Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[CH2:11][CH2:10][C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[C:7]1=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>O1CCOCC1>[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[N:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[CH2:11][CH2:10][C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[C:7]2=[O:18])[CH2:27][CH2:26]1
Reactant: O=C1CCc2ccccc2C(=O)N1CCCCBr
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: C1COCCO1
Product: O=C1CCc2ccccc2C(=O)N1CCCCN1CCN(c2ncccn2)CC1
Yield: 86.5 %

Procedure:
To a solution of 99.3 mg of the compound of Example 16 dissolved in 10 ml of dioxane was added 158 mg (3 equivalents) of 1-(2-pyrimidinyl)piperazine, followed by heating under reflux for 8 hours. The reaction treatment and purification were conducted similarly as in Example 17 to obtain 109 mg of the desired compound (yield 87%). The maleate was obtained by converting the product to maleate in a conventional manner, followed by recrystallization from methylene chloride-ether.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[CH2:31]([N:34]=[C:35]=[O:36])[CH2:32][CH3:33]>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:34]([CH2:31][CH2:32][CH3:33])[C:35]2=[O:36])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN=C=O
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: CCCN1C(=O)N(S(=O)(=O)c2ccccc2)CC1C(=O)N1CCN(c2cc(C)ccc2C)CC1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and propyl isocyanate to give the title compound as a colorless solid. MS: 485.2 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH:16]([CH3:18])[CH3:17])[NH2:15])[C:3]([OH:5])=[O:4].[CH:20](O)([CH3:22])[CH3:21]>>[CH:20]([O:4][C:3](=[O:5])[C:2]([CH3:19])([CH3:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH:16]([CH3:17])[CH3:18])[NH2:15])([CH3:22])[CH3:21]
Reactant: CC(C)C(N)CCCCCCCCC(C)(C)C(=O)O
Reactant: CC(C)O
Product: CC(C)OC(=O)C(C)(C)CCCCCCCCC(N)C(C)C
Yield: 76 %

Procedure:
The procedure described in Example (1b) is repeated, using 50 g (0.185 mole) of 2,2-dimethyl-11-isopropyl-11-aminoundecanoic acid and 100 ml of isopropanol. Distillation yields 44 g (0.141 mole) of 2,2-dimethyl-11-isopropyl-11-aminoundecanoic acid isopropyl ester, corresponding to a yield of 76% of theory;
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[C:21](=[O:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([CH3:24])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([NH:8][C:9]1[C:10]2[C:15]([N:16]=[C:17]3[C:22]=1[CH:21]([OH:23])[CH2:20][CH2:19][CH2:18]3)=[CH:14][C:13]([CH3:24])=[CH:12][CH:11]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc2c(NCc3ccccc3)c3c(nc2c1)CCCC3=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc2c(NCc3ccccc3)c3c(nc2c1)CCCC3O
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To a cooled suspension of 3.6 g of 9-benzylamino-3,4-dihydro-6-methylacridin-1(2H)-one in 80 ml of tetrahydrofuran was added 6 ml of 1 M solution of lithium aluminum hydride in THF. This was stirred for 1 hour, and thereafter quenched with 7 ml of saturated ammonium chloride solution. The inorganics were filtered and rinsed with ethyl acetate and the combined organics were dried over anhydrous magnesium sulfate. The resulting solid was triturated with ethyl ether to obtain 3.15 g of a solid, mp 148°-153° C. This was recrystallized from toluene (70 ml) to obtain 2.5 g of an analytically pure solid, mp 149°-152° C.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[NH:9][C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][O:27][Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C=O)C.[CH2:43](Br)[C:44]#[CH:45]>CCOCC>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:45][C:44]#[CH:43])[C:8]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:26][O:27][Si:28]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:35]([CH3:37])[CH3:36])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CO[Si](C(C)C)(C(C)C)C(C)C)[nH]c2c1
Reactant: C#CCBr
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCn1c(-c2ccccc2CO[Si](C(C)C)(C(C)C)C(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
To an ice cooled solution of methyl 3-cyclohexyl-2-(2-{[(triisopropylsilyl)oxy]methyl}phenyl)-1H-indole-6-carboxylate in DMF (0.13 M) NaH (2 eq.) was added. After 20 min. propargyl bromide (80% solution in toluene) (1.5 eq.) was added and the mixture stirred at 0° C. for 1 h, diluted with Et2O, washed with sat aq. NH4Cl and brine. The organic phase was dried over Na2SO4 and evaporated in vacuo. The residual material was subjected to flash chromatography (PE:EtOAc, 20:1). After evaporation of the solvents the product was obtained as yellow oil (67%). MS (ES+): 558.7 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH:19]1([C:22]2[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=2)[NH2:25])[CH2:21][CH2:20]1>>[CH:19]1([C:22]2[CH:23]=[C:24]([NH:25][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[CH:26]=[CH:27][CH:28]=2)[CH2:21][CH2:20]1
Reactant: Nc1cccc(C2CC2)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(C2CC2)c1
Yield: 66.3 %

Procedure:
The product is prepared according to the following procedure, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 395 mg of 3-cyclopropylaniline (prepared according to Wallace et al., in Tetrahedron Lett. 2002, 43, 6987) in place of the 2,4-difluoroaniline. 225 mg of N-(3-cyclopropylphenyl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].C(N)(=[O:31])C>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:26])=[O:31])=[CH:27][CH:28]=3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CC(N)=O
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C#N)cc3)CC2)nc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C(N)=O)cc3)CC2)nc1
Temperature: 25 °C

Procedure:
The product of step A (150 mg, 0.398 mmol), acetamide (101 mg, 1.71 mmol) and Pd(OAc)2 (13.4 mg, 0.02 mmol) in THF (4.5 mL) and H2O (1.5 mL) was heated at 65° C. for 24 h. The mixture was cooled to RT and diluted with H2O. The solution was extracted with EtOAc (×3). The combined organic layers were washed with brine (1×), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by silica gel column chromatography (elution with 20:1 DCM:MeOH) to yield the desired compound. MS (ESI) m/z 395 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2.[Br:14]Br.O>ClC(Cl)Cl>[Br:14][C:6]1[C:5]2[C:4]3[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:13])[C:3]=3[CH:12]=[CH:11][CH:10]=2
Reactant: BrBr
Reactant: O=C1Nc2cccc3cccc1c23
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=C1Nc2ccc(Br)c3cccc1c23
Temperature: 0 °C
Yield: 95.4 %

Procedure:
Benz[cd]indol-2(1H)-one (2.1 g, 12.4 mmol) was dissolved in 50 ml trichloromethane and cooled to 0° C. To this stirred and cooled solution was added dropwise bromine (0.64 ml, 12.4 mmol) within 5 minutes. The reaction was allowed to warm up to room temperature for 24 hours. The reaction mixture was then poured into water and extracted with trichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated to give 2.935 g product (95% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][C:10](Cl)=[O:11].[NH2:13][CH2:14][C@H:15]1[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17][C@@H:16]1[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(OCC)C.[OH-].[Na+]>[CH2:31]([O:30][C@@H:16]1[C@@H:15]([CH2:14][NH:13][C:10](=[O:11])[CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])[O:19][C@@H:18]([N:20]2[CH:27]=[C:26]([CH2:28][CH3:29])[C:24](=[O:25])[NH:23][C:21]2=[O:22])[CH2:17]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)Cc1c(Cl)cccc1Cl
Reactant: CCc1cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CN)O2)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: CCc1cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](CNC(=O)Cc3c(Cl)cccc3Cl)O2)c(=O)[nH]c1=O
Reaction time: 0.17 h

Procedure:
A solution of (2,6-dichlorophenyl)acetyl chloride (prepared from 103 mg of the acid) in 2 ml of diethyl ether was added to a solution of 173 mg of 5'-amino-3'-O-benzyl- 2',5'-dideoxy-5-ethyluridine in 4.5 ml of 0.11M sodium hydroxide solution. The mixture was shaken vigorously for 10 minutes and then filtered. The solid was recrystallized from ethanol to give 120 mg of 3'-O-benzyl-5'-[2-(2,6-dichlorophenyl)acetamido]2',5'-dideoxy-5-ethyluridine in the form of a white solis of melting point 174°-177° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[CH3:11][O:10][C:4]1[CH:3]=[C:2]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: OB(O)c1ccco1
Product: COc1cc(OC)cc(-c2ccco2)c1

Procedure:
1-Bromo-3,5-dimethoxybenzene was coupled with 2-furylboronic acid following the procedure for Example 21. 2-(3,5-Dimethoxyphenyl)furan was isolated as a colorless liquid (0.746 g, 79% yield).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.OS(O)(=O)=O.[CH3:15][CH2:16]O>>[CH2:15]([O:8][C:7]([C:5]1[S:6][C:2]([CH3:1])=[CH:3][CH:4]=1)=[O:9])[CH3:16]
Reactant: CCO
Reactant: Cc1ccc(C(=O)O)s1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(C)s1
Yield: 85 %

Procedure:
A solution of 5-methyl-thiophene-2-carboxylic acid (25.2 g, 177 mmol) in EtOH (500 mL) is treated with conc. H2SO4 (15 mL) and heated to a gentle reflux for 72 h. The solution is partially concentrated and poured into water (500 mL) and extracted with Et2O (3×). The combined extracts are washed with aq Na2CO3, water, dried over Na2SO4, filtered and concentrated in vacuo. Vacuum distillation of the residue afforded 5-methyl-thiophene-2-carboxylic acid ethyl ester (25.6 g, 85%): bp 98-99° C./9-10 mbar; 1H NMR (CDCl3, 300 MHz) δ 7.6 (s, 1 H), 6.78 (s, 1 H), 4.30 (q, J=6.0 Hz, 2 H), 2.50 (s, 3 H), 1.34 (t, J=6.0 Hz, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[C:9](=[O:27])[C:8]=2[C:7]([O:28][CH2:29][CH3:30])=[C:6]2[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=12)[CH3:2].O1CCCC1.[BH4-].[Na+]>CO>[CH2:29]([O:28][C:7]1[C:8]2[C:9](=[O:27])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=3[F:26])[CH:11]([OH:13])[C:12]=2[C:4]([O:3][CH2:1][CH3:2])=[C:5]2[CH:34]=[CH:33][CH:32]=[CH:31][C:6]=12)[CH3:30]
Reactant: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2=O)c(F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(N2C(=O)c3c(c(OCC)c4ccccc4c3OCC)C2O)c(F)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Ethyl {4-[4,9-bis(ethyloxy)-1,3-dioxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-3-fluorophenyl}acetate (0.112 g, 0.24 mmol) was suspended in methanol (2 ml) and tetrahydrofuran (3 ml) added to dissolve the reactant. The reaction mixture was cooled to 0° C. in an ice bath and sodium borohydride (0.027 g, 0.72 mmol) added portionwise. Stirred under argon for 2-3 hours at 0° C. Further sodium borohydride was added to the reaction to push it to completion. The reaction mixture was evaporated to a solid and partitioned between EtOAc and ammonium chloride (saturated). The aqueous layer was extracted with EtOAc (×2) and the combined organics washed with brine and dried over MgSO4. Solvent was evaporated to give the title product as a gummy residue, which was triturated with hexane to afford a solid (0.111 g, 0.23 mmol).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[O:68][C:67]([C:69]([O:71][CH3:72])=[O:70])=[CH:66][CH:65]=1>>[CH3:72][O:71][C:69]([C:67]1[O:68][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:37])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)=[O:70]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COC(=O)c1ccc(N)o1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cccc(Cl)c2F)o1
Yield: 1.6 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.6 mmol), diphenylphosphinic chloride (0.25 g, 1 mmol), then reacted with methyl 5-aminofuran-2-carboxylate (Lancaster) (0.11 g, 0.78 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-furan-2-carboxylic acid methyl ester as a yellow solid (Yield 5 mg, 2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[C:5]#[N:6].[CH2:11]([NH2:14])[CH2:12][CH3:13]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:14][CH2:11][CH2:12][CH3:13])[C:5]#[N:6]
Reactant: CCCN
Reactant: N#Cc1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Product: CCCNc1ccc(C#N)cc1Cl
Temperature: 50 °C
Yield: 93.8 %

Procedure:
Step AR1. A mixture of 3-chloro-4-florobenzonitrile (312 mg, 2 mmol) and propylamine (236 mg, 4 mmol) in THF (4 mL) was heated at 50° C. overnight. After the solvent was removed, the residue was purified by flash chromatography with DCM to give 3-chloro-4-(propylamino)benzonitrile (365 mg, 94%).
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)[C:10]([F:30])=[CH:9][C:8]=1[F:31].Cl.Cl.[CH3:34][NH:35][CH:36]1[CH2:39][NH:38][CH2:37]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:38]4[CH2:39][CH:36]([NH:35][CH3:34])[CH2:37]4)[C:21]=3[Cl:23])[C:16](=[O:26])[C:15]([C:27]([OH:29])=[O:28])=[CH:14]2)[C:10]([F:30])=[CH:9][C:8]=1[F:31]
Reactant: CNC1CNC1
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CNC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4nc(N)c(F)cc4F)c3c2Cl)C1
Temperature: 90 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To 400 mg of N,N-dimethylformamide were added 90 mg of 1-(6-amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 80 mg of 3-methylaminoazetidine dihydrochloride, and 160 mg of N-methylpyrrolidine, and the mixture was stirred at 90° C. for 1 hour. After adding 0.5 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 92 mg of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([N+:17]([O-])=O)[CH:8]=2)[CH:6]=1>[Pd].C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:8]=[C:9]([NH2:17])[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[CH:12]=2)[CH:6]=1
Reactant: Cc1cn(-c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)cn1
Agent: [Pd]
Solvent: CCO
Product: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
In an autoclave a suspension of 5% palladium on activated carbon (0.6 g) in 94% aqueous ethanol (200 mL) is pre-hydrogenated. After that, 4-methyl-1-(3-nitro-5-trifluoromethyl-phenyl)-1H-imidazole (6.0 g, 22.1 mmol) is added, and the mixture is hydrogenated at 70° C. and 4 bar pressure for 3 hours. Thereafter, most of the starting material is converted. The suspension is filtered over filter aid. The obtained filtrate is slowly added to water (250 mL) of 0-5° C. The resulting mixture is concentrated to a weight of 270 g, stirred, cooled to 0° C. and further stirred for almost 3 hours. The formed solid is filtered, washed with water (20 mL) and dried at 50° C. under reduced pressure to afford 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenylamine as an off-white solid. Yield: 85.8% (HPLC purity: 94 area %), Melting range: 123-124° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH3:10])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:30]N1C(=O)CCC1=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Br:30])=[C:4]([CH3:10])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Br)ccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of (4-bromo-2-methyl-phenyl)-methanol (Intermediate 133, 319.0 mg, 1.58 mmol) and triphenylphosphine (466.0 mg, 1.74 mmol) in 5 mL CH2Cl2 was cooled to 0° C. and N-bromosuccinimide (309.0 mg, 1.74 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25° C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 350.0 mg (84%), was isolated by column chromatography (2-3% EtOAc-hexanes) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:3]=1[F:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCOCC1>[C:12]([C:11]1[C:2]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:3]([F:21])[CH:4]=[C:5]2[C:10]=1[N:9]([CH:14]1[CH2:16][CH2:15]1)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:6]2=[O:20])#[N:13]
Reactant: C1CCNC1
Reactant: N#Cc1c(Cl)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: C1COCCO1
Product: N#Cc1c(N2CCCC2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
3.05 g of the product from Example 1 and 2.5 ml of pyrrolidine are boiled in 50 ml of dioxane for 3 hours. The mixture is concentrated in vacuo and the residue is taken up in water. The mixture is rendered neutral with 1N HCl. The solid which has precipitated out is filtered off with suction, dried and stirred with acetonitrile. 1.8 of the title compound with a melting point of 274°-6° C. are obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([CH3:9])=[CH:8][C:4]=2[CH:3]=1.[C:12](=[O:14])=[O:13]>>[CH3:9][C:7]1[S:6][C:5]2[CH:10]=[CH:11][C:2]([C:12]([OH:14])=[O:13])=[CH:3][C:4]=2[CH:8]=1
Reactant: Cc1cc2cc(Br)ccc2s1
Reactant: O=C=O
Product: Cc1cc2cc(C(=O)O)ccc2s1

Procedure:
Conversion of 5-bromo-2-methylbenzo[b]thiophene to the Grignard reagent followed by reaction with carbon dioxide by the method of Example 3(i) gave 2-methylbenzo[b]thiophene-5-carboxylic acid, m.p. 220°-222°.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27](O)=[O:28])[C:24]([CH3:30])=[CH:23][CH:22]=2)=[C:17]([CH3:31])[C:16]=1[CH:32]1[C:45]2[C:44](=[O:46])[CH2:43][C:42]([CH3:48])([CH3:47])[CH2:41][C:40]=2[O:39][C:38]2[CH2:37][C:36]([CH3:50])([CH3:49])[CH2:35][C:34](=[O:51])[C:33]1=2.[CH3:52][S:53]([NH2:56])(=[O:55])=[O:54].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:26]=[C:25]([C:27]([NH:56][S:53]([CH3:52])(=[O:55])=[O:54])=[O:28])[C:24]([CH3:30])=[CH:23][CH:22]=2)=[C:17]([CH3:31])[C:16]=1[CH:32]1[C:45]2[C:44](=[O:46])[CH2:43][C:42]([CH3:47])([CH3:48])[CH2:41][C:40]=2[O:39][C:38]2[CH2:37][C:36]([CH3:50])([CH3:49])[CH2:35][C:34](=[O:51])[C:33]1=2
Reactant: COc1ccc(-c2ccc(C)c(C(=O)O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reactant: CS(N)(=O)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2ccc(C)c(C(=O)NS(C)(=O)=O)n2)c(C)c1C1C2=C(CC(C)(C)CC2=O)OC2=C1C(=O)CC(C)(C)C2
Reaction time: 0.75 h
Yield: 84.2 %

Procedure:
1,1′-Carbonyldiimidazole (99.5 mg, 0.61 mmol) was added to a solution of the 6-[4-methoxy-2-methyl-3-(3,3,6,6-tetramethyl-1,8-dioxo-2,3,4,5,6,7,8,9-octahydro-1H-xanthen-9-yl)phenyl]-3-methylpyridine-2-carboxylic acid produced in Example 10-3 (250 mg, 0.47 mmol) in DMF (5 ml) at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 1 hour and 45 minutes. Thereafter, methanesulfonamide (58.4 mg, 0.61 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.092 ml, 0.61 mmol) were added to the resulting solution at room temperature, and the mixture thus obtained was then stirred at the same temperature as above for 4 hours. Thereafter, an aqueous solution of citric acid (454 mg, 2.36 mmol) was added to the reaction solution, and the mixed solution was then extracted with ethyl acetate. The organic layer thus obtained was washed with water, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue thus obtained was then purified by silica gel column chromatography (methanol:dichloromethane=0:1 to 1:9, v/v). The solid thus obtained was washed with diethyl ether, followed by collection by filtration and drying, to obtain the title compound (240 mg, yield: 84%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH:31]1[CH2:33][CH:32]1[CH:34]=O.C([BH3-])#N.[Na+]>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH:31]1[CH2:33][CH:32]1[CH2:34][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1
Reactant: O=CC1CC1c1cc(F)ccc1F
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc2c(c1)N(CCN1CCC(NCC3CC3c3cc(F)ccc3F)CC1)C(=O)CO2
Yield: 42 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 58) (1 mmol), 2-(2,5-difluorophenyl)cyclopropanecarbaldehyde (Intermediate 68) (200 mg, 1.1 mmol) and sodium cyanoborohydride (125 mg, 2 mmol) were reacted as described under Example 21 to give 196 mg (42%) product as a gum.