Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:22]([CH2:23][CH2:24][CH2:25][N:26]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[CH:27]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:8][N:9]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: c1ccc(CNCCCNCc2ccccn2)nc1
Reactant: ClC(c1ccccn1)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: c1ccc(CN(CCCN(Cc2ccccn2)C(c2ccccn2)c2ccccn2)C(c2ccccn2)c2ccccn2)nc1
Yield: 64.9 %

Procedure:
A mixture of 1.7 g dipyridyl-methylchloride (14), 1 g N,N′-bis(pyrid-2-ylmethyl)-1,3-diamino-propane (15) and 0.5 g potassium carbonate in 20 ml acetonitrile was stirred and refluxed under argon for 48 h. TLC (silica/eluent CH2Cl2/MeOH(7N NH3) 90/10) indicated the reaction to be almost complete. The mixture was filtered and evaporated. The residue was chromatographed on silica using dichloromethane with increasing methanol concentration (up to 5%) to give 1.5 g pure product as a yellow/brown glassy gum.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.[C:29]([Si:33]([O:36][C:37]1[C:42]([F:43])=[CH:41][CH:40]=[CH:39][C:38]=1[C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:35])[CH3:34])([CH3:32])([CH3:31])[CH3:30].CC(O)=O>O.C1COCC1>[C:44]([C:38]1[CH:39]=[CH:40][C:41]([B:16]([OH:21])[OH:17])=[C:42]([F:43])[C:37]=1[O:36][Si:33]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:35])[CH3:34])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)c1cccc(F)c1O[Si](C)(C)C(C)(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(B(O)O)c(F)c1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1.08 h
Yield: 71.7 %

Procedure:
To a 100 mL round-bottomed flask were added a stir bar, dry THF (15.0 mL) and 2,2,6,6-tetramethylpiperidine (2.3 mL, 13.6 mmol). The flask was cooled to −78° C. (bath temp) and then treated with 2.5 M n-BuLi in hexanes (5.46 mL, 13.6 mmol) over 2 min. The resultant mixture was stirred for 5 min and then warmed to 0° Celsius. After 65 min, the mixture was re-cooled to −78° Celsius and treated with B(O-iPr)3 (17.5 mL, 13.6 mmol) over 4 min. After 20 min, a solution consisting of tert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (2.57 g, 9.1 mmol) and dry THF (5.0 mL) was added over the course of 2 min and stirring continued for 3 hours. The reaction was gradually warmed to room temperature while stirring for 18 hours, after which time, HOAc (5.2 mL, 91 mmol) was added. The mixture was then poured into water and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (200 mL), the extract dried over Na2SO4, filtered and concentrated to dryness. Purification by FCC yielded (4-(tert-butyl)-3-((tert-butyldimethylsilyl)oxy)-2-fluorophenyl)boronic acid (2.13 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH2:13]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14]>C(O)C>[ClH:1].[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:15]([CH2:13][CH3:14])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: CCNc1ccccc1
Reactant: Clc1ccc2c(Cl)ncnc2c1
Solvent: CCO
Product: CCN(c1ccccc1)c1ncnc2cc(Cl)ccc12
Product: Cl
Yield: 41.4 %

Procedure:
A mixture of 3.0 g of 4,7-dichloroquinazoline and 2.0 g of N-ethylaniline in 10 ml of ethanol was heated for 5 minutes. After completion of the reaction the reaction mixture was cooled, whereupon crystals separated. These were collected by filtration and recrystallized from a small amount of ethanol to give 2.0 g (yield 47%) of the desired Compound No. 58 in the form of pale yellow needles melting at 222°-226° C. (with decomposition).
Reaction SMILES: FC(F)(F)C(O)=[O:4].CC(N1[C:16]([C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[C:29]4[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=3)[NH:32][CH:31]=[C:30]4[CH:39]3[CH2:44][CH2:43][N:42]([S:45]([CH2:48][CH3:49])(=[O:47])=[O:46])[CH2:41][CH2:40]3)=[CH:23][CH:22]=2)=[O:18])=[CH:15][C:14]([CH3:50])=N1)(C)C.CC(N1C(C(NCC2C=CC(B(O)O)=CC=2)=O)=CC(C)=N1)(C)C>>[CH2:48]([S:45]([N:42]1[CH2:41][CH2:40][CH:39]([C:30]2[C:29]3[C:33](=[C:34]([C:36]([NH2:38])=[O:37])[CH:35]=[C:27]([C:24]4[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:17]([C:16]5[O:4][CH:50]=[CH:14][CH:15]=5)=[O:18])=[CH:22][CH:23]=4)[CH:28]=3)[NH:32][CH:31]=2)[CH2:44][CH2:43]1)(=[O:47])=[O:46])[CH3:49]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5cc(C)nn5C(C)(C)C)cc4)cc23)CC1
Reactant: O=C(O)C(F)(F)F
Agent: Cc1cc(C(=O)NCc2ccc(B(O)O)cc2)n(C(C)(C)C)n1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC(=O)c5ccco5)cc4)cc23)CC1
Yield: 25 %

Procedure:
The title compound was prepared according to the general procedure of 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (4-{[(2-furanylcarbonyl)amino]methyl}phenyl)boronic acid (118 mg, 0.480 mmol) for {4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid to afford 16 mg of the title compound (25%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl[CH:23]([CH3:27])[C:24](Cl)=[O:25].[OH-].[K+]>ClCCl.CC(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][O:12][CH:23]([CH3:27])[C:24]2=[O:25])=[CH:13][CH:14]=1
Reactant: CC(Cl)C(=O)Cl
Reactant: COc1ccc(CNCCCO)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1ccc(CN2CCCOC(C)C2=O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78.6 %

Procedure:
To a solution of 3-(4-methoxy-benzylamino)-propan-1-ol (2.00 g, 10.2 mmol) in dichloromethane (30 ml) was added triethylamine (1.09 g, 10.8 mmol) and 2-chloropropionyl chloride (1.37 g, 10.8 mmol) at 0° C. The mixture was stirred at 0° C. for one hour and partitioned between 0.5N hydrochloric acid and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved into 2-propanol (50 ml) and potassium hydroxide (1.15 g, 20.5 mmol) was added at 0° C. The resulting mixture was stirred at 0° C. for 4 hours and partitioned between saturated ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant: hexane/ethyl acetate=3/1) to afford 4-(4-methoxybenzyl)-2-methyl-[1,4]oxazepan-3-one as colorless oil (2.00 g, 78%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].O=[C:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[C:25]([O:24][C:23]([NH:22][CH:19]1[CH2:20][CH2:21][CH:16]([NH:1][C:2]2[C:3]([CH2:13][CH3:14])=[C:4]([CH:9]=[C:10]([Cl:12])[CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH2:17][CH2:18]1)=[O:29])([CH3:28])([CH3:26])[CH3:27]
Reactant: CCc1c(N)cc(Cl)cc1C(=O)OC
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CCc1c(NC2CCC(NC(=O)OC(C)(C)C)CC2)cc(Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.2 %

Procedure:
To a stirred solution of methyl 3-amino-5-chloro-2-ethylbenzoate (365 mg, 1.7 mmol) in 1,2-dichloroethane (20 ml) under nitrogen, was added tert-butyl (4-oxocyclohexyl)carbamate (364 mg, 1.7 mmol) followed by acetic acid (587 μl, 10.3 mmol). The solution was stirred for 10 minutes before the portionwise addition of sodium triacetoxyborohydride (1.09 g, 5.1 mmol) over 1 hour. The resulting solution was stirred at room temperature for 17 hours, before treating with tert-butyl (4-oxocyclohexyl)carbamate (364 mg, 1.7 mmol). The reaction mixture was stirred for 30 minutes and then treated with sodium triacetoxyborohydride (1.09 g, 5.1 mmol) over 2.5 hours. The reaction mixture was stirred at room temperature for a further 26 hours before addition of deionized water (40 ml). The mixture was neutralised with solid NaHCO3 (2.95 g) and was extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with brine (35 ml), dried (MgSO4), filtered and concentrated in-vacuo. The crude residue was purified by column chromatography (25 g SNAP cartridge, Isolera, 0-18% EtOAc/Heptanes) to give as an oil the title compound (623 mg, 85%) as a mixture of cis/trans isomers. LC-MS 46.1%, 2.61 min (3.5 minute LC-MS method), m/z=411.1, 413.1 and 50.2%, 2.66 min (3.5 minute LC-MS method), m/z=411.1, 413.1; 1H NMR (500 MHz, Chloroform-d) d ppm 7.05 (dd, J=7.09, 2.05 Hz, 1H) 6.68 (t, J=2.36 Hz, 1H) 4.36-4.63 (m, 1H) 3.88 (d, J=3.31 Hz, 3H) 3.62-3.78 (m, 1H) 3.49 (br. s., 1H) 3.23 (br. s., 1H) 2.63-2.76 (m, 2H) 2.07-2.18 (m, 2H) 1.77-1.89 (m, 2H) 1.69 (br. s., 1H) 1.46 (s, 9H) 1.27 (m, 3H) 1.13-1.24 (m, 3H).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH:27]([CH3:29])[CH3:28])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.C(OC(N1CCN(C2[C:52]3[C:47](=[CH:48][C:49](F)=[C:50](F)[CH:51]=3)[N:46]=CN=2)CC1)=O)(C)(C)C>>[CH:27]([O:26][C:20]1[CH:19]=[C:18]2[C:23]([C:14]([N:11]3[CH2:10][CH2:9][N:8]([C:6]([NH:46][C:47]4[CH:48]=[CH:49][C:50]([O:24][C:21]5[CH:22]=[CH:23][CH:18]=[CH:19][CH:20]=5)=[CH:51][CH:52]=4)=[O:7])[CH2:13][CH2:12]3)=[N:15][CH:16]=[N:17]2)=[CH:22][C:21]=1[O:24][CH3:25])([CH3:28])[CH3:29]
Reactant: COc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OC(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3cc(F)c(F)cc23)CC1
Product: COc1cc2c(N3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)ncnc2cc1OC(C)C
Yield: 100 %

Procedure:
Substantially the same procedure as in Example 329 was repeated, except that 4-(7-isopropoxy-6-methoxy-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester obtained in Reference Example 9 was used in place of 4-(6,7-difluoro-4-quinazolinyl)-1-piperazinecarboxylic acid tert-butyl ester, to give the desired compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[OH:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[NH:16][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(O)c1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Solvent: ClCCl
Product: Cc1cccc(Nc2cc(Nc3cccc(O)c3)ncn2)c1
Temperature: 140 °C
Yield: 39 %

Procedure:
A mixture of 4-chloro-6-(3'-methylanilino)pyrimidine (9.56 g) and 3-aminophenol (5.22 g) was stirred and heated at 140° C. for 3 hours. The product so obtained was dissolved in methylene chloride and a few drops of methanol, and chromatographed on silica using a mixture of methylene chloride and methanol, increasing in polarity from pure methylene chloride to a 19:1 mixture of methylene chloride and methanol as eluent. The product so obtained was recrystallised from a mixture of ethyl acetate and hexane to give 4-(3'-hydroxyanilino)-6-(3'-methylanilino)pyrimidine in 39% yield, m.p. 188°-189° C.;
Reaction SMILES: [CH3:1]C1(C)OC(=O)CC(=O)O1.N1C=CC=CC=1.[C:17]([CH:19]([C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24](Cl)=[O:25])[CH3:20])#[N:18]>ClCCl>[C:24]([C:23]1[CH:22]=[C:21]([CH:19]([CH3:20])[C:17]#[N:18])[CH:29]=[CH:28][CH:27]=1)(=[O:25])[CH3:1]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C#N)c1cccc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1cccc(C(C)C#N)c1
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
Next, to a solution of Meldrum's acid (408 mg, 2.84 mmol) in dichloromethane (15 mL) at 0° C. was added pyridine (0.457 mL, 5.68 mmol). The resulting mixture was stirred for 15 min and then 3-(1-cyanoethyl)benzoyl chloride (482.5 mg, 2.5 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min and then for 1 h at room temperature. The reaction mixture was diluted with dichloromethane and washed with 1 N HCl. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude product was dissolved in AcOH—H2O (1:2) and heated at reflux for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with NaHCO3 solution and brine, then dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography using hexane-ethyl acetate (9:1) as eluent to give 13 (138 mg, 28%). 1H NMR (CDCl3, 400 MHz) δ 1.68 (d, J=7.2 Hz 3H), 2.63 (s, 3H), 3.99 (q, J=7.2 Hz, 1H), 6.60 (d, J=7.6 Hz, 1H), 7.53 (d, J=2.8 Hz, 1H), 7.60 (d, J=7.2 Hz, 1H), 7.91 (t, J=2 Hz, 1H), 7.94 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:27][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]([C:24]([OH:26])=O)[CH3:23])[C:7]=2[C:6]=1[CH3:28])=[O:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:51][CH2:52][CH2:53][CH2:54][NH:55]C(=O)OC(C)(C)C>C(#N)C.O>[CH3:1][O:2][C:3]([C:5]1[S:27][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=3[O:21][CH:22]([C:24](=[O:26])[NH:51][CH2:52][CH2:53][CH2:54][NH2:55])[CH3:23])[C:7]=2[C:6]=1[CH3:28])=[O:4]
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)O)c2c1C
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CC#N
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)C(=O)NCCCN)c2c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product from 55 (170 mg) and TBTU (150 mg) was dissolved in ACN (5 ml). TEA (150 μl) was added to the mixture. The mixture was stirred for 15 min. at rt. Then tert-butyl N-(3-Aminopropyl)carbamate (200 mg) was added. The mixture was stirred at 50° C. for 2 days. Afterwards the mixture was diluted with water and filtrated. The solid was washed with water and dried in an oven
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH:8]([C:15](=O)[CH3:16])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=O)=[CH:4][CH:3]=1.[N:20]1([NH2:25])[CH:24]=[CH:23][CH:22]=[CH:21]1.C(OCC)(=O)C.O>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:13]([O:12][C:10](=[O:11])[CH2:9][C:8]1[C:15]([CH3:16])=[N:25][N:20]2[CH:24]=[CH:23][CH:22]=[C:21]2[C:6]=1[C:5]1[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: CCOC(=O)CC(C(C)=O)C(=O)c1ccc(F)cc1
Reactant: Nn1cccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CCOC(=O)Cc1c(C)nn2cccc2c1-c1ccc(F)cc1
Yield: 116.2 %

Procedure:
A mixture of ethyl 3-(4-fluorobenzoyl)-4-oxopentanoate (800 mg), 1H-pyrrol-1-amine (265 mg), and p-toluenesulfonic acid monohydrate (31 mg) in ethanol (5 ml) was refluxed for 5 hours. The mixture was partioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:4) to give ethyl[4-(4-fluorophenyl)-2-methylpyrrolo[1,2-b]pyridazin-3-yl]acetate (1.09 g) as an oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:24]=[CH:23][C:11]([C:12]([N:14]2[CH2:19][CH2:18][C:17]3[O:20][CH:21]=[CH:22][C:16]=3[CH2:15]2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:25][NH:26][CH3:27].[CH2:28]=O>C(O)(=O)C>[CH3:25][N:26]([CH2:28][C:21]1[O:20][C:17]2[CH2:18][CH2:19][N:14]([C:12](=[O:13])[C:11]3[CH:23]=[CH:24][C:8]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:9][CH:10]=3)[CH2:15][C:16]=2[CH:22]=1)[CH3:27]
Reactant: CCCCCCCc1ccc(C(=O)N2CCc3occc3C2)cc1
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CCCCCCCc1ccc(C(=O)N2CCc3oc(CN(C)C)cc3C2)cc1
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
To a solution of 0.190 g (0.584 mmol) of 5-(4-heptylbenzoyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.079 ml (0.88 mmol) of 50% aqueous dimethylamine and 0.071 ml (0.88 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 50 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=25/1) to yield the desired product.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[OH2:10].[CH3:11][CH2:12][O:13][CH2:14][CH3:15]>>[CH3:2][CH:1]([CH:11]([C:1]([OH:3])([CH3:2])[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)[C:12]([O:13][CH2:14][CH3:15])=[O:10])[CH2:4][CH3:9]
Reactant: CCOCC
Reactant: CC(=O)c1cccnc1
Reactant: O
Product: CCOC(=O)C(C(C)CC)C(C)(O)c1cccnc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
To the above solution is added, with stirring, a solution of 3-acetylpyridine (24.2 grams, 0.2 mole) in 80 milliliters of ether. The mixture is stirred for 15 minutes at -78° C. and then allowed to warm up to room temperature (2 hours). Water is added and the ether layer is separated, washed with water, dried with magnesium sulfate and evaporated under reduced pressure to give an oil which weighs 48.0 grams. The oil is distilled in a Kugelrohr apparatus to yield 39.5 grams (74.5%) of the pure product, b.p. 95°-96° C. (air bath temperature) at 0.05 mm Hg.
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)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1COCCN1
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and morpholine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16]O)[N:11]=2)[N:9]=1)[NH2:3].S(Cl)([Cl:20])=O.C(OCC)C>ClCCl.O1CCCC1>[Cl:20][CH2:16][C:12]1[N:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: NC(N)=Nc1nc(-c2cccc(CO)n2)cs1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: NC(N)=Nc1nc(-c2cccc(CCl)n2)cs1
Temperature: 25 °C
Reaction time: 70 h

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-(6-hydroxymethylpyridin-2-yl)thiazole (1.0 g) and thionyl chloride (10 ml) in a mixture of dichloromethane (10 ml) and tetrahydrofuran (10 ml) was stirred for 70 hours at ambient temperature. To the reaction mixture was added a diethyl ether (30 ml) and isolated precipitate was collected by filtration. The precipitate was added to a mixture of tetrahydrofuran, ethyl acetate and water and the mixture was adjusted to pH 9.5 with 20% aqueous potassium carbonate. The separated organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 4-(6-chloromethylpyridin-2-yl)-2-(diaminomethyleneamino)thiazole (0.97 g).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11]([OH:13])=O)[CH2:10][CH2:9]1.[CH:14]1([CH2:20][NH:21][CH2:22][C@H:23]2[N:27]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][CH:39]4[CH3:43])=[CH:30][CH:29]=3)[C:26](=[O:44])[CH2:25][CH2:24]2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:14]1([CH2:20][N:21]([CH2:22][C@@H:23]2[CH2:24][CH2:25][C:26](=[O:44])[N:27]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH:39]3[CH3:43])=[CH:30][CH:29]=2)[C:11]([CH:8]2[CH2:10][CH2:9]2)=[O:13])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CNCC2CCCCC2)cc1
Reactant: O=C(O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCCN1CCCOc1ccc(N2C(=O)CC[C@H]2CN(CC2CCCCC2)C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.6 %

Procedure:
Triethylamine (0.13 ml, 0.93 mmol, 2 eq) is added to a solution of cyclopropanecarboxylic acid (40 mg, 0.47 mmol, 1 eq) and ((5S)-5-{[(cyclohexylmethyl)amino]methyl}-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}pyrrolidin-2-one 1 (200 mg, 0.47 mmol, 1 eq) in dichloromethane (5 ml). The mixture is cooled with an ice bath. 1-Hydroxybenzotriazole (12 mg, 0.093 mmol, 0.2 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (99 mg, 0.52 mmol, 1.1 eq) are added. The mixture is stirred at room temperature for 5 hours, washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give 0.246 g of yellow oil that is purified by chromatography over silicagel (dichloromethane/methanol/ammonia 96/4/0.4) to afford 0.135 g of N-(cyclohexylmethyl)-N-[((2S)-1-{4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-5-oxopyrrolidin-2-yl)methyl]cyclopropanecarboxamide 77 as a yellow lacquer.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][C:10](=[O:17])[CH2:9]3)[CH:5]=[CH:4][CH:3]=[CH:2]1.CN(C)C=O.[CH:23](OC)(OC)[O:24][CH3:25]>C(OC(=O)C)(=O)C>[CH3:23][O:24]/[CH:25]=[C:9]1/[C:10](=[O:17])[NH:11][C:12](=[O:16])[C:13]2[C:8]/1=[CH:7][C:6]([N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)=[CH:15][CH:14]=2
Reactant: COC(OC)OC
Reactant: O=C1Cc2cc(-n3cccc3)ccc2C(=O)N1
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CO/C=C1/C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Temperature: 120 °C
Yield: 39.6 %

Procedure:
6-(1H-pyrrol-1-yl)isoquinoline-1,3(2H,4H)-dione (0.1 g, 0.442 mmol) is dissolved in acetic anhydride (0.6 mL), N,N-dimethylformamide (0.15 mL) and trimethyl orthoformate (0.1 mL, 0.919 mmol). After heating at 120° C. for 0.5 h, it is cooled and the solid is filtered and washed successively with acetic anhydride, ether and hexane to yield 47 mg (40%) solid of the title compound; mp 272-273° C.; HRMS (ESI) m/z calcd for C15H12N2O3 269.09207. found 269.09210 (M+H)+1.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:7](=[O:18])[N:8]([CH:10]([C:14]([O:16]C)=[O:15])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>C1COCC1.CO.C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]3[NH:36][N:35]=[N:34][N:33]=3)=[CH:22][CH:21]=2)[C:7](=[O:18])[N:8]([CH:10]([C:14]([OH:16])=[O:15])[CH:11]([CH3:12])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(C(C(=O)OC)C(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nn(C(C(=O)O)C(C)C)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The hydrolysis of 5-n-butyl-2-[1-(carbomethoxy)isobutyl]-2,4-dihydro-4-[[2'-(5-tetrazolyl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 38) using methanolic sodium hydroxide in THF was carried out as described in Example 7. The material obtained after work-up (71%) was homogeneous by TLC in 10% MeOH/CH2Cl2, mass spectrum (FAB) m/e 475 (M+1)+.