Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)=[CH:5][CH:4]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2nc(=O)c3ccccc3s2)cn1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1ccc(-c2nc(=O)c3ccccc3s2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.1 %

Procedure:
2-[6-(Methylthio)-3-pyridyl]-4H-1,3-benzothiazine-4-one (0.28 g, 1.00 mmol) was dissolved in chloroform (30 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.00 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.085 g, 28%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[S:8])[NH:5][CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=2)[C:3]=1[C:18]([O:20]C(C)C)=[O:19].[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Cl)=[CH:28][CH:27]=1>O1CCCC1.CCOCC>[CH3:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][S:8][C:6]2[NH:7][C:2]([CH3:1])=[C:3]([C:18]([OH:20])=[O:19])[CH:4]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[CH:10]=3)[N:5]=2)=[CH:28][CH:27]=1
Reactant: CC1=C(C(=O)OC(C)C)C(c2cccc([N+](=O)[O-])c2)NC(=S)N1
Reactant: COc1ccc(CCl)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CSC2=NC(c3cccc([N+](=O)[O-])c3)C(C(=O)O)=C(C)N2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(-)-1,2,3,4-Tetrahydro-6-methyl-4-(3-nitrophenyl)-2-thioxo-5-pyrimidinecarboxylic acid, 1-methylethyl ester (2.6 mmol, 884 mg) was dissolved in dry tetrahydrofuran and cooled to 0° C. 4-Methoxybenzyl chloride (1.1 eq, 32.9 mmol, 393 μl) was added dropwise. After the addition was complete, the bath was removed and the reaction stirred at room temperature for two hours. The mixture was then heated at 65° C. for 16 hours. TLC 35:65:acetone:hexane showed an incomplete reaction, so additional 4-methoxybenzyl chloride (1.1 eq, 1.3 mmol, 393 μl) was added to the mixture. After 7 hours at 65° C., the mixture was allowed to come to room temperature and diluted with ether. As the mixture cooled to 0° C., a white solid formed. The solid was collected by suction filtration, washed with ether, and dried to afford 1,4-dihydro-2-[[(4-methoxyphenyl)methyl]thio]-6-methyl-4-(3-nitrophenyl)-5-pyrimidinecarboxylic acid, 1-methylether ester hydrochloride, 636 mg (49%).
Reaction SMILES: [Cl:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].Cl.[NH2:8][CH2:9][C:10]#[N:11]>ClC=C(Cl)Cl>[Cl:1][CH:2]([CH3:6])[C:3]([NH:11][CH2:10][C:9]#[N:8])=[O:4]
Reactant: CC(Cl)C(=O)Cl
Reactant: N#CCN
Agent: Cl
Solvent: ClC=C(Cl)Cl
Product: CC(Cl)C(=O)NCC#N
Yield: 96.7 %

Procedure:
In this preparation 42 g of 2-chloropropionyl chloride and 27.8 g aminoacetonitrile hydrochloride were admixed with 100 ml of trichloroethylene and stirred at reflux for 5 hours. The reaction mixture was then filtered and the filtrate was distilled to remove the solvent affording 42.6 g of an oily 2-chloro-N-cyanomethylpropionamide product.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[N:15]=1.[C:22](=[O:24])=[O:23].Cl>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]([Cl:20])[C:17]([C:22]([OH:24])=[O:23])=[C:16]([Cl:21])[N:15]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1c(Cl)nc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 49 %

Procedure:
To a solution of diisopropylamine (23.42 mL, 164 mmol) in THF (200 mL) was slowly added butyllithium (100 mL, 160 mmol) at −78° C. The mixture was stirred at −78° C. for 15 min. To this mixture was slowly added a solution of 2,4,6-trichloropyrimidine (20.06 g, 109 mmol) in THF (50 mL) at −78° C. The mixture was stirred for 1 h. Dry ice was added and the mixture was stirred at RT for 1 h. To the mixture was added 1N HCl, which was subsequently extracted with EtOAc. The organic layers were basified with aqueous NaHCO3, and washed with EtOAc. The aqueous layer was then acidified with 1N HCl, and extracted with EtOAc. The organic layers were washed with 1N HCl, water, and brine, were dried over anhydrous MgSO4, and then filtered. The filtrate was concentrated under reduced pressure. The residue was washed with hexane to give the desired product as a pale brown solid (12.28 g, 49%). 1H NMR (500 MHz, CDCl3) δ ppm 7.65 (br s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=[C:3]12.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:22]([N:7]1[CH2:6][CH2:5][N:4]2[CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=[C:3]2[C:2]1=[O:1])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)c1cc2n(c1)CCNC2=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)c1cc2n(c1)CCN(Cc1ccccc1)C2=O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a vial charged with ethyl 1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate (0.0298 g, 0.143 mmol) was added cesium carbonate (0.061 g, 0.186 mmol), benzyl bromide (0.037 g, 0.2145 mmol), and acetonitrile (1 mL). The vial was capped and was shaken at 70° C. overnight. The solids were removed by filtration and the solution was concentrated to give crude ethyl 2-benzyl-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-7-carboxylate Intermediate 12.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:29]I>O1CCCC1>[CH:1]1([N:6]([CH3:29])[C:7]2[C:8]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(NC3CCCC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N(C)C3CCCC3)nc2c1
Temperature: 0 °C

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 3-(cyclopentylamino)-2-phenylquinoxaline-6-carboxylate (214.1 mg, 0.62 mmol, 1.00 equiv) in tetrahydrofuran (10 mL). This was followed by the addition of sodium hydride (246.8 mg, 6.17 mmol, 10.00 equiv, 60%) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at room temperature. To this was added a solution of CH3I (1.75 g, 12.32 mmol, 20.00 equiv) in tetrahydrofuran (2 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of water. The resulting mixture was concentrated under vacuum. This resulted in 200 mg (crude) of methyl 3-(cyclopentyl(methyl)amino)-2-phenylquinoxaline-6-carboxylate as yellow oil.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]2=[C:4]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([NH:19][CH3:20])=[O:18])=[O:14])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1B(O)O>O1CCOCC1.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd].[Pd]>[Cl:38][C:36]1[CH:35]=[CH:34][C:33]([C:2]2[N:6]3[CH2:7][CH2:8][CH2:9][N:10]([CH3:12])[CH2:11][C:5]3=[C:4]([C:13]([NH:15][C@@H:16]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:17]([NH:19][CH3:20])=[O:18])=[O:14])[N:3]=2)=[C:32]([F:31])[CH:37]=1
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(Br)n2c1CN(C)CCC2
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(-c2ccc(Cl)cc2F)n2c1CN(C)CCC2
Temperature: 110 °C
Yield: 40 %

Procedure:
A mixture of intermediate 55B (47 mg, 0.12 mmol), potassium carbonate (40 mg, 0.29 mmol), 2-fluoro-4-chlorophenylboronic acid (0.25 mmol) and palladium tetrakis(triphenylphosphine) (20 mg) in dioxane (1.0 mL) and water (0.5 mL) was heated at 110° C. in a sealed vial for 4 h. After cooling down to room temperature, the mixture was passed through a thiol-based palladium scavenger resin (PolymerLabs). The residue was concentrated to dryness, to which MeOH (0.5 mL) was added. The solution was filtered to remove insoluble material and purified by prep LC-MS with 5% MeCN/water to 95 MeCN/water (0.1% formic acid) in 15 min. Pure fractions were evaporated with a Savant speedvac. The oil residue was taken up in DCM (1.0 mL) and diluted with hexane (1.0 mL). Evaporation under air flow with mild heating give white solid product Compound 529 at 40% yield. 1H-NMR (400 MHz, CDCl3) δ: 0.96 (t, J=4.8 Hz, 6H), 1.59-1.72 (m, 2H), 1.81-1.90 (m, 3H), 2.47 (s, 3H), 2.56 (br, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.98 (br, 2H), 3.96 (br, 2H), 4.52-4.58 (m, 1H), 6.48 (br, 1H), 7.21-7.24 (dd, J=2.0, 9.6 Hz, 1H), 7.29-7.31 (dd, J=1.7, 10.0 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.50 (t, J=8.0 Hz, 1H). LCMS (+ESI) m/z 450.2, 452.2 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][C:15]4[O:21][CH2:20][CH2:19][C:18]([C:22]([OH:24])=O)=[CH:17][C:16]=4[CH:25]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][N:27]([CH2:34][C:35]1[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=1)[CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C1CCN2C(=NCCC2)CC1>CN(C)C=O.CN(C)C1C=CN=CC=1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[CH:13]=[CH:14][C:15]4[O:21][CH2:20][CH2:19][C:18]([C:22]([NH:39][C:38]5[CH:40]=[CH:41][C:35]([CH2:34][N:27]([CH:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)[CH3:26])=[CH:36][CH:37]=5)=[O:24])=[CH:17][C:16]=4[CH:25]=3)=[CH:10][CH:11]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Reactant: O=C(O)C1=Cc2cc(-c3ccc(N4CCCC4)cc3)ccc2OCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CN(Cc1ccc(NC(=O)C2=Cc3cc(-c4ccc(N5CCCC5)cc4)ccc3OCC2)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.3 %

Procedure:
To a solution of 7-(4-(pyrrolidin-1-yl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxylic acid (0.15 g), 4-(N-methyl-N-(tetrahydropyran-4-yl)aminomethyl)aniline (0.1 g) and 1-hydroxybenzotriazole (0.07 g) in dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydro-chloride (0.13 g) under ice-cooling, and the mixture was stirred under nitrogen atmosphere at room temperature for 3 hours. To the mixture were added 4-dimethylaminopyridine (catalytic amount) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.2 ml), and the mixture was stirred over night. The solvent was evaporated, and the residue was purified with silica gel column (methanol/ethyl acetate/triethylamine) to give crude crystals, which were recrystallized from ethanol-hexane to give 7-(4-(pyrrolidin-1-yl)phenyl)-N-(4-((N-tetrahydropyran-4-yl-N-methylamino)-methyl)phenyl)-2,3-dihydro-1-benzoxepine-4-carboxamide (Compound 150) (0.08 g) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:24](O)=O)=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:27])=[N:6][CH:7]=1.[CH2:28]([CH2:30][NH2:31])[OH:29]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:16][C:15]=3[CH2:24][NH:31][CH2:30][CH2:28][OH:29])=[CH:10][C:9]=2[F:27])=[N:6][CH:7]=1
Reactant: Nc1cnc(-c2ccc(-c3ccc(C(F)(F)F)cc3C(=O)O)cc2F)cn1
Reactant: NCCO
Product: Nc1cnc(-c2ccc(-c3ccc(C(F)(F)F)cc3CNCCO)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Intermediate IF using 4′-(5-Aminopyrazin-2-yl)-3′-fluoro-4-(trifluoromethyl)biphenyl-2-carboxylic acid and ethanolamine. MS (ESI): mass calcd. for C20H18F4N4O, 406.39; m/z found, 407.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.18 (s, 1H), 8.12-8.01 (m, 2H), 7.86 (dd, J=8.1, 1.7, 1H), 7.65 (d, J=8.1, 1H), 7.34 (dd, J=3.5, 1.6, 1H), 7.33-7.31 (m, 1H), 4.38 (s, 2H), 3.78-3.63 (m, 2H), 3.09-3.00 (m, 2H).
Reaction SMILES: C(#N)C.Br[CH2:5][C:6]([NH:8][CH:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][CH2:12][CH2:11][CH2:10]1)=[O:7].[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(N(CC)CC)C>[O:20]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][N:36]([CH2:5][C:6]([NH:8][CH:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=4[O:13][CH2:12][CH2:11][CH2:10]3)=[O:7])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(Oc2ccc(C3CCNCC3)cc2)cc1
Reactant: O=C(CBr)NC1CCCOc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CN1CCC(c2ccc(Oc3ccccc3)cc2)CC1)NC1CCCOc2ccccc21
Temperature: 0 °C
Yield: 98 %

Procedure:
To a 5 ml acetonitrile solution of 190 mg of the compound (8) synthesized in Reference Example 8 were added 184 mg of the compound (4) synthesized in Reference Example 4 and 0.14 ml of triethylamine. This was heated at reflux for 3 hours. To the reaction was added 10 ml of ice water, then extraction was performed with ethyl acetate. The extract was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=25:1) to obtain the above-identified compound (28) in an amount of 300 mg (yield of 98%).
Reaction SMILES: [C:1]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(C1C2C(=CC=CC=2)NC=1)(=O)CCCCCC.Br[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=1)=[O:43]>>[C:1]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)=[O:43])[CH:13]=1)(=[O:11])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)c1c[nH]c2ccccc12
Reactant: COc1ccc(COC(=O)CCCBr)cc1
Agent: CCCCCCC(=O)c1c[nH]c2ccccc12
Product: CCCCCCC/C=C/C(=O)c1cn(CCCC(=O)OCc2ccc(OC)cc2)c2ccccc12

Procedure:
The procedure of Ex. 1 was repeated except that (E)-3-(2-decenoyl)indole obtained in Pre. Ex. 23 was used in place of 3-heptanoylindole, and 4-methoxybenzyl 4-bromobutyrate was used in place of 4-bromobutyrate to give (E)-4-methoxybenzyl 4-[3-(2-decenoyl)-1-indolyl]butyrate.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[C:9]([O:30]C)=[CH:10][C:11]([O:28]C)=[C:12]3[C:17]=2[O:16][C:15]([C:18]2[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[CH3:26])=[CH:14][C:13]3=[O:27])[CH2:6][CH2:5][N:4]1[CH3:32].Cl.N1C=CC=CC=1>>[OH:28][C:11]1[CH:10]=[C:9]([OH:30])[C:8]([C@@H:7]2[CH2:6][CH2:5][N:4]([CH3:32])[C@H:3]2[CH2:2][OH:1])=[C:17]2[C:12]=1[C:13](=[O:27])[CH:14]=[C:15]([C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=1[CH3:26])[O:16]2
Reactant: COc1cc(OC)c2c(=O)cc(-c3ccc(C#N)cc3C)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(C#N)ccc1-c1cc(=O)c2c(O)cc(O)c([C@@H]3CCN(C)[C@H]3CO)c2o1

Procedure:
Compound of example 59 (0.6 g, 1.38 mmol) was demethylated using pyridine hydrochloride (6 g, 51.95 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:13])([CH3:12])[CH3:11])=[CH:6][CH:5]=1.[Cl:14][C:15]([Cl:19])([Cl:18])[C:16]#[N:17]>CCOCC>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([O:13][C:16](=[NH:17])[C:15]([Cl:19])([Cl:18])[Cl:14])([CH3:11])[CH3:12])=[CH:8][CH:9]=1.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:13])([CH3:11])[CH3:12])=[CH:8][CH:9]=1
Reactant: N#CC(Cl)(Cl)Cl
Agent: CC(C)(O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccc(Cl)cc1
Reaction time: 1.5 h

Procedure:
To a suspension of sodium hydride (5.63 mg, 0.117 mmol) in ether was added a solution of 2-(4-chloro-phenyl)-propan-2-ol (CAS 1989-25-9) in ether (1.5 ml) at 0° C. The mixture was stirred for 90 minutes, then trichloroacetonitrile (112 μl, 1.11 mmol) was added and stirring was continued for 3 h at 0° C. Then all volatiles were removed and pentane (1 ml) and MeOH (4.74 μl) were added. The suspension was stirred for 1 h. Filtration and concentration of the filtrate yielded the title compound in a mixture with 2-(4-chloro-phenyl)-propan-2-ol which was used in the next reaction step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2].[N:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40][CH:39]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(O)(=O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([NH:44][C:41]3[CH:42]=[CH:43][N:38]=[CH:39][N:40]=3)(=[O:24])=[O:25])[CH:21]=[CH:22][C:14]1=2)#[N:2]
Reactant: Nc1ccncn1
Reactant: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#Cc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)Nc3ccncn3)ccc21
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
A round bottom flask was charged with perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (INTERMEDIATE AB, 46.12 mg, 0.084 mmol), pyrimidin-4-amine (11.95 mg, 0.126 mmol), and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (176 μL, 0.176 mmol) was added dropwise over 30 s to give a light-yellow solution. After 5 min, the flask was lowered into an ice bath for 1 h. Glacial acetic acid (2 drops) was added, and the mixture was concentrated under a vacuum. The product was purified by chromatography on silica gel (12 g column with 0 to 10% MeOH/DCM) to give 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (25.2 mg, 0.055 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.10 (br. s., 1 H), 8.65 (s, 1 H), 8.42-8.35 (m, 2 H), 8.09 (dd, J=2.0, 8.8 Hz, 1 H), 7.74 (d, J=8.6 Hz, 1 H), 7.38 (d, J=2.1 Hz, 1 H), 7.31 (dd, J=2.2, 8.6 Hz, 1 H), 7.04 (d, J=6.0 Hz, 1 H), 6.80 (d, J=8.6 Hz, 1 H), 4.38-4.32 (m, 2 H), 3.89-3.84 (m, 2 H). m/z (ESI) 462.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].Cl[C:21]1[N:26]=[C:25]([O:27][CH2:28][CH3:29])[N:24]=[C:23]([O:30][CH2:31][CH3:32])[N:22]=1.Cl>CN(C)C(=O)C.O.C1(C)C=CC=CC=1>[CH2:28]([O:27][C:25]1[N:24]=[C:23]([O:30][CH2:31][CH3:32])[N:22]=[C:21]([CH:7]2[C:6]3[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][C:8]2=[O:11])[N:26]=1)[CH3:29]
Reactant: O=C1Cc2cccc(F)c2N1
Reactant: CCOc1nc(Cl)nc(OCC)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1nc(OCC)nc(C2C(=O)Nc3c(F)cccc32)n1

Procedure:
7-Fluoro-1,3-dihydro-2H-indol-2-one (1.0 g) is introduced as initial charge in 10 ml of N,N-dimethylacetamide. A solution of potassium carbonate (1.8 g) and potassium hydroxide (0.3 g) in 10 ml of water is added and the mixture is briefly after-stirred. Then, a solution of 2-chloro-4,6-diethoxy-1,3,5-triazine (3.0 g, ca. 50% purity) in 10 ml of N,N-dimethylacetamide, and 10 ml of water are added. A solid separates out from the clear yellow solution. The mixture is stirred at room temperature and further 2-chloro-4,6-diethoxy-1,3,5-triazine (1 g, ca. 50% purity) is added in two portions after 2 and 18 hours. The mixture is stirred for a further 3 hours at 30° C., admixed with 10 ml of toluene, adjusted to pH 1-2 with hydrochloric acid (10%) and after-stirred for 30 min. The solid is filtered off with suction, washed twice alternately with water and heptane and dried. This gives the title compound as solid in an HPLC purity of 99% area (1.53 g, 72% of theory).
Reaction SMILES: C([N:8]([CH2:21][CH2:22][CH3:23])[CH:9]1[CH2:20][C:19]2[C:11](=[CH:12][CH:13]=[C:14]3[C:18]=2[CH:17]=[CH:16][NH:15]3)[CH2:10]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:21]([NH:8][CH:9]1[CH2:20][C:19]2[CH:18]=[C:14]3[C:13]([CH:17]=[CH:16][NH:15]3)=[CH:12][C:11]=2[CH2:10]1)[CH2:22][CH3:23]
Reactant: CCCN(Cc1ccccc1)C1Cc2ccc3[nH]ccc3c2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCCNC1Cc2cc3cc[nH]c3cc2C1
Temperature: 50 °C
Yield: 73.4 %

Procedure:
To a solution of benzyl-propyl-(3,6,7,8-tetrahydro-3-aza-as-indacen-7-yl)amine (9k, Chaart 2) (0.87 g, 2.86 mmol) in ethanol (50 mL) was added Pd/C (0.5 g, inert atmosphere) and ammonium formate (1.5 g, 24 mmol). The mixture was heated at 50° C. for 30 min., cooled and filtered through a Celite-pad. The organic solution was evaporated and the residue dissolved in water and basified (10% sodium carbonate). Extraction with diethyl ether, drying (magnesium sulfate), filtering, and evaporation yielded 0.45 g (74%) of the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.Cl[C:34]([C@@H:36]([O:38]C(=O)C)[CH3:37])=[O:35]>>[OH:38][C@@H:36]([CH3:37])[C:34]([N:2]1[CH2:6][CH2:5][C@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)=[O:35]
Reactant: O=C(N[C@H]1CCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: C[C@H](O)C(=O)N1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-pyrrolidin-3-ylamide hydrochloride (example A143) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=O>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:21])[CH2:17][C:18]([CH3:20])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1ccc(NN)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2N=C(C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The starting material is obtained as follows: To the suspension of 2,700 g of p-methoxyphenylhydrazine in 24,600 ml of 50% aqueous ethanol, the solution of 1,411 g of sodium acetate in 3,000 ml of water is added while stirring under nitrogen at room temperature for 15 minutes, followed by 2,148 g of ethyl acetoacetate during 30 minutes at 25°-30°. The mixture is refluxed for 45 minutes, slowly cooled to 10° and stirred overnight. The precipitate formed is filtered off, washed twice with 2,000 ml of cold 50% aqueous ethanol each, and dissolved in 2,000 ml of boiling anhydrous ethanol. The solution is stirred at room temperature overnight, the precipitate formed filtered off and washed twice with 500 ml of cold ethanol, to yield the 1-(p-methoxyphenyl)-3-methyl-2-pyrazolin-5-one melting at 125°-128°.