Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:17](=[O:34])[CH:18]([CH3:33])[CH:19]([CH3:32])[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)=[O:21])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:31][O:30][C:24]1[CH:23]=[C:22]([CH:20]([OH:21])[CH:19]([CH3:32])[CH:18]([CH3:33])[CH:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=2)[OH:34])[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1ccc(C(=O)C(C)C(C)C(=O)c2ccc(OC)c(OC)c2)cc1OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(C(O)C(C)C(C)C(O)c2ccc(OC)c(OC)c2)cc1OC
Reaction time: 8 h

Procedure:
To 1 g of lithium aluminum hydride suspended in 100 ml of tetrahydrofuran and cooled to ice temperatures under dry nitrogen was added 3.86 g of the starting diketone, 1,4-bis(3,4-dimethoxyphenyl),2,3-dimethyl butane-1,4-dione, in 30 ml of dry THF. The mixture was allowed to slowly come to room temperature while stirring and finally refluxed for 1 hour and then allowed to stand overnight. One ml of saturated sodium sulfate solution was added dropwise and stirring continued for several hours. Filtration and evaporation gave a colorless oil that crystallized on addition of ether. A yield of 3.93 g (quant.) was obtained. IR spectra showed no carbonyl.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[NH:6][N:7]=1.[C:11](#[N:14])[CH:12]=[CH2:13].N1C=CC=CC=1>O>[Br:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[C:5](=[O:8])[N:6]([CH2:13][CH2:12][C:11]#[N:14])[N:7]=1
Reactant: C=CC#N
Reactant: Cn1c(=O)[nH]nc(Br)c1=O
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(=O)c(Br)nn(CCC#N)c1=O
Yield: 93.2 %

Procedure:
2.4 g (11.6 mmol) of triazine 2a and 7 ml (106 mmol) of acrylonitrile are placed in 24 ml of a solution of pyridine and water (1:1) at reflux for 3 h. After concentration the reaction medium is extracted by AcOEt, and after drying on MgSO4 the organic phases are dry concentrated. 2.8 g of solid 3a are isolated and then washed with ether (yield=93%). TLC silica gel 60 F 254 Merck, petroleum ether:AcOEt 70:30, Rf=0.18.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1nc(-c2ccccc2)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (81 mg, 0.21 mmol), phenylboronic acid (34 mg, 0.28 mmol), tetrakis(triphenylphosphine)palladium(0)(25 mg, 0.02 mmol) and potassium carbonate (89 mg, 0.64 mmol) in dioxane (3 mL) and water (12 μL) was refluxed for 22 h before it was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and dichloromethane to give the title compound as a white solid (29 mg): 1H NMR (CDCl3, 200 MHz): δ=11.46 (s, 1H), 8.49 (m, 2H), 8.14 (m, 2H), 7.53 (m, 6H), 4.56 (q, J=7.0 Hz, 2H), 1.54 (t, J=7.0 Hz, 3H).
Reaction SMILES: C(N(CC)CC)C.N([C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=1)=C=S.CC1C=CC(NC2(C#N)CCCCC2)=CC=1.ClCCl.CC(C)=O>C1COCC1>[F:20][C:19]([F:21])([F:22])[C:13]1[CH:12]=[CH:11][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Agent: Cc1ccc(NC2(C#N)CCCCC2)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: ClCCl
Product: N#Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (0.05 g, 0.5 mmol) was added to a solution of 1a (0.228 g, 1 mmol) and 9a (0.228 g, 1 mmol) in dry THF (2 ml). The reaction mixture was stirred at room temperature for 2 days and then concentrated to yield a dark residue which was subjected to flash chromatography (dichloromethane/acetone, 95:5) to afford 4-(4-imino)-2-thioxo-1-(4-methylphenyl)-1,3-diazaspiro[4.5]undec-3-yl)-2-trifluoromethylbenzonitrile, 10b (0.036 g, 0.08 mmol, 8%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:19]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:27]3[CH:23]([CH2:24][N:25]([C:9](=[O:11])[CH2:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Reactant: O=C(O)Cc1ccccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3F)CC12
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
N,N'-Carbonyldiimidazole (1.14 g) is added to a solution of 2-fluorophenylacetic acid (1.08 g) in dry dichloromethane (30 cc) cooled to +5° C. The mixture is stirred for 20 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroisoindolone hydrochloride (2.3 g) and triethylamine (1.98 cc) in dichloromethane (20 cc) is then added. The reaction mixture is stirred at 20° C. for 72 hours and then washed with water (2×150 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is crystallized from a mixture of acetonitrile (30 cc) and isopropyl ether (50 cc). The crystals are drained, washed with isopropyl ether and dried. (3aRS,7aRS)-7,7-diphenyl-2-[(2-fluorophenyl)acetyl]-4-perhydroisoindolone (1.53 g) is obtained in the form of white crystals melting at 186° C.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][C:7]([C:11]([OH:13])=O)=[CH:6][C:5]=2[CH:4]=[CH:3][N:2]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](CC[NH-])=[CH:15]1>>[CH2:15]([NH:14][C:11]([C:7]1[CH2:8][CH2:9][C:10]2[CH:1]=[N:2][CH:3]=[CH:4][C:5]=2[CH:6]=1)=[O:13])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: [NH-]CCc1c[nH]c2ccccc12
Reactant: O=C(O)C1=Cc2ccncc2CC1
Product: O=C(NCCc1ccccc1)C1=Cc2ccncc2CC1

Procedure:
Compound #68 7,8-Dihydro-isoquinoline-6-carboxylic acid [2-(1H-indol-3-yl)-ethyl-amide; and
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].O1CCCC1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=1>CN(C)C=O.O>[CH2:1]([S:8][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([CH3:30])([CH3:29])[CH3:28])[N:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCc1ccccc1
Reactant: CC(C)(C)c1cccc(Br)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cccc(SCc2ccccc2)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of benzyl mercaptan (0.22 mL, 1.87 mmol) in anhydrous N,N-dimethylformamide (10 mL) was added a 1.0 M solution of potassium tert-butoxide in tetrahydrofuran (1.87 mL, 1.87 mmol) dropwise over 2 minutes. To the resulting suspension was added 2-bromo-6-tert-butylpyridine (0.20 g, 0.93 mmol), and the resulting mixture was stirred at 50° C. for 16 hours. The cooled mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL), and the ethyl acetate layer was dried over Na2SO4, filtered and concentrated in vacuo to give a crude product. Purification by column chromatography on silica gel using hexanes gave the titled compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (s, 9H), 4.50 (s, 2H), 6.93-7.03 (m, 2H), 7.17-7.45 (m, 6H); MS (APCI) m/z 258.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.CN(C)C1C=CC=CC=1.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>C(OCC)(=O)C>[C:21]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1)(=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: CCCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Product: CCCC(=O)Nc1nccc(C)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-amino-4-methyl-3-nitropyridine (5.0 g) and N,N-dimethylaniline (8.5 ml) was heated at 100° C. under nitrogen atmosphere. To the solution was added butyryl chloride (3.5 ml) and the mixture was stirred at 100° C. for 5 hours. After being cooled to room temperature, ethyl acetate was added to the reaction mixture. The organic layer was separated and washed successively with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was washed with n-hexane to give 2-butyrylamino-4-methyl-3-nitropyridine (7.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[C:18](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.CCOCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Clc1cnc2[nH]nc(I)c2c1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Clc1cnc2c(c1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 5-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine, 31, (11.6 g, 38.5 mmol), and Na2CO3 (12.2 g, 115 mmol) in N,N-dimethylformamide (200 mL) was added trityl chloride (11.8 g, 42.4 mmol). The mixture was stirred at room temperature overnight. After 16 hr, additional trityl chloride (1.61 g, 5.78 mmol) was added. And the mixture was heated to 60° C. for 45 min. The mixture was cooled, diluted with Et2O, washed with water (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo. Flash chromatography (SiO2, 0-40% EtOAc-Hexanes, gradient elution) provided the desired product as a colorless material which was further purified by flash chromatography (SiO2, 100% DCM, isocratic elution): 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=2.3 Hz, 1H), 7.70 (d, J=2.3 Hz, 1H) and 7.23-7.18 (m, 15H) ppm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:22])=[C:6]([C@:8]2([CH3:21])[C@@H:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[CH2:12][O:11][C:10]([NH2:20])=[N:9]2)[CH:7]=1.[F:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:20][C:10]1[O:11][CH2:12][C@H:13]([O:14][CH2:15][C:16]([F:18])([F:19])[F:17])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[CH:29][N:28]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:22])([CH3:21])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F
Reactant: O=C(O)c1ccc(F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(F)cn3)ccc2F)N=C(N)OC[C@@H]1OCC(F)(F)F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-4-methyl-5-(2,2,2-trifluoro-ethoxy)-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.4) and 5-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=445.3 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[C:18]([C:20]4[N:24]([CH:25]([CH3:27])[CH3:26])[C:23]([CH3:28])=[N:22][CH:21]=4)[C:17]([F:29])=[CH:16][N:15]=3)=[CH:9][CH:8]=2)[CH2:3]1.[C:30](O)(=[O:34])[C@H:31]([CH3:33])[OH:32].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[F:29][C:17]1[C:18]([C:20]2[N:24]([CH:25]([CH3:26])[CH3:27])[C:23]([CH3:28])=[N:22][CH:21]=2)=[N:19][C:14]([NH:13][C:10]2[CH:9]=[CH:8][C:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:30](=[O:34])[C@@H:31]([OH:32])[CH3:33])[CH2:3]3)=[CH:12][CH:11]=2)=[N:15][CH:16]=1
Reactant: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](N)C4)cc3)ncc2F)n1C(C)C
Reactant: C[C@H](O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(-c2nc(Nc3ccc(N4CC[C@H](NC(=O)[C@H](C)O)C4)cc3)ncc2F)n1C(C)C
Yield: 30.4 %

Procedure:
N-{4-[(3S)-3-Aminopyrrolidin-1-yl]phenyl}-5-fluoro-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidin-2-amine (Example 153; 220 mg, 0.556 mmol), L—lactic acid (61 mg, 0.667 mmol), HOBt mono hydrate (103 mg, 0.667 mmol) and Hunig's base (0.12 ml, 0.667 mmol) in DCM (5 ml) were reacted with EDAC (128 mg, 0.667 mmol) at room temperature under nitrogen for 18 hours. The mixture was diluted with DCM (20 ml) and washed with water (20 ml), 1 N aqueous potassium hydroxide (20 ml) and saturated aqueous sodium chloride (15 ml). The mixture was dried and after evaporation under reduced pressure purified by HPLC on a Phenomenex column, (0-50% acetonitrile/water, 0.2% TFA). The fractions were diluted with water (20 ml), basified with solid potassium carbonate, and extracted twice with EtOAc/DCM (20 ml, 2:1). The solution was washed with saturated aqueous sodium chloride (15 ml), dried and after evaporation under reduced pressure gave the title compound as a yellow solid, (79 mg, 30%). NMR: 1.20 (d, 3H), 1.37 (d, 6H), 1.90-2.04 (m, 1H), 2.11-2.27 (m, 1H), 2.47 (s, 3H), 3.00-3.09 (m, 1H), 3.20-3.47 (m, 3H), 3.91-4.00 (m, 1H), 4.32-4.47 (m, 1H), 5.38 (s, 1H), 5.40-5.49 (m, 1H), 6.49 (d, 2H), 7.30 (s, 1H), 7.32 (d, 2H), 7.76 (d, 1H), 8.40 (d, 1H), 9.06 (s, 1H); m/z 468.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](B(O)O)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26](SC2C=CC=CC=2)=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].S1C=CC=C1C([O-])=O.[Cu+]>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([C:26]([C:8]2[CH:7]=[CH:6][C:5]3[O:1][CH2:2][CH2:3][C:4]=3[CH:9]=2)=[O:27])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Sc2ccccc2)CC1
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: [Cu+]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc3c(c2)CCO3)CC1
Yield: 89.7 %

Procedure:
To a mixture of 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.56 g, 1.56 mmol), ligand TFP (0.07 g, 0.3 mmol), Pd2dba3 (0.28 g, 0.30 mmol), copper (I) thiophene-2-carboxylate (0.45 g, 2.4 mmol) was added a solution of 4-phenylsulfanylcarbonyl-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 1.6 mmol) in 15 mL of DME while purging with N2 at 50° C. After 18 hours the reaction mixture was diluted with ethyl acetate, filtered through celite then concentrated in vacuo. Purification by flash chromatography gave the title compound (0.5 g, 1.4 mmol). MS (ESI) m/z 331.8 (M+H+); HPLC (Novapak 150×3.9 mm C-18 column: mobile phase: 35-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 2 min.) t 1.54 min.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][S:7]([CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11]([OH:14])([CH3:13])[CH3:12])(=[O:9])=[O:8].FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>ClCCl>[OH:14][C:11]([CH3:13])([CH3:12])[CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[S:7]([NH2:6])(=[O:8])=[O:9]
Reactant: COc1ccc(CNS(=O)(=O)C(c2ccccc2)C(C)(C)O)c(OC)c1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1ccccc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
A solution of 2.67 g of N-(2,4-dimethoxybenzyl)-2-hydroxy-2-methyl-1-phenylpropane-1-sulfonamide in 20 ml of dichloromethane was admixed with 3.74 ml of trifluoroacetic acid and stirred at room temperature for 2 hours. The starting solution was coevaporated twice with 100 ml of toluene and the crude product was purified using by means of normal phase chromatography using a Flashmaster with an n-heptane/ethyl acetate gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (0.90 g) with a molecular weight of 229.3 g/mol (C10H15NO3S).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]4[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=4)[N:21]=3)[CH2:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([CH3:6])[C:3]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[O:19][CH2:18][CH2:17][N:16]([C:20]3[N:25]([CH3:26])[C:24](=[O:27])[CH:23]=[C:22]([C:28]4[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=4)[N:21]=3)[CH2:15]2)=[CH:12][CH:13]=1)=[O:4]
Reactant: CN(C)C(=O)Cl
Reactant: Cn1c(N2CCO[C@@H](c3ccc(N)cc3)C2)nc(-c2ccncc2)cc1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)Nc1ccc(C2CN(c3nc(-c4ccncc4)cc(=O)n3C)CCO2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 29.3 %

Procedure:
N,N-Dimethylcarbamoyl chloride (0.24 g, 2.23 mmol) was added to a solution of 2-[(2S)-2-(4-aminophenyl)morpholin-4-yl]-3-methyl-6-(pyridin-4-yl)-pyrimidin-4(3H)-one (0.40 g, 1.10 mmol) and triethylamine (1.1 g, 10.9 mmol) in tetrahydrofuran (20 ml) and the solution was stirred at 50° C. for 48 hours. The mixture was partitioned between water and chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 1,1-Dimethyl-3-{4-[4-(1-methyl-6-oxo-4-pyridin-4-yl-1,6-dihydro-pyrimidin-2-yl) morpholin-2-yl]-phenyl}-urea (0.14 g, 30%) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.CCN(CC)CC.[C:19](OC(=O)C)(=[O:21])[CH3:20].O>C(Cl)Cl>[C:19]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([NH2:1])[CH2:3]1)(=[O:21])[CH3:20]
Reactant: Nc1cnc2ccccc2c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(N)=Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-Aminoquinoline (6.04 g, 41.89 mmol) and Et3N (5.85 mL, 41.89 mmol) were dissolved in CH2Cl2 (75 mL). Acetic anhydride (3.95 mL, 41.89 mmol) was added and reaction stirred at ambient temperature for 18 hours. The reaction mixture was poured into H2O and filtered. The filtered solid was dried in vacuo to yield the above-titled compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.C(C/[C:28](=[CH:32]\[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)/[C:29]([OH:31])=O)(O)=O.C(N(CC)CC)C.ClCCl>C1COCC1>[CH3:3][O:2][C:1](=[O:9])[C:36]1[CH:35]=[CH:34][C:33](/[CH:32]=[CH:28]/[C:29](=[O:31])[N:11]2[CH2:12][C:13]3[C:22](=[O:23])[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[NH:15][C:14]=3[CH:10]2[C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[CH:38][CH:37]=1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Reactant: O=C(O)C/C(=C\c1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(/C=C/C(=O)N2Cc3c([nH]c4ccccc4c3=O)C2c2ccc3c(c2)OCO3)cc1

Procedure:
Following the procedure outlined in Example 20, 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (398 mg, 1.30 mmol) (prepared as in Example 5) was reacted with the acid chloride of (E)-carboxymethyl cinnamic acid (301 mg, 1.34 mmol), in the presence of triethylamine (0.54 mL, 3.87 mmol) in a 1:1 mixture of dichloromethane:THF (40 mL) to yield the product as a tan solid.
Reaction SMILES: [CH2:1]([PH:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([Mg]Br)CCC.C(OP([O-])OCC)C.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:1]([P:5]([CH2:6][CH2:7][CH2:8][CH3:9])[O:10][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: CCCC[PH](=O)CCCC
Agent: CCCC[Mg]Br
Agent: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCP(CCCC)O[Si](C)(C)C
Temperature: 80 °C
Yield: 86 %

Procedure:
The procedure described in Tetrahedron, 1967, 23, 1065 (M. Grayson et al.) was followed. Dibutylphosphine oxide, prepared from butyl magnesium bromide and diethylphosphite, (3.3 g, 20 mmol) and triethylamine (2.02 g, 20 mml) were dissolved in toluene (20 mL) and treated with a solution of trimethylsilyl chloride (2.17 g, 20 mmol) in toluene (5 mL) at room temperature. The solution got very warm and a precipitate formed immediately. The mixture was heated at 80° C. for two hours, then filtered, washed with toluene, and concentrated. Kugelrohr distillation at 80° C. (1.5 mmHg) afforded 4.1 g (86%) of the desired product. 1H NMR (CDCl3) δ1.8-1.2 (m, 6H), 1.1-0.7 (m, 3H), 0.17 (s, 9H).
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[CH:10]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:16][CH2:15]1)([CH3:12])[CH3:11].[CH3:29][O:30][CH:31]([O:39][CH3:40])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:40][O:39][CH:31]([O:30][CH3:29])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][N:13]([CH:10]([CH3:12])[CH3:11])[CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:18][CH2:19]1
Reactant: COc1ccncc1CN1CCC(NC(C)C)CC1
Reactant: COC(CCCCCC=O)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C(O)c1ccccc1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccncc1CN1CCC(N(CCCCCCC(OC)OC)C(C)C)CC1
Reaction time: 1 h

Procedure:
To a reactor containing dichloromethane (4 L) was added 4-isopropylamino-1-(4-methoxypyrid-3-ylmethyl)piperidine monobenzoic acid salt (1.5 kg, 3.89 mol) while maintaining the temperature of the mixture at −5° C. to 5° C. The container used to add the salt was rinsed with dichloromethane (1.5 L) and the rinse was added to the reaction mixture. The temperature of the reaction mixture was then adjusted to 0° C. to 5° C. and 7,7-dimethoxyheptanal (790 g, 4.25 mol, 93.8% purity by GC) was added while maintaining the temperature of the reaction mixture between 0° C. to 5° C. The container used to add the 7,7-dimethoxyheptanal was rinsed with dichloromethane (0.8 L) and the rinse was added to the reactor. The resulting reaction mixture was then stirred at 0° C. to 5° C. for 1 hour. Sodium triacetoxyborohydride (1.07 kg, 5.05 mol) was then added in 7 equal portions over a period of 1 hour while maintaining the temperature of the reaction mixture between −5° C. to 5° C. The container used to add the sodium triacetoxyborohydride was rinsed with dichloromethane (0.8 L) and the rinse was added to the reaction mixture. The reaction mixture was then stirred at 0° C. to 5° C. for 21 hours. An aqueous solution of potassium carbonate (500 g) in deionized water (8.6 L) was then added to the reaction mixture while maintaining the temperature of the mixture between to 0° C. to 25° C. The resulting mixture was stirred for 2 hours at a temperature between 15° C. to 25° C. The layers were then allowed to separate over a period of 30 minutes and the organic layer was collected. The washing procedure with aqueous potassium carbonate solution was repeated 2 times. To the organic layer was then added an aqueous solution of sodium chloride (5.7 kg) in deionized water (15 L) while maintaining the temperature between to 15° C. to 25° C. The resulting mixture was stirred for 30 minutes at a temperature between 15° C. to 25° C. and then the layers were allowed to separate over a period of 30 minutes. The organic layer was collected and to this layer was added dichloromethane (1.5 L). The resulting solution containing the title compound was stored under a nitrogen atmosphere, protected from light, at 0° C. to 5° C. until used in the subsequent reaction.