Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:36]Cl)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC3C=CC(OCC4C=CC=CC=4)=C(OCC4C=CC=CC=4)C=3)N=2)CC1)=O)(C)(C)C>>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:36][N:14]1[C:15]2[CH2:16][CH2:17][NH:8][CH2:9][CH2:10][C:11]=2[C:12]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)=[N:13]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: ClCc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: CC(C)(C)OC(=O)N1CCc2nn(Cc3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c(-c3ccc(Cl)cc3)c2CC1
Product: Clc1ccc(-c2nn(Cc3ccc(OCc4ccccc4)c(OCc4ccccc4)c3)c3c2CCNCC3)cc1
Yield: 20 %

Procedure:
The title compound (22 mg) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.2 mmol) using 3,4-bis(benzyloxy)benzyl chloride (0.3 mmol) in place of 2-chloromethyl-thiophene. The reaction sequence also provided 2-(3,4-bis-benzyloxy-benzyl)-3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C34H32ClN3O2, 549.22; found, m/z 550.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.36-7.16 (m, 14H), 6.86 (d, J=8.3 Hz, 1H), 6.65 (d, J=1.9 Hz, 1H), 6.56 (dd, J=8.3, 1.9 Hz, 1H), 5.13 (s, 2H), 4.99 (s, 2H), 4.97 (s, 2H), 2.78-2.76 (m, 2H), 2.73-2.71 (m, 2H), 2.65 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N:9]=[C:10]=[S:11].Cl.[OH:13][CH:14]1[CH2:17][NH:16][CH2:15]1.C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:16]1[CH2:17][CH:14]([OH:13])[CH2:15]1)=[S:11]
Reactant: OC1CNC1
Reactant: S=C=Nc1ccc(Br)cc1Br
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OC1CN(C(=S)Nc2ccc(Br)cc2Br)C1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
2,4-Dibromophenylisothiocyanate (CAS #13037-63-3, 3.02 g, 0.0103 mole), and 3-hydroxyazetidine hydrochloride (CAS #18621-18-6, 1.18 g, 10.8 mmol) were suspended in acetonitrile (35 mL). Triethylamine (1.53 mL, 0.011 mole) was added dropwise to the stirred suspension. After 20 minutes of stirring at room temperature, the reaction mixture had become a light yellow solution. After another 10 minutes of stirring at room temperature, the isothiocyanate was consumed and the intermediate, N-(2,4-dibromophenyl)-3-hydroxyazetidine-1-carbothioamide had formed. Although not necessary, this intermediate thiourea was isolated and purified by partitioning between 1:1 hexane/ethyl acetate (150 mL) and 1 M aqueous KH2PO4 (35 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (10 mL) and dried (Na2SO4). The filtrate was partially concentrated at which point the thiourea crystallized. The crystals were collected by filtration and dried under vacuum to provide N-(2,4-dibromophenyl)-3-hydroxyazetidine-1-carbothioamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[CH3:25])[C:21]([NH2:26])=[N:20][CH:19]=[CH:18]3)[CH2:9]1)=O)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[CH3:25][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][N:20]=[C:21]2[NH2:26])=[CH:16][C:15]=1[O:14][CH:10]1[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: Cc1cc2c(N)nccc2cc1OC1CCCN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(N)nccc2cc1OC1CCCNC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester (231 mg, 1.15 mmol), triphenylphosphine (301 mg, 1.15 mmol), 1-amino-7-methylisoquinolin-6-ol (200 mg, 1.15 mmol) in DMF (5 ml) at 0° C., under argon, was added dropwise diethylazodicarboxylate (181 [μL, 1.15 mmol). The mixture was then warmed to ambient temperature and stirred for 24 h. Methanol was added and the mixture loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to give 3-(1-Amino-7-methylisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester. A mixture of the (3-(1-Amino-7-methylisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (10 ml) and trifluoroacetic acid (3 ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using prep-HPLC to give 7-methyl-6-(piperidin-3-yloxy)isoquinolin-1-ylamine, El-MS: m/z=258.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][O:13][C:14]1[CH:29]=[CH:28][C:17]3[O:18][CH2:19][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH:22](O)[C:16]=3[CH:15]=1)[CH:8]=[CH:7]2.[SH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:33]([CH2:32][CH2:31][S:30][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=3)=[CH:15][C:16]1=2)([OH:35])=[O:34]
Reactant: O=C(O)CCS
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4cccc(F)c4n3)cc21
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4cccc(F)c4n3)cc21

Procedure:
2-(8-Fluoroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[NH:14]1[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15]1.C(N(CC)CC)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([N:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH2:15]2)=[C:3]2[CH2:13][CH2:12][CH2:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (40.0 mg, 0.201 mmol), tert-butyl (3S)-piperidin-3-ylcarbamate (80.7 mg, 0.403 mmol) and triethylamine (84.2 μL, 0.604 mmol) in isopropyl alcohol (0.462 mL) was stirred at 100° C. for 30 min. The mixture was concentrated and purified by flash chromatography on a silica gel column (12 g column, 0-40% EtOAc in hexanes) to give the sub-title compound as light yellow powder (43 mg, 59%). LCMS calc. for C18H27N4O4 (M+H)+: m/z=363.3. Found: 363.2.
Reaction SMILES: C([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=2)[O:26][C:27]=1[CH3:28]>>[CH2:18]([O:17][CH:5]([CH2:6][C:7]1[C:8]([CH3:16])=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([CH3:36])[CH:30]=3)[O:26][C:27]=1[CH3:28])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:20])[CH3:19]
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1C)OCC
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccc(F)c(C)c3)oc2C)c1C)C(=O)O

Procedure:
In analogy to the procedure described in example 44, rac-2-ethoxy-3-(4-methyl-1H-indol-5-yl)-propionic acid ethyl ester [preparation 10h)] was reacted with 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole to give rac-2-ethoxy-3-{-[2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-4-methyl-1H-indol-5-yl}-propionic acid as yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH3:21])[CH3:20].O>CN(C=O)C>[CH:19]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11])([CH3:21])[CH3:20]
Reactant: COc1cc(C=O)ccc1O
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)ccc1OC(C)C
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A mixture of 4-hydroxy-3-methoxybenzaldehyde (100 g), anhydrous potassium carbonate (182 g) and 2-bromopropane (81 ml) in DMF (500 ml) was stirred at 65° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine. The organic layer was dried (MgSO4), filtered and concentrated in vacuo.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20](F)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30].Cl.Cl.[CH3:33][NH:34][CH:35]1[CH2:38][NH:37][CH2:36]1.CN1CCCC1>C(O)C>[NH2:6][C:7]1[N:12]=[C:11]([N:13]2[C:22]3[C:17](=[CH:18][C:19]([F:25])=[C:20]([N:37]4[CH2:38][CH:35]([NH:34][CH3:33])[CH2:36]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[CH:10]=[CH:9][C:8]=1[F:30]
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)ccc1F
Reactant: CNC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCO
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)c(N)n4)c3c2Cl)C1
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
To 300 mg of N,N-dimethylformamide were added 101 mg of 1-(6-amino-5-fluoropyridine-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 85 mg of 3-methylaminoazetidine dihydrochloride, and 150 mg of N-methylpyrrolidine, and the mixture was stirred at 85° C. for 30 minutes. After adding 0.3 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 82 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1O[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:22])=[CH:10][CH:9]=2)=[O:4].COC(C1OC(=O)C2C(C=1C1C=CC(C)=CC=1)=CC=C(Cl)C=2)=O.[CH2:47]([NH:50][NH2:51])[CH2:48][OH:49].S(=O)(=O)(O)O>CO>[CH3:1][O:2][C:3]([C:5]1[N:51]([NH:50][CH2:47][CH2:48][OH:49])[C:7](=[O:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=1)=[CH:12][C:11]([Cl:22])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccc(C)cc1
Reactant: NNCCO
Agent: COC(=O)c1oc(=O)c2cc(Cl)ccc2c1-c1ccc(C)cc1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1c(-c2ccc(C)cc2)c2cc(Cl)ccc2c(=O)n1NCCO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution (5.0 ml) of 6-chloro-1-oxo-4-(p-tolyl)-1H-isochromen-3-carboxylic acid methyl ester and 7-chloro-1-oxo-4-p-tolyl-1H-isochromen-3-carboxylic acid methyl ester (mixture, 250 mg) in methanol was added hydrazine ethanol (540 μl), and the mixture was heated under reflux for 2 hrs. After cooling the reaction mixture, conc. sulfuric acid (0.5 ml) was added to the reaction mixture, and the mixture was stirred at room temperature for 18 hrs. The solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by medium pressure preparative LC (hexane/ethyl acetate=5/1-2/3) to give the title compound (50 mg) as colorless crystals.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14](I)[C:13]([NH2:17])=[N:12][CH:11]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O.[Cu]I.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>[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])[C:13]([NH2:17])=[N:12][CH:11]=1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cnc(N)c(I)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(N)c(C#C[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
Trimethylsilyl acetylene (10.5 mL, 79.1 mmol) was added to a solution of 6-amino-5-iodo-nicotinic acid methyl ester (11 g, 39.6 mmol), copper (I) iodide (754 mg, 4.0 mmol), tetrakis(triphenylphosphine)palladium(0) (2.3 g, 2.0 mmol) and diisopropylethylamine (21 mL, 118.7 mmol) in N,N-dimethyl formamide (80 mL) at 0° C. After addition, the reaction mixture was allowed to warm up to 25° C. and stirred for 2 h. The mixture was extracted with ethyl acetate, washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (QingDao silica gel, 200-300 mesh, 5% dichloromethane/hexanes to 60% dichloromethane/hexanes) to afford 6-amino-5-trimethylsilanylethynyl-nicotinic acid methyl ester (7.1 g, 72%) as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 0.28 (s, 9H), 3.88 (s, 3H), 5.58 (br. s., 2H), 8.14 (d, J=2.2 Hz, 1H), 8.66 (d, J=2.2 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1Cl.[I-:13].[Na+]>CC(O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1[I:13]
Reactant: Nc1nc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(I)c(Cl)cc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of 5,6-dichloro-3-nitropyridin-2-amine (15 g, 72.1 mmol) in AcOH (70 mL) was added sodium iodide (43.2 g 149.9 mmol). The mixture was stirred at 90° C. for 2 h, cooled to rt, diluted with water (70 mL) and filtered. The solid residue was washed with water, and then dried under vacuum to afford the desired product as a pale yellow solid, which was used in the next step without further purification. LC-MS: calculated for C5H3ClIN3O 2299.45, observed m/e: 299.94 (M+H)+ (Rt 2.18/5 min).
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=2)[CH2:3]1.Cl[C:14]1[N:19]=[C:18]2[N:20]([CH3:34])[C:21](=[O:33])[N:22]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])[C:23](=[NH:24])[C:17]2=[CH:16][N:15]=1.ClC1N=C2NC(=O)N(C3C(Cl)=CC=CC=3Cl)C(=N)C2=CN=1>>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:32])[C:25]=1[N:22]1[C:23](=[NH:24])[C:17]2[C:18](=[N:19][C:14]([NH:12][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[CH2:3][N:2]([CH3:1])[CH2:11][CH2:10]4)=[N:15][CH:16]=2)[N:20]([CH3:34])[C:21]1=[O:33]
Reactant: Cn1c(=O)n(-c2c(Cl)cccc2Cl)c(=N)c2cnc(Cl)nc21
Reactant: CN1CCc2cc(N)ccc2C1
Agent: N=c1c2cnc(Cl)nc2[nH]c(=O)n1-c1c(Cl)cccc1Cl
Product: CN1CCc2cc(Nc3ncc4c(=N)n(-c5c(Cl)cccc5Cl)c(=O)n(C)c4n3)ccc2C1

Procedure:
28 mg of the entitled compound was obtained as a white solid according to the same method as in Example 2, for which, however, 2-methyl-1,2,3,4-tetrahydroisoquinolin-6-amine was used in place of 2,4,4-trimethyl-1,2,3,4-tetrahydroisoquinolin-7-amine in Example 2, and 7-chloro-3-(2,6-dichlorophenyl)-4-imino-1-methyl-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one obtained in Production Example 7 was used in place of 7-chloro-3-(2,6-dichlorophenyl)-4-imino-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: Br[C:2]1[CH:6]=[C:5]([CH3:7])[S:4][C:3]=1[O:8][CH3:9].[B:10](OC(C)C)([O:15]C(C)C)[O:11]C(C)C.C([Li])CCC>C1(C)C=CC=CC=1.C1COCC1>[CH3:9][O:8][C:3]1[S:4][C:5]([CH3:7])=[CH:6][C:2]=1[B:10]([OH:15])[OH:11]
Reactant: COc1sc(C)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1sc(C)cc1B(O)O
Temperature: -70 °C
Reaction time: 0.67 h

Procedure:
A stirred mixture of 3-bromo-2-methoxy-5-methylthiophene (Step B, 296 mg, 1.43 mmol) and triisopropyl borate (396 μL, 2.15 mmol) in toluene/THF (2.3/0.6 mL) was cooled to −70° C. under an atmosphere of N2. n-Butyl lithium (2.0M in pentane, 1.07 mL, 2.15 mmol) was added dropwise via a syringe pump over 1 h. The reaction stirred at −70° C. for 40 min more and was quenched with 2N HCl (2 mL) at −20° C. The reaction was partitioned between EtOAc (15 mL) and H2O (15 mL). The aqueous layer was extracted with EtOAc (10 mL); the combined organic layers were washed with brine (15 mL), dried (Na2SO4), filtered, and concentrated in vacuo to afford (2-methoxy-5-methyl-3-thienyl)boronic acid as a yellow oil. This material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1C1C=CC=CC=1O.O.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[O:9]1[C:5]2[CH:6]=[CH:7][CH:11]=[CH:12][C:4]=2[N:10]=[C:8]1[C:7]1[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:20])=[CH:12][CH:11]=1
Reactant: COC(=O)c1ccc(C(N)=O)cc1-c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2nc3ccccc3o2)cc1
Temperature: 0 °C
Yield: 91.1 %

Procedure:
A solution of (2-hydroxyphenyl)-terephthalamic acid methyl ester (0.35 g, 1.3 mmol) in polyphosphoric acid (5 mL) was heated to reflux for 3 h. The solution was cooled to 0° C., water added (100 mL) and solid K2CO3 introduced until pH 7-9 was attained. The residue was diluted with ethyl acetate (2×100 mL) and the organic extract dried (MgSO4), filtered and concentrated to give cyclized methyl 4-(benzoxazol-2-yl)-benzoate (0.15 g, 45%) as a beige powder. 1H NMR (CDCl3) δ3.98 (s, 3H), 7.40 (m, 2H), 7.61 (m, 1H), 7.81 (m, 1H), 8.20 (d, 2H, J=7.8 Hz), 8.34 (d, 2H, J=7.8 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[CH2:19][NH:18][N:17]([S:22]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:24])=[O:23])[C:16]=3[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[C@@H:9]1[C@@H:8]([NH2:7])[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[CH2:19][NH:18][N:17]([S:22]([CH:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)(=[O:23])=[O:24])[C:16]=3[CH2:15]2)[CH2:11][O:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CCCC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2CC3=C(C2)N(S(=O)(=O)C2CCCC2)NC3)CO[C@@H]1c1cc(F)ccc1F
Reaction time: 1.5 h

Procedure:
A solution of the intermediate obtained in Step A above (49 mg, 0.089 mmol) in dichloromethane (4 mL) was treated with trifluoroacetic acid (2 mL) at room temperature. After 1.5 h, the reaction mixture was concentrated and purified by preparative thin layer chromatography eluting with 5% methanol containing 10% NH4OH in dichloromethane to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[NH:19][CH:20]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.I[CH2:25][CH3:26]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:16]=[CH:17][C:18](=[O:21])[N:19]([CH2:25][CH3:26])[CH:20]=2)([OH:14])[C:10]([F:13])([F:11])[F:12])=[C:4]([Cl:23])[CH:3]=1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc(=O)[nH]c1)C(F)(F)F
Reactant: CCI
Product: CCn1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccc1=O

Procedure:
In analogy to Example 195, 5-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 205) was alkylated with iodoethane to give the title compound as a light yellow oil. MS (m/e)=438.2 [M+H+].
Reaction SMILES: C([O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[CH:7]=[CH:8]/[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)C.O[Li].O>CCO>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9](/[CH:8]=[CH:7]/[CH:6]=[CH:5]/[C:4]([OH:22])=[O:3])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOC(=O)/C=C/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]O
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(/C=C/C=C/C(=O)O)CC1
Temperature: 50 °C
Yield: 98.2 %

Procedure:
A solution of the above ethyl ester (22) (2.60 g, 8.4 mmol) in absolute EtOH (30 mL) was added LiOH—H2O (720 mg, 17 mmol, in 10 mL of water). The reaction was heated to 50° C. for 1 h, then concentrated to remove excess EtOH. After acidification with 5% citric acid (50 mL), the product was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated to give a white solid (23) (2.32 g, 98%). 1H NMR (500 MHz, CDCL3) δ 7.31 (dd, J=15.5, 11.0 Hz, 1H), 6.18 (dd, J=15.5, 11.0 Hz, 1H), 6.08 (dd, J=15.5, 7.0 Hz, 1H), 5.80 (d, J=15.5 Hz, 1H), 4.10 (m, 2H), 2.75 (m, 2H), 2.25 (m, 1H), 1.70 (m, 2H) 1.44 (s, 9H), 1.33 (m, 2H); MS (ESI−) m/z 280.74 (M−H+).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[CH3:24][O:25][CH2:26][O:27][C:28]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:29]=1[C:30](OCOC)=[O:31]>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:7]1[C:2]([C:30](=[O:31])[C:29]2[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:28]=2[O:27][CH2:26][O:25][CH3:24])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ncccc1C1OCCO1
Reactant: COCOC(=O)c1cc(C)ccc1OCOC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1ccc(C)cc1C(=O)c1ncccc1C1OCCO1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 41.1 %

Procedure:
To a solution of 2-bromo-3-(1,3-dioxolan-2-yl)pyridine (3.50 g) in THF (50 ml) was added, at -78° C. under argon atmosphere, a 1.6M n-butyl lithium hexane solution (10.5 ml), which was stirred for 20 minutes. This reaction mixture was added, at the same temperature under argon atmosphere, to a solution of methoxymethyl 2-methoxymethoxy-5-methylbenzoate (3.66 g) in THF (50 ml). The mixture was stirred for 40 minutes, then for further one hour while warming up to room temperature. The reaction mixture was poured into a saturated aqueous saline solution, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give 3-(1,3-dioxolan-2-yl)-2-(2-methoxymethoxy-5-methylbenzoyl)pyridine (2.06 g) (Compound E-14). The physical properties and spectrum data are shown in Table 16 and Table 19.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[CH2:10][C:11](OC)=[O:12])=[O:4].[BH4-].[Na+].O>CO>[OH:12][CH2:11][CH2:10][C:6]1[O:7][CH:8]=[CH:9][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)Cc1occc1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccoc1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.287 g (6.494 mmol) of methyl 3-methoxycarbonylfuran-2-ylacetate in 50 ml of methanol, 1.23 g (32.5 mmol) of sodium borohydride was added at room temperature, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield the desired product.