Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[C:10](Br)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29]B(O)O.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.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]([N:8]1[C:17]2[C:12](=[C:13]([C:18]3[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=3[CH3:26])[CH:14]=[CH:15][CH:16]=2)[C:11](=[O:27])[C:10]([CH3:29])=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(-c2cccc3c2c(=O)c(Br)cn3Cc2ccccc2)c(C)c1
Reactant: CB(O)O
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: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(-c2cccc3c2c(=O)c(C)cn3Cc2ccccc2)c(C)c1
Temperature: 95 °C
Reaction time: 22 h
Yield: 59.5 %

Procedure:
1-Benzyl-3-bromo-5-mesitylquinolin-4(1H)-one (0.277 g, 0.64 mmol), methyl boronic acid (0.384 g, 6.4 mmol), potassium carbonate (0.443 g, 3.2 mmol), and Pd(PPh3)4 (0.37 g, 0.32 mmol) were diluted in dioxane (4 mL). Water (0.11 mL, 6.4 mmol) was added and the reaction stirred at 95° C. for 22 hr. The solution was then cooled and filtered through GF/F paper and concentrated. Flash chromatography (40% ethyl acetate/hexanes) gave the title compound as a white solid (0.14 g, 60%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH:32]([CH3:34])[CH3:33]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([CH:19]2[CH2:24][CH2:23][N:22]([CH:32]([CH3:34])[CH3:33])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1)[CH3:2]
Reactant: CCOc1ccccc1-c1cc(NC(=O)C2CCNCC2)ncn1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccccc1-c1cc(NC(=O)C2CCN(C(C)C)CC2)ncn1
Temperature: 60 °C
Yield: 54.3 %

Procedure:
To a stirred solution of piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #1A) (0.35 g, 1.0 mmol) and potassium carbonate (0.17 g, 1.2 mmol) in DMF (4 ml) was added 2-bromopropane (0.10 ml, 1.07 mmol) at room temperature. The reaction mixture was heated at 60° C. for one hour. The progress of the reaction was monitored by TLC. The reaction mixture was poured onto ice water and extracted with ethyl acetate (3×100 ml). The organic layers were separated, combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC (C-18, AcN:H2O with 0.05% TFA) and lyophilized to afford 1-isopropyl-piperidine-4-carboxylic acid [6-(2-ethoxy-phenyl)-pyrimidin-4-yl]-amide (compound #4A) (0.2 g, 51%) as a white solid.
Reaction SMILES: [C:1]1([C:7](=[N:17][O:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:29]>>[ClH:29].[NH2:21][CH2:20][CH2:19][O:18][N:17]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]1[NH:16][C:11]2=[CH:12][N:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(c1ccccc1)c1cc2ccncc2[nH]1
Agent: Cl
Product: NCCON=C(c1ccccc1)c1cc2ccncc2[nH]1

Procedure:
Phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone O-(2-aminoethyl)oxime hydrochloride was prepared by treating tert-butyl 2-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]ethylcarbamate (Example 60) with ethereal hydrogen chloride as an off-white solid (a mixture of isomers): mp 176-184° C. dec.; 1H NMR (500 MHz, CD3OD) δ 3.22 (2H, br s), 3.37 (2H, br s), 4.44-4.81 (2H, m), 6.68 (0.17H, s) 7.00 (0.83H, s), 7.37-7.54 (6H, m), 7.97-8.20 (1H, m), 8.96 (0.17H, br s), 9.14 (0.83H, br s); ESI MS m/z 281 [C16H16N4O+H]+; HPLC (Method A) 98.3% (AUC), tR=13.0 and 13.2 min.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[N:9]([CH2:12][CH2:13][CH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([C:23]2[N:24]=[CH:25][N:26]3[CH:30]=[C:29]([C:31]4[C@H:32]([CH3:55])[C@@H:33]5[C@@H:50]([C@H:51]([OH:53])[CH3:52])[C:49](=[O:54])[N:34]5[C:35]=4[C:36]([O:38]CC4C=CC([N+]([O-])=O)=CC=4)=[O:37])[S:28][C:27]=23)=[O:22])[CH:16]=1)=[N+]=[N-]>CO>[NH2:9][CH2:12][CH2:13][CH2:14][N+:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([C:23]2[N:24]=[CH:25][N:26]3[CH:30]=[C:29]([C:31]4[C@H:32]([CH3:55])[C@@H:33]5[C@@H:50]([C@H:51]([OH:53])[CH3:52])[C:49](=[O:54])[N:34]5[C:35]=4[C:36]([O-:38])=[O:37])[S:28][C:27]=23)=[O:22])[CH:16]=1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(c3cn4cnc(C(=O)c5ccc[n+](CCCN=[N+]=[N-])c5)c4s3)[C@H](C)[C@H]12
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CO
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(c3cn4cnc(C(=O)c5ccc[n+](CCCN)c5)c4s3)[C@H](C)[C@H]12
Yield: 13.7 %

Procedure:
A reaction was carried out in the same manner as in step b) of Example 1, except that 450 mg of 4-nitrobenzyl (1S,5R,6S)-2-[7-[1-(3-azidopropyl)pyridinium-3-yl]carbonylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate trifluoromethanesulfonate was used as the starting compound. The reaction product was subjected to column chromatography on Cosmosil 40C18-PREP (10% aqueous methanol solution). The fraction, which had been eluted earlier, was collected and was then ion exchanged by column chromatography (water) on Amberlyst (A-26) to give 38 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[C:9]([F:14])([F:13])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([NH:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:27])=[CH:24][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:15]1([N:7]2[CH2:8][C:9]([F:14])([F:13])[C:10](=[O:12])[NH:11][C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:23]=[CH:24][C:25]([C:26]([NH:28][CH:29]5[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]5)=[O:27])=[CH:36][CH:37]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CN1CCC(NC(=O)c2ccc(N)cc2)CC1
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC1(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4)cc2)CC1
Yield: 35.3 %

Procedure:
A mixture of 0.05 g (0.17 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-20), 0.05 g (0.20 mmole) of 4-amino-N-(1-methyl-piperidin-4-yl)-benzamide and 0.05 g (0.25 mmole) of p-toluenesulfonic acid monohydrate in 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The reaction mixture was cooled and then concentrated under reduced pressure. The residue was diluted with dichloromethane and saturated aqueous sodium bicarbonate solution. The precipitate was collected by filtration, washed with water and dried to give 0.030 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)-N-(1-methyl-piperidin-4-yl)-benzamide (I-134).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].Cl[C:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[S:18](=[O:26])(=[O:25])[N:17]=1>C(Cl)(Cl)Cl>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[S:18](=[O:25])(=[O:26])[N:17]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: ClC(Cl)Cl
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)(=O)c3ccccc32)o1
Temperature: 25 °C
Yield: 11.1 %

Procedure:
To a refluxing solution of 2.14 g (10 mmol) of 2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamine in 150 ml of chloroform is added incrementally 2.02 g (10 mmol) of 3-chlorobenzisothiazole 1,1-dioxide. The reaction mixture is refluxed for an additional 30 minutes, is cooled to room temperature and then solvent is removed on a rotoevaporator. The resulting oil is subjected to preparative column chromatography on silica gel. Elution with methylene chloride followed by methylene chloride: methanol (95:5) yields 420 mg (12%) of a white solid. The solid is suspended in ethyl ether, separated by suction filtration and dried in vacuo to give 270 mg (7%) of the title compound: m.p. 91-94.C.
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=C[CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[N:36]1C=CN=CC=1C(O)=O>>[C:1]([C:3]1[C:8]([O:9][C:10]2[C:24]([O:25][C:26]3[CH:27]=[N:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)=[CH:23][C:13]3[NH:14][C:15]([C:17]4[CH:22]=[N:36][CH:20]=[CH:19][N:18]=4)=[N:16][C:12]=3[CH:11]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2cccnc2C#N)cn1
Reactant: O=C(O)c1cnccn1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2cccnc2C#N)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2-cyanopyridin-3-yloxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 218 (step 3) and pyrazine-2-carboxylic acid.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:5]=1[CH2:6]Cl)([CH3:3])[CH3:2].[C:15]1(=[O:25])[NH:19][C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12.[K].CN(C)C=O>O>[CH:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([CH3:14])[CH3:13])[C:5]=1[CH2:6][N:19]1[C:18](=[O:20])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[C:15]1=[O:25])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1CCl
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1CN1C(=O)c2ccccc2C1=O
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 71.4 %

Procedure:
A mixture of 0.92 g (4.4 mmol) of 2, 6-diisopropylbenzyl chloride, 0.97 g (5.24 mmol) of potassium phthalimide and 8 ml of N, N-dimethylformamide was stirred at 70° C. for 1.5 hours. After cooling, the reaction mixture was mixed with water and extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate and the solvent evaporated in vacuo. The residue was mixed with 15 ml of hexane and 2 ml of ethyl acetate, stirred at room temperature, and the precipitated crystals were filtered to give 1.01 g of N-(2, 6-diisopropylbenzyl)-phthalimide.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.[F:22][CH:23]([F:31])[C:24]1[S:28][C:27]([CH2:29]O)=[CH:26][CH:25]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:29][C:27]5[S:28][C:24]([CH:23]([F:31])[F:22])=[CH:25][CH:26]=5)=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1
Reactant: OCc1ccc(C(F)F)s1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(F)F)s4)cc3=O)cn12
Temperature: 60 °C
Reaction time: 3 h
Yield: 15 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (350 mg), (5-(difluoromethyl)-2-thienyl)methanol (409 mg) and tributylphosphine (755 mg) in THF (12 ml) was added 1,1′-(azodicarbonyl)dipiperidine (942 mg), and the reaction mixture was stirred at 60° C. for 3 h. The reaction mixture was cooled to room temperature, concentrated and purified by silica gel column chromatography (hexane/EtOAc then MeOH/EtOAc). The resulting solid was recrystallized from EtOH-hexane to give the title compound (80 mg) as a white solid.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]>ClCCl>[OH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cccc(-c2ccccc2OC)c1
Solvent: ClCCl
Product: COC(=O)c1cccc(-c2ccccc2O)c1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
Part C: In a dry 50 ml flask, methyl 3-(2-methoxyphenyl)benzoate (1.2 g, 4.95 mmol) was dissolved in dichloromethane (10 ml) under nitrogen, and chilled in a dry-ice/2-propanol bath. Boron tribromide dimethyl sulfide complex (20 ml of a 1M solution in methylene chloride) was added slowly drop-wise and the mixture was allowed to come to room temperature, then the mixture was heated at reflux for 30 hours, then mixed with ice-water (100 ml). The organic material was separated, washed with saturated sodium bicarbonate solution (50 ml), water (50 ml), saturated sodium chloride (60 ml) then dried (MgSO4) and concentrated under reduced pressure. The residue was re-esterified by treatment with methanol and catalytic sulfuric acid, and the product subsequently purified by flash chromatography (SiO2, 3:1 hexane/ethyl acetate) which gave 0.95 g (84%) of methyl 3-(2-hydroxyphenyl)benzoate as a clear oil.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][C:16](Cl)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>[CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][C:16]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)CCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C(CCC1c2ccccc2-c2ccccc21)N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 8 h

Procedure:
3-(Fluoren-9-yl)propionyl chloride (described in Example 33; without crystallization) (3.0 g, 11.7 mmol) in dioxane (40 mL) was added to a stirred solution of L-phenylalanine ((2.0 g, 11.7 mmol) in 75 mL of 10% potassium carbonate solution and 38 mL of dioxane at room temperature. The reaction mixture was stirred overnight. The dioxane was removed under reduced pressure. The residue was diluted with water (100 mL) and extracted with ethyl acetate (4×30 mL). The water solution was treated with Norit then acidified to pH 1. The precipitate was filtered off, washed with 1N HCl, water and dried. Short path chromatography (RP-18 Silica, 50% methanol/water) afforded white solid. Final purification was accomplished by washing the product with ether. The resulting yield of N-[9H-(3-fluoren-9-ylpropionyl)]-L-phenylalanine was 1.2 g 26.5%), mp 194°-195° C.
Reaction SMILES: C([CH:5]1[CH:14]2[N:9]([CH2:10][CH:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:12][CH2:13]2)[CH2:8][CH2:7][C:6]1=[O:21])(OC)=O.OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+]>>[C:15]1([CH:11]2[CH2:12][CH2:13][CH:14]3[N:9]([CH2:8][CH2:7][C:6](=[O:21])[CH2:5]3)[CH2:10]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)C1C(=O)CCN2CC(c3ccccc3)CCC12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C1CCN2CC(c3ccccc3)CCC2C1
Yield: 96.5 %

Procedure:
The ketoester (II) (6.82 g.) was dissolved in 50 ml. 1.8 M H2SO4 and the mixture refluxed overnight. The solution was cooled and made alkaline with Na2CO3. The organic material was extracted with CHCl3, dried and solvent removed. Yield, 5.6 g. Some ester was still present so the mixture was recycled. The reaction was worked up as above. Yield, 5.25 g. (96.5% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6](=O)[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:8]N(C)C)[CH3:2].[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([NH:48][C:49]([NH2:51])=[NH:50])[CH:39]=[CH:40][C:41]=1[N:42]1[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]1>>[CH3:34][O:35][C:36]1[CH:37]=[C:38]([NH:48][C:49]2[N:51]=[C:6]([CH:5]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]([O:3][CH2:1][CH3:2])=[O:25])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][N:50]=2)[CH:39]=[CH:40][C:41]=1[N:42]1[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(C(=O)C(=CN(C)C)c1ccccc1)c1ccccc1
Solvent: O=[N+]([O-])O
Product: CCOC(=O)C(c1ccccc1)c1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)ncc1-c1ccccc1

Procedure:
The title compound was prepared from ethyl-5-dimethylamino-3-oxo-2,4-diphenyl-pent-4-enoate (102 mg, 0.3 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (83 mg, 0.22 mmol) using in analogous manner the procedure described in example 28b). Obtained as a light-brown solid (5 mg, 3%). Mp 84-86° C.
Reaction SMILES: [CH2:1]([SnH:5]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[C:14]1([C:20]#[CH:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>N(C(C)(C)C#N)=NC(C)(C)C#N>[CH2:10]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([CH2:6][CH2:7][CH2:8][CH3:9])/[CH:21]=[CH:20]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#Cc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/c1ccccc1)(CCCC)CCCC
Temperature: 50 °C
Reaction time: 24 h
Yield: 87 %

Procedure:
The synthesis was carried out according to the methods described in (a) Labadie, J. W.; Tueting, D.; Stille, J. K. J. Org. Chem. 1983, 48, 4634 and (b) Lappert, M. F.; Jones, K. J. Organomet. Chem. 1965, 3, 295. A mixture of tributyltin hydride (5.82 g, 20.0 mmole), phenylacetylene (1.95 g, 19.0 mmole), and 2,2′-azobis(isobutyronitrile) (0.14 g, 0.085 mmole) was slowly heated to 50° C., followed by stirring for 24 hours. Next, the mixture was cooled to room temperature and filtered by a Celite pad to remove the white precipitate. The filtrate was distilled to obtain 6.50 g of tributyl[(E)-2-phenyl-1-ethenyl]stannane. Yield: 84%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([F:21])[C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.Cl[C:23]1[N:24]=[CH:25][C:26]([F:35])=[C:27]2[C:32]=1[N:31]=[CH:30][C:29]([C:33]#[N:34])=[CH:28]2>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:17])([F:16])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:23]3[N:24]=[CH:25][C:26]([F:35])=[C:27]4[C:32]=3[N:31]=[CH:30][C:29]([C:33]#[N:34])=[CH:28]4)[CH:3]=[C:4]([F:21])[C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: N#Cc1cnc2c(Cl)ncc(F)c2c1
Reactant: C[C@@]1(c2cc(N)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1
Product: C[C@@]1(c2cc(Nc3ncc(F)c4cc(C#N)cnc34)cc(F)c2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The titled compound was synthesized by procedure and steps analogous to those described in Method B, Step 2, Example 8 above, but using (4S,6S)-4-(5-amino-2,3-difluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (17i, Example 163, Method Y step 9) and 8-chloro-5-fluoro-1,7-naphthyridine-3-carbonitrile (intermediate 17) in step 2. MS m/z=481.1 [M+H]+. Calculated for C21H14F6N6O: 480.4
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].[CH3:13]I>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:10]([CH3:13])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1ccc2ncnc(Cl)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a stirred solution of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (27) (J. Org. Chem., 2001, 66, 17, 5723-5730) (643 mg, 4.15 mmol) in DMF (41 mL) was added NaH (60% in mineral oil, 330 mg, 8.3 mmol) in one portion at 0° C. and the mixture was stirred for 1 h followed by addition of methyl iodide (0.28 mL, 4.5 mmol). The reaction mixture was allowed to warm up to the room temperature, stirred for an additional hour and quenched with AcOH (1 mL) to form a suspension which was stirred for 10 min and concentrated under reduced pressure to give a solid. This material was dissolved in AcOEt, the solution was washed with cold saturated NaHCO3 solution and water, dried over Na2SO4, and concentrated to produce the title compound 28 as a pale yellow solid (640 mg, 93% yield). 1H NMR (400 MHz, CD3OD) δ(ppm): 8.51 (s, 1H), 7.75 (d, J=3.3 Hz, 1H), 6.62 (d, J=3.3 Hz, 2H), 4.15 (s, 1H). LRMS (M+1) 168.1 (100%), 170.1 (34%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14](O)=[O:15])=[CH:9][CH:8]=1)=[O:6].[N:19]1(C(N)=O)[CH2:23]CC[CH2:20]1>>[CH3:20][N:19]([CH3:23])[C:14](=[O:15])[C:13]([C:10]1[CH:11]=[CH:12][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:8][CH:9]=1)([CH3:18])[CH3:17]
Reactant: NC(=O)N1CCCC1
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Product: CN(C)C(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1

Procedure:
2-[4-(4-Chloro-butyryl)-phenyl]-2-methyl-propionic acid, pyrroldineamide;
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[C:33](O)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:33]([C:34]3[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=3)=[O:40])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=C(O)c1cccnc1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C(=O)c3cccnc3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and nicotinic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(pyridin-3-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.10 (s, 3H), 3.05 (br s, 4H), 3.32-3.40 (br s, 4H), 3.54 (br s, 2H), 3.68 (br s, 4H), 3.84 (br s, 2H), 6.50 (br s, 1H), 7.16 (br s, 1H), 7.28 (br s, 1H), 7.56 (br s, 2H), 7.78 (s, 1H), 7.90 (d, J=7.6 Hz, 1H), 8.36 (s, 1H), 8.67 (s, 2H). Mass Spectrum (ESI) m/e=545.7 (M+1).