Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[CH:12]=[C:13]1[C:19]2[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:18]=2[CH2:17][CH2:16][C:15]2[CH:25]=[CH:26][CH:27]=[CH:28][C:14]1=2>>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]2[C:13](=[CH:12][C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:14]3[CH:28]=[CH:27][CH:26]=[CH:25][C:15]=3[CH2:16][CH2:17][C:18]=2[CH:23]=1
Reactant: Clc1ccc2c(c1)CCc1ccccc1C2=CBr
Reactant: OB(O)c1ccc(O)cc1
Product: Oc1ccc(C=C2c3ccccc3CCc3cc(Cl)ccc32)cc1

Procedure:
Following procedures essentially as described in Example 219, below, and using (4-hydroxyphenyl)boronic acid (55 mg, 0.40 mmol) and 5-bromomethylene-2-chloro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (103 mg, 0.32 mmol) provides the title compound. Mass Spec (EI+) 332.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[C:11]4[CH:23]=[CH:22][S:21][C:12]=4[C:13](=[O:20])[NH:14][C:15]=3[CH:16]=[CH:17][C:18]=2[OH:19])=[CH:5][CH:4]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[OH:19][C:18]1[CH:17]=[CH:16][C:15]2[NH:14][C:13](=[O:20])[C:12]3[S:21][CH:22]=[CH:23][C:11]=3[C:10]=2[C:9]=1[C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Reaction time: 1.5 h
Yield: 43.7 %

Procedure:
A solution of 9-[4-(aminomethyl)phenyl]-8-hydroxythieno[2,3-c]quinolin-4(5H)-one (50 mg, 0.16 mmol) and methanesulfonyl chloride (43 mg, 0.37 mmol) in methylene chloride (5 mL) was stirred at room temperature for 10 min. N,N-diisopropylethylamine (48 mg, 0.37 mmol) was added and the reaction mixture was stirred for 1.5 h, concentrated under reduced pressure and the residue was purified by preparatory HPLC (C18 silica, water/acetonitrile w/0.05% TFA gradient) to afford the desired product (28 mg, 45%) as a white solid: 1H NMR (500 MHz, DMSO-d6) δ 11.77 (s, 1H), 9.22 (s, 1H), 7.70-7.67 (m, 2H), 7.49 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.9 Hz, 1H), 7.23 (d, J=8.0 Hz, 2H), 7.15 (d, J=8.9 Hz, 1H), 5.89 (d, J=5.4 Hz, 1H), 4.29 (d, J=6.4 Hz, 2H), 2.94 (s, 3H); ESI MS m/z 401 [C19H16N2O4S+H]+; HPLC >99% (AUC), tR=12.12 min.
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[CH2:3][O:4][C:5]([O:7][CH2:8][C:9]1[S:10][CH:11]=[C:12]([CH:14]=O)[N:13]=1)=[O:6].C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:25]([CH3:28])[CH:26]=[O:27])C=CC=CC=1>C1C=CC=CC=1>[CH3:28][C:25](=[CH:14][C:12]1[N:13]=[C:9]([CH2:8][O:7][C:5]([O:4][CH2:3][C:2]([Cl:17])([Cl:16])[Cl:1])=[O:6])[S:10][CH:11]=1)[CH:26]=[O:27]
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Solvent: c1ccccc1
Product: CC(C=O)=Cc1csc(COC(=O)OCC(Cl)(Cl)Cl)n1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A mixture of 2-(2,2,2-trichloroethoxycarbonyloxymethyl)thiazole-4-carboxaldehyde (21.0 g) and 2-(triphenylphosphoranylidene)propionaldehyde (20.6 g) in 300 mL of benzene is heated at reflux for 3 hours, then cooled to ambient temperature and concentrated. Purification by flash column chromatography on SiO2 (hexanes/ethyl acetate, 4:1) yields the product as a clear oil (21.0 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:25])[C:23]#[CH:24]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:25][CH2:22][C:23]#[CH:24])=[O:11])[CH2:7]1
Reactant: Cc1cccc(OC2CN(C(=O)Cl)C2)c1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCNC(=O)N1CC(Oc2cccc(C)c2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
A stirred mixture of 3.92 g (0.01 mole) of crude (57.59%) 3-(3-methylphenoxy)-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 15 ml of tetrahydrofuran was treated with 0.55 g (0.01 mole) of 2-propynylamine added dropwise from a needle and syringe. After 10 min, approximately 1 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated slowly solidified. The precipitated solid was collected by filtration to yield 4.7 g of crude wet product. After air drying, the solid was recrystallized from benzene-ligroin to yield 1.78 g (72.9%) of fine white crystals, m.p. 140°-142° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[H-].[Na+].[F:12][C:13]([F:43])([F:42])[C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH2:23][CH2:22][N:21]2[C:30](OC2C=CC([N+]([O-])=O)=CC=2)=[O:31])=[CH:16][CH:15]=1.O>C1COCC1>[C:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][C:30]([N:21]2[CH2:22][CH2:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:20]2[C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:42])([F:12])[F:43])=[CH:15][CH:16]=2)=[O:31])=[CH:3][CH:4]=1)#[N:9]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(N)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-amino-2-pyridinecarbonitrile (81 mg, 678 μmol) in THF (1.0 mL) was added sodium hydride, 60% dispersion in mineral oil (17 mg, 452 μmol). The resulting mixture was then subjected to a microwave irradiation at 160° C. for 15 min. Then, (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (100 mg, 226 example 88) was added and the mixture was stirred at RT for overnight. Then, H2O (0.5 mL) was added and the mixture was extracted with EtOAc (2×1 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was dissolved in DMSO (1.0 mL) and the solution was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the desired compound, which was dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP-Resin (200 mg per 6 mL tube) and the resin was washed with MeOH (2×0.3 mL). The combined washings were concentrated and dried under vacuum to give the title compound as a light yellow solid. MS (ESI, positive ion) m/z: 423 (M+H).
Reaction SMILES: [CH3:1][C:2](O)([CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[C:3]#[CH:4].C[O:13][C:14]([CH3:16])=[CH2:15]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CCCCCCC>[CH3:1][C:2]([CH2:5][CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])=[C:3]=[CH:4][CH2:15][C:14](=[O:13])[CH3:16]
Reactant: C=C(C)OC
Reactant: C#CC(C)(O)CCCC(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCCCCCC
Product: CC(=O)CC=C=C(C)CCCC(C)C
Yield: 82 %

Procedure:
30.9 g 3,7-dimethyl-1-octin-3-ol, 28.9 g isopropenyl methyl ether and 60 ml n-heptane were initially introduced into a 250 ml flask and 25 mg pyridinium toluene-4-sulfonate were then added. The reaction mixture was stirred under reflux for 7 hours. During this period of time, 14.4 g isopropenyl methyl ether and 25 mg pyridinium toluene-4-sulfonate were added in two portions. When the reaction had ended, the solution was evaporated. The residue was distilled in vacuo. 31.9 g 6,10-dimethyl-4,5-undecadien-2-one were obtained, which corresponds to a yield of 82%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9](OCC)[CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.[CH2:15]([NH2:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:15]([NH:23][C:9](=[N:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH3:11])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCOC(CC)=Nc1cccc(Cl)c1
Reactant: CCCCCCCCN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCCCCCCCNC(CC)=Nc1cccc(Cl)c1

Procedure:
Ethyl N-(3-chlorophenyl)propionimidate (1 part), n-octyl-amine (1 part), and a catalytic amount of p-toluenesulfonic acid monohydrate were charged to a flask fitted with a condenser and drying tube (CaSO4) and the mixture was refluxed for 15 hours, after which the flask was fitted with a 10 cm Vigreaux column and the ethanol that had formed (0.8 part) distilled off slowly (3 hours). The reaction mixture was then distilled at reduced pressure (0.15 mm Hg) to give N-n-octyl-N'-(3-chlorophenyl)propionamidine (0.7 part). The fraction boiling at 167.5° - 169° C. was collected and analyzed.
Reaction SMILES: [CH:1]([O:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:51]1[N:52]=[C:53]([NH:56]C=O)[S:54][CH:55]=1)[C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([O:35][CH:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[O:34])=[C:28]([CH:31]=[CH2:32])[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+]>CO.O1CCCC1>[CH:1]([O:14][C:15]([CH2:17][O:18][N:19]=[C:20]([C:51]1[N:52]=[C:53]([NH2:56])[S:54][CH:55]=1)[C:21]([NH:23][CH:24]1[C:49](=[O:50])[N:26]2[C:27]([C:33]([O:35][CH:36]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:34])=[C:28]([CH:31]=[CH2:32])[CH2:29][S:30][C@H:25]12)=[O:22])=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(NC=O)n3)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(c3ccccc3)c3ccccc3)c3csc(N)n3)[C@H]2SC1
Temperature: 30 °C
Yield: 90.1 %

Procedure:
To a stirred solution of benzhydryl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (8.14 g) in methanol (50 ml) and tetrahydrofuran (10 ml) was added 35% hydrochloric acid (2.3 ml). After stirring at 30° C. for an hour, the reaction mixture was poured into ice-water and then adjusted to pH 3.5 with a saturated aqueous sodium bicarbonate. The precipitates were collected by filtration and then dried to give benzhydryl 7-[2-benzhydryloxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (7.08 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11]>O>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:8]1[CH2:14][CH2:13][CH2:12][C@H:9]1[CH2:10][OH:11]
Reactant: Clc1ccccn1
Reactant: OC[C@@H]1CCCN1
Solvent: O
Product: OC[C@@H]1CCCN1c1ccccn1
Temperature: 160 °C
Reaction time: 4 h
Yield: 54.6 %

Procedure:
A mixture of 2-chloropyridine (118 g) and L-prolinol (70 g) was heated under nitrogen atmosphere at 160° C. with stirring for 4 h. The mixture was cooled to room temperature and poured into water and the solution was extracted with chloroform repeatedly. The combined organic extracts were dried (Na2SO4) and concentrated. The crude product was purified by column chromatography using 2% MeOH in CHCl3 as eluent to get 67.3 g (54.5%) of the title compound as a syrupy liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](OCC)=[O:12])=[CH:5]2.[Al].[Li]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][OH:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: [Al]
Agent: [Li]
Product: OCc1cc2cc(Br)ccc2[nH]1

Procedure:
The title compound was prepared from ethyl 5-bromo-1H-indole-2-carboxylate and lithium aluminum in substantially the same manner, as described in step 3 of Example 1. The product was obtained as a solid; mp: 111-112° C. Mass spectrum (ESI, [M−H]−) m/z 224. 1H NMR (400 MHz, DMSO-d6) δ 7.62 (s, 1H), 7.27 (d, 1H, J =8.02 Hz), 7.12 (d, 1H, J=8.02 Hz), 6.25 (s, 1H), 5.29 (t, 1H, J=5.50 Hz), 4.59 ppm (d, 2H, J=5.6 Hz).
Reaction SMILES: COC1C=CC(C([NH:24][C:25]2[CH2:26][O:27][C:28]([CH3:53])([CH3:52])[C:29]([F:51])([F:50])[C@:30]([C:33]3[CH:38]=[C:37]([C:39]4[O:40][C:41]5[CH:47]=[C:46]([Cl:48])[CH:45]=[CH:44][C:42]=5[N:43]=4)[CH:36]=[CH:35][C:34]=3[F:49])([CH3:32])[N:31]=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=CC=1.FC(F)(F)C(O)=O.Cl>C(OCC)C>[ClH:48].[Cl:48][C:46]1[CH:45]=[CH:44][C:42]2[N:43]=[C:39]([C:37]3[CH:36]=[CH:35][C:34]([F:49])=[C:33]([C@:30]4([CH3:32])[C:29]([F:50])([F:51])[C:28]([CH3:53])([CH3:52])[O:27][CH2:26][C:25]([NH2:24])=[N:31]4)[CH:38]=3)[O:40][C:41]=2[CH:47]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4nc5ccc(Cl)cc5o4)ccc3F)C(F)(F)C(C)(C)OC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(-c3nc4ccc(Cl)cc4o3)ccc2F)C1(F)F
Yield: 131.5 %

Procedure:
In a manner analogous to that described in Example 18b), the treatment of [bis-(4-methoxy-phenyl)-phenyl-methyl]-{(R)-5-[5-(6-chloro-benzo oxazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl}-amine (38 mg, 51.3 μmol) with trifluoro acetic acid (40 μl, 513 μmol), treatment with hydrochloric acid and followed by trituration with diethyl ether yielded the (R)-5-[5-(6-chloro-benzooxazol-2-yl)-2-fluoro-phenyl]-6,6-difluoro-5,7,7-trimethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine hydrochloride (16 mg, 66% yield) as an off-white solid. MS (ISP): m/z=438.2 [M+H]+ and 440.3 [M+2+H]+.
Reaction SMILES: [OH:1][C:2]1([CH2:9][N:10]2[CH2:15][CH2:14][C:13]3[NH:16][C:17]([CH:20]=O)=[C:18]([CH3:19])[C:12]=3[C:11]2=[O:22])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[CH2:27]2>>[Cl:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28](=[O:33])[C:27]2=[CH:20][C:17]1[NH:16][C:13]2[CH2:14][CH2:15][N:10]([CH2:9][C:2]3([OH:1])[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)[C:11](=[O:22])[C:12]=2[C:18]=1[CH3:19]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Product: Cc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c2c1C(=O)N(CC1(O)CCN(C)CC1)CC2
Yield: 59.14 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-chloro-1,3-dihydro-indol-2-one as starting materials to give 2-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-5-(4-hydroxy-1-methyl-piperidin-4-ylmethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (44 mg, 59.14%) as a yellow solid.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:29])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34].C[O-].[Na+]>>[CH:16]1([CH2:15][N:11]2[C:12]3[C:7](=[C:6]([OH:29])[C:5]([C:3]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:4])=[N:14][CH:13]=3)[CH:8]=[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]2=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A mixture of 1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (35 mg, 0.089 mmol), β-alanine (795 mg, 8.9 mmol) and NaOMe solution (13 mL, 6.7 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude product was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 6 M HCl, and the resulting precipitate was isolated by filtration to give 25 mg of the title compound as a light yellow solid. MS: (+) m/z 450.30 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1B(O)O>>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:19])[CH2:3][C:2]2([CH3:20])[CH3:1]
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: CC1(C)CC(=O)c2ccc(-c3ccc(Cl)cc3Cl)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 2,4-dichlorophenyl boronic acid according to the procedure described in example 21. MS m/z 305; HRMS: calcd for C17H14Cl2O+H+, 305.04944; found (ESI, [M+H]+), 305.0494.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[N:28][OH:29])=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1cc(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(C(CC(c2ccc(Br)cc2)c2ccccc2C)=NO)ccn1

Procedure:
In analogy to example 74, step 7, from 3-(4-bromo-phenyl)-1-(2-methoxy-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a mixture of E and Z isomers (2.7:1) as a white foam, MS (ESI+): m/z=425.1 ([M+H]+, 1Br).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][C:11]([N+:20]([O-:22])=[O:21])=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=c1c2[nH]cnc2n(CC2CC2)c(=O)n1CC1CC1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=c1c2[nH]c([N+](=O)[O-])nc2n(CC2CC2)c(=O)n1CC1CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
1,3-Di-cyclopropylmethyl xanthine (20 g, 0.076 mol) was dissolved in acetic acid (33 ml) and then treated with concentrated nitric acid (13.2 g) at 87° C. After 1 hour, the mixture was cooled to 5° C. and the resulting yellow precipitate filtered off. The yellow crystals were dissolved in dichloromethane and washed with water. The separated organic layer was then dried over anhydrous sodium sulphate and concentrated in vacuo. The product crystallized from the concentrate to yield a yellow crystalline product yield 12.2 g, (56.5%), m.pt. 207° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[NH:15][CH3:16])=[C:4]([O:17][CH3:18])[CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([OH:25])=O>>[Br:19][C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23]([N:15]([C:9]1[CH:10]=[N:11][C:12]([CH3:14])=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[O:17][CH3:18])[CH3:16])=[O:25]
Reactant: CNc1cnc(C)cc1-c1ccc(F)cc1OC
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(Br)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from 4-(4-fluoro-2-methoxyphenyl)-N,6-dimethylpyridin-3-amine and 3-bromo-5-(trifluoromethyl)benzoic acid after a reaction time of 20 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). Colorless solid (88%). MS (ESI): m/z=497.05 [M+H]+.
Reaction SMILES: NC1C=CC=CC=1.C(OC([O:14][C@@H:15]([C@H:17]1[C:32](=[O:33])[N:19]2[C:20]([C:26]([O:28]CC=C)=[O:27])=[C:21]([CH2:24]O)[C@H:22]([CH3:23])[C@H:18]12)[CH3:16])=O)C=C.C(OC([N:40]([CH2:45][C:46]1[S:50][C:49]2=[CH:51][N:52]=[CH:53][N:48]2[C:47]=1[CH3:54])[S:41]([NH2:44])(=[O:43])=[O:42])=O)C=C>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].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>[OH:14][C@@H:15]([C@H:17]1[C:32](=[O:33])[N:19]2[C:20]([C:26]([O-:28])=[O:27])=[C:21]([CH2:24][N:52]3[CH:51]=[C:49]4[S:50][C:46]([CH2:45][NH:40][S:41]([NH2:44])(=[O:42])=[O:43])=[C:47]([CH3:54])[N+:48]4=[CH:53]3)[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: C=CCOC(=O)N(Cc1sc2cncn2c1C)S(N)(=O)=O
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CO)[C@H](C)[C@H]12
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Nc1ccccc1
Product: Cc1c(CNS(N)(=O)=O)sc2cn(CC3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)c[n+]12
Yield: 10 %

Procedure:
The same procedure as in Example 1 was repeated except that in a deprotective reaction, two catalysts, i.e., 23.4 mg of tris(dibenzylideneacetone)dipalladium and 59.1 mg of tetrakis(triphenylphosphine)palladium were used, 0.14 ml of aniline was used as a trapping agent, and 110.3 mg of allyl (1S,5R,6S)-6-[(1R)-1-allyloxycarbonyloxyethyl]-2-hydroxymethyl-1-methyl-1-carbapen-2-em-3-carboxylate and 196 mg of 2-[N-allyloxycarbonyl-N-(aminosulfonyl)amino]methyl-3-methylimidazo[5,1-b]thiazole were used, thereby obtaining 14.2 mg of the title compound.
Reaction SMILES: Br[C:2]1[S:19][C:5]2[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[S:19][C:5]3[N:6]([CH3:18])[C:7](=[O:17])[N:8]([CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C:9](=[O:10])[C:4]=3[C:3]=2[CH3:20])=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)CCn1c(=O)c2c(C)c(Br)sc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: COC(=O)CCn1c(=O)c2c(C)c(-c3ccc(Cl)cc3)sc2n(C)c1=O
Temperature: 100 °C
Yield: 46.5 %

Procedure:
To a solution of methyl 3-(6-bromo-1,5-dimethyl-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (180 mg, 0.498 mmol) in toluene (5 mL) was added 4-chlorophenylboronic acid (78 mg, 0.498 mmol) and aq. Cs2CO3 solution (1 M, 1 mL). The reaction was degassed under nitrogen gas (3×) then Pd(PPh3)4 (10 mg) was added. The reaction was heated at 100° C. for 18 h, cooled to RT then diluted with EA (10 mL). The organic layer was washed with brine (10 mL), dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with DCM/MeOH (80:1) to give methyl 3-(6-(4-chlorophenyl)-1,5-dimethyl-2,4-dioxo-1,2-dihydro thieno[2,3-d]pyrimidin-3(4H)-yl)propanoate (91 mg, 46.5% yield) as a yellow solid. LCMS: MH+ 393 and TR=1.956 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([O:13][CH3:14])=[CH:7][C:6]=1[O:15][CH3:16])=O.[NH2:17][C:18]([NH2:20])=[S:19]>CCO>[CH3:16][O:15][C:6]1[CH:7]=[C:8]([O:13][CH3:14])[CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[C:3]1[N:17]=[C:18]([NH2:20])[S:19][CH:2]=1
Reactant: COc1cc(OC)c(C(=O)CBr)c(OC)c1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1cc(OC)c(-c2csc(N)n2)c(OC)c1
Yield: 76.4 %

Procedure:
A mixture of 2-bromo-1-(2,4,6-trimethoxyphenyl)ethanone (2.49 g, 8.6 mmol) and thiourea (0.67 g, 8.7 mmol) in 95% EtOH (16 mL) was heated at reflux for 60 min. The solution was concentrated and mixed with water (100 mL) and saturated aqueous Na2CO3 (5.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,4,6-trimethoxyphenyl)thiazol-2-amine (1.75 g) as yellow solids in >99% yield: 1H NMR (500 MHz, DMSO-d6) δ 9.00 (s, 2 H), 6.78 (s, 1 H), 6.36 (s, 2 H), 3.84 (s, 3 H), 3.79 (s, 6 H).