH:37]=[CH:38][C:39]4[C:40](=[CH:8][CH:7]=[CH:11][CH:10]=4)[N:35]=3)=[CH:16][CH:17]=2)=[C:7]1[C:38]1[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=1
Reactant: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC1(C)NC(=O)C(c2ccc(OCc3ccc4ccccc4n3)cc2)=C1c1ccncc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
To a solution of 2,2-dimethyl-5-oxo-4-(4-(quinolin-2-ylmethoxy)phenyl)-2,5-dihydro-1H-pyrrol-3-yl trifluoromethanesulfonate (2.0 g, 0.004 mol) 1,4-dioxane (50 mL) were added pyridin-4-yl boronic acid (598 mg, 4.8 mol), Na2CO3 (1.0 g, 0.012 mol) and water (20 mL) at RT under an inert atmosphere. The mixture was stirred for 30 min and then Pd(PPh3)4 (468 mg, 0.4 mol) was added. The mixture was then heated at 80° C. for 16 h, diluted with water, and extracted with EtOAc (2×200 mL). The combined organic layers were washed with water and brine, and then dried over Na2SO4 and concentrated in vacuo to afford 5,5-dimethyl-4-(pyridin-4-yl)-3-(4-(quinolin-2-ylmethoxy)phenyl)-1H-pyrrol-2(5H)-one (250 mg, 15%) as a white solid. 1H NMR (500 MHz, d6-DMSO): δ 8.74-8.68 (m, 1 H), 8.66-8.56 (m, 2 H), 8.06-7.94 (m, 2 H), 7.78 (t, J=7.2 Hz, 1 H), 7.66-7.56 (m, 3 H), 7.30-7.18 (m, 4 H), 6.98-6.88 (m, 3 H), 5.36 (s, 2 H), 1.36 (s, 6 H). MS: M+H: m/z=422.1; M+Na: m/z=444.1. HPLC: 89%, (Condition-I).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH2:31]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:31][C:30]2[CH:33]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=2[F:34])[C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(Cl)cc1CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc3c(c2)OCCO3)CC1
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(Cl)ccc2F)c2ccc3c(c2)OCCO3)CC1
Yield: 94.5 %

Procedure:
Using general procedure H, 4-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 188) (502 mg, 1.50 mmol) and 5-chloro-2-fluoro-benzyl bromide (80%, 630 mg, 2.26 mmol) gave 4-[(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow foam (676 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13](Cl)Cl.S(=O)(=O)(O)[OH:17]>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13]=[O:17]
Reactant: O=S(=O)(O)O
Reactant: Clc1cnc2c(C(Cl)Cl)c(Cl)ccc2c1
Product: O=Cc1c(Cl)ccc2cc(Cl)cnc12
Yield: 87 %

Procedure:
56 parts of 3,7-dichloro-8-dichloromethylquinoline in 250 parts of 90% strength sulfuric acid were stirred for 6 hours at 100° C. The solution was cooled and then poured onto ice, and the precipitated solid was filtered off under suction, washed neutral with water and dried to give 39 parts (87% of theory) of 3,7-dichloroquinoline-8-carbaldehyde of melting point 208° C.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1([CH3:44])[CH3:43])=[O:36])([CH3:33])([CH3:32])[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:30]([O:34][C:35]([N:37]1[CH2:42][CH2:41][N:40]([CH2:18][C:13]2[N:14]([CH3:17])[C:15]3[C:11]([N:12]=2)=[C:10]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)[N:9]=[C:8]([N:7]2[C:6]4[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=4[N:4]=[C:3]2[CH2:1][CH3:2])[N:16]=3)[CH2:39][C:38]1([CH3:44])[CH3:43])=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCNCC1(C)C
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(=O)OC(C)(C)C)C(C)(C)C3)n(C)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (530 mg, 1.35 mmol), 2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester (350 mg, 1.63 mmol) and molecular sieves (4 Å, powdered, 2.5 g) in DCE (30 mL) was stirred at ambient temperature for 5 h. Sodium triacetoxyborohydride (427 mg, 2.02 mmol) was added and the mixture stirred for 17 h, then loaded onto an Isolute® SCX-2 cartridge (25 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, EtOAc:MeOH; 100:0 to 95:5 to 90:10) to give 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester. TFA (3 mL) was added to a solution of 4-[2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl]-2,2-dimethylpiperazine-1-carboxylic acid tert-butyl ester in DCM (10 mL) and the mixture stirred at ambient temperature for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH before the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 98:2 to 95:5 to 90:10 to 80:20) to afford 552 as a cream solid (144 mg, 22%). LCMS (Method I): RT=2.56 min, M+H+=490. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H); 7.75 (m, 1 H); 7.29 (m, 2 H); 4.35 (m, 4 H); 3.92-3.83 (m, 7 H); 3.70 (s, 2 H); 3.36 (q, J=7.5 Hz, 2 H); 2.97 (m, 2 H); 2.47 (m, 2 H); 2.28 (s, 2 H); 1.49-1.42 (m, 3 H) and 1.19 (s, 6 H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].CO.[F:20][C:21]([F:31])([F:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>>[F:20][C:21]([F:30])([F:31])[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:1][CH2:2][C:3]2[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=2)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCc1cccc(CNCc2ccc(C(F)(F)F)cc2)c1
Reaction time: 0.17 h
Yield: 47.9 %

Procedure:
To a solution of tert-butyl 3-(aminomethyl)benzylcarbamate (0.80 g, 3.39 mmol) in methanol (0.11 g, 3.39 mmol) was added 4-(trifluoromethyl)benzaldehyde (0.45 mL, 3.39 mmol) under nitrogen. The reaction mixture was stirred for 10 min, followed by the addition of sodium triacetoxyborohydride (1.08 g, 5.08 mmol). The resulting mixture was stirred at rt. for 20 h. To the reaction mixture was added 1 N HCl solution and the mixture was concentrated. The residue was extracted with ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine, dried over MgSO4, and concentrated to give an oil. The sample was purified by silica gel flash chromatography. Elution with dichloromethane to 30% of ethyl acetate in dichloromethane gave a colorless oil (0.64 g, 47%). 1H NMR (CDCl3): δ 7.61 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.33-7.22 (m, 4H), 4.34 (m, 2H), 3.89 (s, 2H), 3.82 (s, 2H), 1.48 (s, 9H); MS (ESI): (M+H)+=395.4.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:9]([Br:28])[CH:8]=1)[C:3]([OH:5])=[O:4].[C:29]1([N:35]([CH2:39][CH2:40]O)[CH2:36][CH2:37]O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Br:28][C:9]1[CH:8]=[C:7]([CH2:6][C@H:2]([N:1]2[CH2:37][CH2:36][N:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:39][CH2:40]2)[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21]
Reactant: OCCN(CCO)c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1Br
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C[C@@H](C(=O)O)N2CCN(c3ccccc3)CC2)cc1Br
Yield: 30 %

Procedure:
Following the procedures described in Example 1, Intermediate 3B was used in place of Intermediate 3A, and 2,2′-(phenylazanediyl)diethanol was used in place of 2,2′-(m-tolylazanediyl)diethanol to give (2S)-3-{3-bromo-4-[2-(5-methyl-2-phenyl-1,3-oxazol-4-yl)-ethoxy]-phenyl}-2-(4-phenylpiperazin-1-yl)-propanoic acid as a white solid with the yield of 30% and mp of 220-222° C.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:9]=[CH:8][N:7]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=1.C1COCC1.O[Li].O>O>[C:13]1([S:10]([N:7]2[CH:8]=[CH:9][C:5]([CH2:4][C:3]([OH:19])=[O:2])=[CH:6]2)(=[O:12])=[O:11])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)Cc1ccn(S(=O)(=O)c2ccccc2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccn(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of (1-benzenesulfonyl-1H-pyrrol-3-yl)-acetic acid methyl ester (1.4 g, 5.01 mmol) in co-solvents of THF and water (1:1, 10 mL) was added LiOH hydrate (0.84 g, 20 mmol). The mixture was stirred at room temperature for 45 minutes and diluted with 50 mL of water. The resulting aqueous solution was washed once with EtOAc, acidified with 6N HCl, and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to a sticky yellow oil (1.33 g, 100%). The crude product was used directly. MS (ES+): m/e=266.1 (M+H); LC/Method A/3.08 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:26]=[CH:25][C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=1>>[CH2:23]([O:22][C:20](=[O:21])[C:19]1[CH:25]=[CH:26][C:16]([NH:15][C:9](=[O:11])[C:8]2[CH:7]=[C:6]([C:12](=[O:13])[NH2:14])[CH:5]=[CH:4][C:3]=2[O:2][CH3:1])=[CH:17][CH:18]=1)[CH3:24]
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(NC(=O)c2cc(C(N)=O)ccc2OC)cc1

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and ethyl 4-amino-benzoate by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [OH:1][CH:2]([CH2:30][OH:31])[CH2:3][O:4][C:5](=[O:29])[C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[CH:8][CH:7]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33].C(Cl)(Cl)Cl>O>[C:32]([N:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:9]1[CH:10]=[CH:11][C:6]([C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:30][OH:31])=[O:29])=[CH:7][CH:8]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)cc1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C(=O)OCC(O)CO)cc1

Procedure:
A solution of 3.26 g. of 2,3-dihydroxypropyl-4-(n-hexadecylamino)benzoate and 0.85 ml. of acetic anhydride in 50 ml. of chloroform is heated to reflux for 1 hour and then cooled. The mixture is washed with 90 ml. of water and solid at the interface filtered. The chloroform layer on concentration in vacuo gives a residue which on trituration with methylene chloride yields a white solid (starting material) after filtration. The filtrate on concentration in vacuo yields a pale yellow oil. The oil is stirred overnight with water, extracted with chloroform and azeotroped free of acetic acid with benzene. The pale yellow oil obtained by evaporation in high vacuum is then chromatographed to remove a trace of N,O-diacetylated material. The liquid product is characterized by elemental analyses, infrared spectrum and nuclear magnetic resonance.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.CO.[CH3:11][NH2:12]>O>[CH3:11][NH:12][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CN
Solvent: O
Solvent: CO
Product: CNc1ccc(Cl)nn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 104.7 %

Procedure:
3,6-Dichloropyridazine (107, 500 mg, 3.36 mmol) was slowly added to a 2.0 M methylamine methanol solution (NH2Me in MeOH, 5 mL, 10 mmol) and stirred at room temperature for 24 hours. Water was added to the reaction mixture, and organic compounds were extracted with ethyl acetate. The recovered organic solution was washed with an aqueous solution of saturated sodium chloride and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 3-(N-monomethylamino)-6-chloropyridazine (108e, 505 mg, 88%) as a white solid.
Reaction SMILES: CO[C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:4].[CH2:31]([NH2:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:31]([NH:38][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:4])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Reactant: NCc1ccccc1
Product: O=C(N[C@H]1C[C@@H](C(=O)NCc2ccccc2)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O

Procedure:
(2S,4S)-1-Cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid benzylamide was prepared from (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester and benzylamine in an analogous manner to example 12. MS calcd. for C30H36N3O3 [(M+H)+] 486.0, obsd. 486.4.
Reaction SMILES: [BH4-].[Na+].[Cl-].[Li+].C[O:6][C:7](=O)[CH:8]=[CH:9][C:10]1[CH:22]=[CH:21][C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH:23]=[CH:24][C:25](OC)=[O:26])=[CH:17][CH:18]=3)[CH2:13][C:12]=2[CH:11]=1.Cl>C(O)C.COCCOCCOC>[OH:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]2[C:20]([C:19]3[CH:18]=[CH:17][C:16]([CH2:23][CH2:24][CH2:25][OH:26])=[CH:15][C:14]=3[CH2:13]2)=[CH:21][CH:22]=1
Reactant: COC(=O)C=Cc1ccc2c(c1)Cc1cc(C=CC(=O)OC)ccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Cl-]
Solvent: CCO
Solvent: COCCOCCOC
Product: OCCCc1ccc2c(c1)Cc1cc(CCCO)ccc1-2
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
A mixture of sodium borohydride (3.7 g, 98 mmol) and lithium chloride (4.2 g, 101 mmol) in ethanol (70 ml) was stirred at 5° C. for 15 min, 9H-fluorene-2,7-diacrylic acid dimethyl ester (5.0 g, 15 mmol) in diglyme (150 ml) was added portionwise at 20-50° C. and the mixture was refluxed for 18 h. Diluted hydrochloric acid was added dropwise after cooling and the mixture was extracted with diethyl ether. Organic layer was separated, dried (MgSO4) and evaporated to give a residue, which was purified by chromatography on silica gel. Elution with ethyl acetate afforded 1.85 g (44%) of the title compound as white crystals.