Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:4][CH:3]=1.O.O[N:16]1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.N.CO>CN(C)C=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:16])=[O:13])=[CH:4][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CCCc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: NC(=O)CCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 60.7 %

Procedure:
To a stirred solution of 4-(4-chlorophenyl)butanoic acid (3.97 g, 20.0 mmol) and 1-hydroxybenzotriazole hydrate (3.37 g, 22.0 mmol) in N,N-dimethylformamide (40 mL) at ambient temperature was added solid 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.21 g, 22 mmol). The resulting mixture was stirred at ambient temperature for 25 minutes, and a solution of ammonia in methanol (7M, 14.3 mL, 100 mmol) was added. After stirring at ambient temperature for a further 15 minutes, the reaction mixture was diluted with water (400 mL) and extracted with chloroform (100 mL) The organic layer was dried over sodium sulfate and concentrated. The residual oil was triturated with hexane to afford a solid, which was collected by filtration, washed with hexane, and dried under vacuum to afford 4-(4-chlorophenyl)butanamide as an off-white powder (2.40 g, 61% yield).
Reaction SMILES: [CH:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(C1C(=O)C(Cl)=C(Cl)[C:15](=[O:16])C=1C#N)#N.CO>C1(C)C=CC=CC=1>[C:1]([O:16][CH3:15])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Reactant: O=CC=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C=Cc1ccccc1
Yield: 96 %

Procedure:
A homogeneous mixture containing cinnamaldehyde (7.5 mmol), DDQ (11.3 mmol), MeOH (15 mL) and toluene (10 mL) is taken in a round bottom flask and catalytic amount of neutral alumina (0.1 g) is added to it. The mixture is refluxed for 6 hrs under Dean Stark apparatus. After completion of the reaction (observed by TLC and by GC analysis), the reaction mixture is filtered and washed with MeOH (5 ml×2). Concentrate the filtrate under reduced pressure and the crude product thus obtained is loaded on a neutral alumina column and eluted with diethyl ether. Methyl cinnamate is isolated in 96% yield whose NMR values are found matching with reported values as in example 1.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=C)[C:13]([OH:15])=[O:14].CSC>ClCCl>[CH3:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:1])[C:13]([OH:15])=[O:14]
Reactant: C=C(C(=O)O)c1ccccc1OC
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: ClCCl
Product: COc1ccccc1C(=O)C(=O)O
Yield: 69 %

Procedure:
A stream of ozone is sparged at -75° C. for 3 hours 30 minutes into a solution of 1 g (5.62 mmol) of 2-(2-methoxyphenyl)acrylic acid, obtained under the conditions described in Example 38, in dichloromethane. 1.66 cm3 (22.5 mmol) of dimethyl sulphide are added and stirring is continued, the temperature being allowed to rise to the region of 20° C. After concentrating the reaction mixture to dryness, 0.7 g (69%) of (2-methoxyphenyl)oxoacetic acid is obtained in the form of crystals, the characteristics of which are as follows: mass spectrum (E.I.) M/Z=180 (M+)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].S(Cl)(Cl)=O.[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21].CCN(CC)CC>ClCCl>[Cl:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH:21][C:9](=[O:11])[C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=1
Reactant: Nc1ccccc1Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-(methylsulfonyl)benzoic acid 1 (1.0 g, 5 mmol) in 50 mL of dichloromethane was added thionyl chloride (5 mL). The mixture was stirred at ambient temperature for 18 hours. After removal of all solvent, the residue was dissolved in 50 mL of dichloromethane. To the solution was added o-chloroaniline (0.766 g, 6 mmol) followed by 1.4 mL of Et3N. The mixture was stirred at ambient temperature for 2 hours. After washing with 1N HCl and water, the organic layer was concentrated to give N-(2-chlorophenyl)-4-(methylsulfonyl)benzamide 3 as a solid. Yield: 1.18 g, 76%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([N:11]3[CH2:15][CH2:14][CH:13]([O:16][CH3:17])[CH2:12]3)[N:10]=2)[CH:7]=1.[N:18]1(C2N=C3C=CC(N)=CN3N=2)CCOCC1>>[CH3:17][O:16][CH:13]1[CH2:14][CH2:15][N:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([NH2:18])=[CH:7][N:6]3[N:8]=2)[CH2:12]1
Reactant: COC1CCN(c2nc3ccc(Br)cn3n2)C1
Reactant: Nc1ccc2nc(N3CCOCC3)nn2c1
Product: COC1CCN(c2nc3ccc(N)cn3n2)C1

Procedure:
Using 6-Bromo-2-(3-methoxy-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine, this compound was prepared following the same method as for the synthesis of 2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine. Brown solid (1.4 g, 71%). MS: m/z=234 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:51][C:52]1[CH:63]=[CH:62][C:55]2[NH:56][C:57]([C@@H:59]([NH2:61])[CH3:60])=[N:58][C:54]=2[CH:53]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:51][C:52]1[CH:63]=[CH:62][C:55]2[NH:56][C:57]([C@@H:59]([NH:61][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:11]([CH2:12][N:13]4[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]4)=[C:3]([O:2][CH3:1])[CH:4]=3)[CH3:60])=[N:58][C:54]=2[CH:53]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: COc1cc(C(=O)O)ccc1CN1CCNC(=O)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1CN1CCNC(=O)C1
Yield: 35 %

Procedure:
Prepared analogously to Example 1g from 3-methoxy-4-(3-oxopiperazin-1-ylmethyl)benzoic acid, TBTU, diisopropylethylamine and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 35%; Rf value: 0.39 (silica gel; dichloromethane/ethanol=4:1); C22H24ClN5O3 (441.92); mass spectrum: (M+H)+=442/444 (chlorine isotope) and (M−H)-=440/442 (chlorine isotope).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:47])([CH3:46])[CH2:9]/[CH:10]=[CH:11]/[C:12](=[O:45])[N:13]([C@@H:15]([C:27](=[O:44])[N:28]([C@H:30]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH3:29])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH3:14])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([CH3:47])([CH3:46])[CH2:9]/[CH:10]=[CH:11]/[C:12]([N:13]([C@@H:15]([C:27](=[O:44])[N:28]([C@H:30]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:31][NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH3:29])[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1)[CH3:14])=[O:45]
Reactant: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)N)[C@@H](CNS(C)(=O)=O)Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 71.1 %

Procedure:
(3E)-4-(N-((1R)-1-(N-((1R)-1-Benzyl-2-(methylsulfonylamino)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enylcarbamic acid tert-butyl ester (729 mg, 1.07 mmol) was dissolved in dichloromethane (3 ml). The solution was cooled to 0° C. Trifluoroacetic acid (3 ml) was added. The reaction mixture was stirred for 15 min at 0° C. The solvents were removed in vacuo at 20° C. The residue was dissolved in dichloromethane (100 ml) and the solvent was removed in vacuo. The latter procedure was repeated two times. The crude product was purified by flash chromatography on silica (60 g), using dichloromethanelmethanol/25% aqueous ammonia as eluent, to give 440 mg of the title compound as free base.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[CH2:5][C:4](=[O:13])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[CH3:4][C:3]1[C:3]2[C:4](=[O:13])[CH2:5][CH:6]([C:8]3[CH:12]=[CH:11][S:10][CH:9]=3)[CH2:7][C:2]=2[N:1]=[CH:7][CH:2]=1
Reactant: NC1=CC(=O)CC(c2ccsc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1C(=O)CC(c1ccsc1)C2
Temperature: 115 °C
Yield: 103.3 %

Procedure:
In a mixture of ethanol (200 ml) and toluene (600 ml) was dissolved 1-amino-5-(3-thienyl)cyclohexen-3-one (10 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (17.4 g) and granulated potassium hydroxide (2.87 g). The mixture was stirred at 115° C. (bath temperature), and to the reaction solution were added granulated potassium hydroxide (590 mg), 30 minutes later; 1 hour later; and 1.5 hours later; respectively. The reaction solution was stirred at the same temperature for 1 hour and cooled. Under reduced pressure, the solvent was evaporated, and to the residue were added ethyl acetate (250 ml) and water (70 ml). The mixture was shaken, and the separated ethyl acetate layer was washed with water (40 ml, thrice) and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (EtOAc/hexane) and eluted with ethyl acetate/hexane to give 4-methyl-7-(3-thienyl)-5,6,7,8-tetrahydroquinolin-5-one (6.5 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1Br.CC(C)([O-])C.[K+].[Cl-].[Na+]>C(OCC)(=O)C>[C:2]1([CH3:1])[CH:7]=[CH:6][C:5]([S:8][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[Br:9])=[CH:4][CH:3]=1
Reactant: Brc1ccccc1Br
Reactant: Cc1ccc(S)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc(Sc2ccccc2Br)cc1
Temperature: 120 °C
Reaction time: 0.33 h

Procedure:
In a stirred nitrogen covered reactor N-methyl-pyrrolidone, NMP (4.5 L) was flushed with nitrogen for 20 minutes. 4-Methylbenzenethiol (900 g, 7.25 mol) was added and then 1,2-dibromobenzene (1709 g, 7.25 mol). Potassium tert-butoxide (813 g, 7.25 mol) was finally added as the last reactant. The reaction was exothermic giving a temperature rise of the reaction mixture to 70° C. The reaction mixture was then heated to 120° C. for 2-3 hours. The reaction mixture was cooled to room temperature. Ethyl acetate (4 L) was added and aqueous sodium chloride solution (15%, 2.5 L). The mixture was stirred for 20 minutes. The aqueous phase was separated and extracted with another portion of ethyl acetate (2 L). The aqueous phase was separated and the organic phases were combined and washed with sodium chloride solution (15%, 2.5 L) The organic phase was separated, dried with sodium sulphate and evaporated at reduced pressure to a red oil which contains 20-30% NMP. The oil was diluted to twice the volume with methanol and the mixture was refluxed. More methanol was added until a clear red solution was obtained. The solution was cooled slowly to room temperature while seeded. The product crystallises as off white crystals, they were isolated by filtration and washed with methanol and dried at 40° C. in a vacuum oven until constant weight.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([CH3:32])([O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:33])[C:5]([CH3:32])([O:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc2ncccc2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 3-(4-Benzyloxy-phenyl)-2-methyl-2-(quinolin-6-yloxy)-propionic acid ethyl ester (2.65 g, 6.0 mmol) in 100 mL of EtOH with 5% Pd/C (530 mg, 20 w %) was allowed to stand under 1 atm H2 for 6 h. Catalyst was filtered off and organic solvent was removed under vacuum. Residue was then dissolved in 200 mL of toluene. 530 mg of 10% Pd/C was added. The mixture was heated to reflux under air for overnight. Reaction was cooled to r.t. and catalyst was filtered off. Organic solvent was removed under vacuum and crude material was clean for next step without further purification. 1H NMR (400 MHz, CDCl3) δδ8.77 (dd, 1H, J=4.0, 1.4 Hz), 8.04 (d, 1H, J=7.6 Hz), 8.02 (d, 1H, J=9.6 Hz), 7.38 (dd, 1H, J=8.4, 4.4 Hz), 7.32 (dd, 1H, J=9.2, 2.8 Hz), 7.09 (d, 2H, J=8.8 Hz), 7.03 (d, 1H, J=2.8 Hz), 6.83 (d, 2H, J=8.8 Hz), 4.22 (q, 2H, J=7.1 Hz), 3.35, 3.13 (ABq, 2H, J=13.6 Hz), 1.52 (s, 3H), 1.19 (t, 3H, J=7.1 Hz). MS (ES+) m/z mass calcd for C21H22NO4 (m+1) 352, found 352.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-])=O)=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].O1CCCC1>CO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(Oc4ccc([N+](=O)[O-])cc4)c3c2c1COC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1ncc2[nH]c3cccc(Oc4ccc(N)cc4)c3c2c1COC

Procedure:
15 g of 5-(4-nitrophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester is hydrogenated in 450 ml of methanol: tetrahydrofuran=1:1 with 7.5 g of palladium on carbon (10%) at room temperature under hydrogen normal pressure. After filtering and concentrating, it is recrystallized from ethanol and 10.8 g (77% of theory) of 5-(4-aminophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester of a melting point of 222°-224° C. is obtained.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9](C)[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[C:24]([F:31])[C:23]=4[F:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(F)(F)[CH2:37][N:38]([CH:59]1[CH2:63]CCC1)[C:39]1[C:44](NC)=[CH:43][N:42]=C(NC2C=CC(C(O)=O)=C(F)C=2F)N=1)(O)=O.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.NC1CCN(C)CC1>CN(C)C=O.C(OCC)(=O)C.O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[NH:9][C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:42][CH:43]5[CH2:44][CH2:39][N:38]([CH3:37])[CH2:59][CH2:63]5)=[O:28])=[C:24]([F:31])[C:23]=4[F:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNc1cnc(Nc2ccc(C(=O)O)c(F)c2F)nc1N(CC(F)(F)C(=O)O)C1CCCC1
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)c(F)c3F)ncc21
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: CN1CCC(N)CC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4)c(F)c2F)CC1
Reaction time: 0.25 h

Procedure:
A mixture of 0.0507 g of the 2:1 mixture of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,3-difluoro-benzoic acid and 4-{4-[(2-carboxy-2,2-difluoro-ethyl)-cyclopentyl-amino]-5-methylamino-pyrimidin-2-ylamino}-2,3-difluoro-benzoic acid in 4 mL of dimethylformamide was treated with 0.0971 g (0.248 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 0.0742 g (0.574 mmole) of diisopropylethylamine. After 15 minutes, 0.0186 g (0.162 mmole) of 4-amino-1-methylpiperidine in 1 mL of dimethylformamide was added. The reaction mixture stirred for 30 minutes and then diluted with 150 mL of ethyl acetate and 25 mL of water. The mixture was then washed successively with 20 mL of ammonium chloride, 20 mL of saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0359 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2,3-difluoro-N-(1-methyl-piperidin-4-yl)-benzamide (I-243) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH3:15])[NH:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[C:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1)(=[O:25])[CH3:24]>C(Cl)(Cl)Cl>[C:23]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:9]2[CH3:15])=[O:35])=[CH:29][CH:28]=1)(=[O:25])[CH3:24]
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Reactant: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccc(OC(C)=O)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.1 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline (20.0 g, 0.097 m) and triethylamine (9.8 ml, 0.097 m) in chloroform (200 ml) under nitrogen was added dropwise a solution of 4-acetoxyphenylacetyl chloride (20.3 g, 0.097 m) in 50 ml chloroform and the mixture stirred at ambient temperature for 16 hours. The mixture was washed with 10% HCl (3×200 ml), water (200 ml), saturated sodium carbonate (3×150 ml) and water (200 ml) and the chloroform layer dried over MgSO4. Evaporation of the solvent afforded 33.0 g of N-(4-acetoxyphenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline as a pale yellow oil (89% yield).
Reaction SMILES: [OH:1][CH:2]([C:5]1[C:13]2[C:8](=[N:9][C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)=[N:11][C:12]=2[N:14]2[CH2:20][CH:19]3[O:21][CH:16]([CH2:17][CH2:18]3)[CH2:15]2)[N:7]([CH2:33][CH3:34])[N:6]=1)CO>C(Cl)Cl.C1COCC1>[CH2:33]([N:7]1[C:8]2=[N:9][C:10]([C:22]3[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:31][CH3:32])=[O:30])=[CH:24][CH:23]=3)=[N:11][C:12]([N:14]3[CH2:15][CH:16]4[O:21][CH:19]([CH2:18][CH2:17]4)[CH2:20]3)=[C:13]2[C:5]([CH:2]=[O:1])=[N:6]1)[CH3:34]
Reactant: CCn1nc(C(O)CO)c2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)NC)cc3)nc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCn1nc(C=O)c2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)NC)cc3)nc21
Reaction time: 1 h

Procedure:
To a solution of 1-{4-[3-(1,2-dihydroxyethyl)-1-ethyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}-3-methylurea (158 mg) (0.34 mmol) in DCM:THF (2:1) (6.0 mL) was added excess sodium NaIO4 on silica gel and the mixture was stirred for 1 hr. at room temperature. The insoluble material was filtered off and the organics were dried (Na2SO4) and filtered off through Magnesol and then concentrated in vacuo. to give a white solid that was collected with diethyl ether to give 110 mg. MS m/z=436.2.2 (M+H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([S:9]([O:12][C:13]2[CH:14]=[CH:15][C:16]([NH:20][C:21]([NH2:23])=[O:22])=[C:17]([CH:19]=2)[NH2:18])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:26][O:27][C:28]([NH:30][C:31](=[N:34][C:35]([O:37][CH3:38])=[O:36])SC)=[O:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C.CO>[CH3:38][O:37][C:35]([NH:34][C:31]([NH:30][C:28]([O:27][CH3:26])=[O:29])=[N:18][C:17]1[CH:19]=[C:13]([O:12][S:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:4]=2)(=[O:11])=[O:10])[CH:14]=[CH:15][C:16]=1[NH:20][C:21]([NH2:23])=[O:22])=[O:36]
Reactant: NC(=O)Nc1ccc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)NC(=Nc1cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)ccc1NC(N)=O)NC(=O)OC

Procedure:
12.5 g of 5-(3-trifluoromethylphenylsulfonyloxy)-2-ureidoaniline, 13.6 g of N,N'-bismethoxycarbonyl-S-methylisothiourea and 100 mg of p-toluenesulfonic acid in 90 ml of ethyl acetate and 45 ml of methanol are stirred under reflux for 20 minutes. After cooling down, the mixture is evaporated to dryness under reduced pressure, and the residue is stirred with diisopropyl ether and filtered off with suction. Recrystallization from ethyl acetate/diisopropyl ether, melting point 131° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13](=[O:28])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:17]=2)[C:3]1=[O:29].[CH3:30]N(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].S(OC)(OC)(=O)=O>O>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:30])=[C:4]([C:13](=[O:28])[CH:14]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:17]=2)[C:3]1=[O:29]
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: COC(=O)COc1cccc(C=CC(=O)c2c(O)c3ccccc3n(C)c2=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: COC(=O)COc1cccc(C=CC(=O)c2c(OC)c3ccccc3n(C)c2=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 0.55 g of 1-methyl-4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone and 5 ml of hexamethylphosphoramide was added 67 mg of sodium hydride (60% oily) under ice-cooling. After stirred at room temperature for 1 hour, 0.2 ml of dimethyl sulfate was added, and this was stirred at room temperature for 3 hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. After dried over anhydrous sodium sulfate, the extract was concentrated under reduced pressure, and the resulting residue was subjected to silica column gel chromatography to obtain 0.21 g of 1-methyl-4-methoxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone [Compound No. (60e)] as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=O.C(OP([CH2:35][C:36]#[N:37])(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=CC#N)=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=[CH:5][C:4]=1[C:13]([C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1)=[CH:35][C:36]#[N:37]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1cc(C(=O)c2ccc(OC)c(OC)c2OC)cc(OC)c1OC
Agent: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C(=CC#N)c2ccc(OC)c(OC)c2OC)cc(OC)c1OC
Yield: 76 %

Procedure:
(2,3,4-trimethoxyphenyl)-(3,4,5-trimethoxyphenyl)methanone (2.87 g, 7.92 mmol), cyanomethylphosphonic acid diethyl ester (2.50 ml, 15.84 mmol) in anhydrous THF (15 ml), and lithium bis (trimethylsilyl)amide (1.0 M solution in THF, 15.84 ml, 15.84 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified via flash column chromatography (20% EtOAc in hexane) to give 3-(2,3,4-trimethoxy-phenyl)-3-(3,4,5-trimethoxy-phenyl)-acrylonitrile as an off-white solid (2.32 g, 76%); mp, 125-127° C.: 1HNMR (DMSO-d6) δ 7.01-6.85 (m, 2H, Ar), 6.63-6.61 (m, 2H, Ar), 5.95 (s, 1H, double bond proton), 3.87-3.32 (multiple singlets, 18H, 6OCH3); 3C NMR (CDCl3) δ 160.6, 160.2, 155.5, 153.3, 153.1, 152.4, 151.8, 142.6, 139.5, 134.7, 133.8, 126.2, 125.8, 125.4, 118.4, 118.0, 107.2, 107.1, 106.4, 106.1, 104.8, 95.9, 61.2, 61.1, 61.0, 61.0, 56.4, 56.4, 56.2; Anal. Calcd. For C21H23NO6 (+0.05 H2O): C, 65.29; H, 6.03; N, 3.63. Found: C, 64.90; H, 5.94; N, 3.55.