Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-])=O)[N:6]([CH3:8])[CH3:7].[C:15](OCC)(=[O:17])C>[Pd]>[CH3:15][O:17][C:4]1[CH:3]=[C:11]([NH2:12])[CH:10]=[CH:9][C:5]=1[N:6]([CH3:7])[CH3:8]
Reactant: CCOC(C)=O
Reactant: COc1cc(N(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Product: COc1cc(N)ccc1N(C)C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A suspension of 3-methoxy-N,N-dimethyl-4-nitroaniline (Bionet) (0.5 g, 2.6 mmol) and Pd/C (Aldrich, 10%, 0.1 g) in ethyl acetate (10 mL) was vigorously shaken in a Parr under atmosphere of H2 (50 psi) for 0.5 h. The mixture was filtered through a short pad of celite. The filtrate was concentrated to give 2-methoxy-N,N-dimethyl-benzene-1,4-diamine as a dark brown oil (0.4 g, 94%).
Reaction SMILES: Br[C:2]1[C:3]([O:12][CH3:13])=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O[C:15]1C=CC(C(=O)C)=C(C)C=1.C(=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:13][O:12][C:3]1[CH:2]=[CH:10][C:6]([C:7](=[O:9])[CH3:15])=[C:5]([CH3:11])[CH:4]=1
Reactant: COc1cc(C)c(C(=O)O)cc1Br
Reactant: CC(=O)c1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(C(C)=O)c(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Alternatively, 5-bromo-4-methoxy-2-methylbenzoic acid can be synthesized from 4′-hydroxy-2′-methylacetophenone as a starting material. Potassium carbonate (0.720 mg, 5.21 mmol) and methyl iodide (0.542 g, 3.82 mmol) were added to an acetone (10 mL) solution of 4′-hydroxy-2′-methylacetophenone (0.552 g, 3.47 mmol) and stirred at room temperature for 12 hours. Methyl iodide (0.24 g, 1.73 mmol) was further added, and the mixture was heated to reflux for two hours. After cooled to room temperature, the solvent was evaporated under reduced pressure. After chloroform was added to the residue, insolubles were filtered off and the filtrate was concentrated to obtain 4′-methoxy-2′-methylacetophenone (0.57 g). Then, oxone (0.79 g, 1.27 mmol) and NaBr (0.13 g, 1.27 mmol) were added to an acetone (4 mL) water (4 mL) solution of 4′-methoxy-2′-methylacetophenone (0.21 g, 1.27 mmol), and stirred at room temperature for one hour. After water and ethyl acetate were added to the reaction mixture, the organic layer was separated and washed with water, a saturated sodium carbonate aqueous solution and brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the solvent was evaporated under reduced pressure to obtain 4:1 mixture (0.28 g) of 5′-bromo-4′-methoxy-2′-methylacetophenone and 3′-bromo-4′-methoxy-2′-methylacetophenone. Then, 4:1 mixture (0.26 g) of 5′-bromo-4′-methoxy-2′-methylacetophenone and 3′-bromo-4′-methoxy-2′-methylacetophenone was added with 5% NaOCl solution (3 mL) and potassium hydroxide (0.92 g) and heated to reflux for 2.5 hours. After cooled to room temperature, the reaction mixture was made acidic with 2M HCl. After the mixture was extracted with ethyl acetate, the organic phase was washed with 1M HCl, brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was washed with methanol to obtain 5-bromo-4-methoxy-2-methylbenzoic acid (112 mg) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[N:7]([CH3:18])[C:6]=2[CH:19]=1.[NH:20]([C:24]1[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=1)[C:21]([NH2:23])=[NH:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:22]=[C:21]([NH:20][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=4)[N:23]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[N:7]([CH3:18])[C:6]=2[CH:19]=1
Reactant: CN(C)C=C1CC(=O)N(C)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Product: CN1C(=O)Cc2cnc(Nc3ccc(C(=O)O)cc3)nc2-c2ccc(Cl)cc21

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-1-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-m) and 4-guanidinobenzoic acid were converted to I-7 (30%): HRMS Calcd. for C20H15ClN4O3: 395.0910, Found 395.0923.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([C:10]3[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][N:11]=3)[C:6]=2[CH:17]=1.N1CCCCC1.[S:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]([OH:33])([C:31]#[CH:32])[CH3:30]>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.[Cu]I>[NH2:16][C:14]1[CH:13]=[CH:12][N:11]=[C:10]([N:7]2[C:6]3[CH:17]=[C:2]([C:32]#[C:31][C:29]([C:25]4[S:24][CH:28]=[CH:27][N:26]=4)([OH:33])[CH3:30])[CH:3]=[CH:4][C:5]=3[N:9]=[CH:8]2)[N:15]=1
Reactant: Nc1ccnc(-n2cnc3ccc(Br)cc32)n1
Reactant: C#CC(C)(O)c1nccs1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Product: CC(O)(C#Cc1ccc2ncn(-c3nccc(N)n3)c2c1)c1nccs1
Temperature: 75 °C
Reaction time: 18 h
Yield: 11.5 %

Procedure:
To a pressure tube was added 2-(6-bromo-1,3-benzodiazol-1-yl)pyrimidin-4-amine (300 mg, 1.03 mmol), piperidine (2 mL), tetrakis(triphenylphosphine)palladium (119.5 mg, 0.10 mmol), copper(I) iodide (19.7 mg, 0.10 mmol) and 2-(1,3-thiazol-2-yl)but-3-yn-2-ol (316.84 mg, 2.07 mmol). The reaction was stirred at 75° C. for 18 h. The reaction mixture was cooled before concentrating in vacuo. The crude product was purified by column chromatography (Biotage) eluted with DCM: methanol gradient (97:3 to 90:1). Material obtained was triturated with methanol to afford the title compound as a beige solid. (43 mg, 11.5% yield); 1H NMR (250 MHz, DMSO) delta 1.91 (3H, s), 6.41 (1H, d, J=5.79 Hz), 7.06 (1H, s), 7.37 (1H, d, J=1.52 Hz), 7.45 (2H, br. s.), 7.65-7.84 (3H, m), 8.19 (1H, d, J=5.79 Hz), 8.62 (1H, d, J=1.07 Hz), 9.00 (1H, s); LC-MS m/z+3.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[C@@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1)(=O)C>O>[OH:4][CH2:5][C:6]1[CH:11]([C:12]([OH:14])=[O:13])[N:10]2[C:15](=[O:26])[C@@H:16]([NH:17][C:18](=[O:25])[CH2:19][C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C@H:9]2[S:8][CH:7]=1
Reactant: CC(=O)OCC1=CS[C@@H]2[C@H](NC(=O)Cc3cccs3)C(=O)N2C1C(=O)O
Solvent: O
Product: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)O)C(CO)=CS[C@H]12
Reaction time: 4.25 h
Yield: 52.5 %

Procedure:
A suspension of 3-acetoxymethyl-7β-(2-thienylacetamido)ceph-2-em-4-carboxylic acid (42 g.) in water (400 ml.) was flushed with nitrogen and potassium carbonate (43 g.) added. The mixture was treated with water (200 ml.) to effect complete solution and methanol (50 ml.) added. The solution was stored at 37° for 4.25 hours and then at 22° for 17 hours. The methanol was removed in vacuo and the mixture diluted with water (200 ml.) and stirred with ethyl acetate (800 ml.). The pH of the mixture was adjusted to 2.5 with orthophosphoric acid and the organic layer separated and washed with water and dried. The ethyl acetate was evaporated in vacuo until crystallisation of the product started, and the mixture cooled. Filtration gave the title compound (19.7 g., 52.5%) as fine needles, m.p. 151.5°-152° (decomp), [α]D + 465° (tetrahydrofuran), λmax. 234 nm. (ε 14,400), νmax. 3250 (NH and bonded OH), 2600 and 1725 (CO2H), 1755 (β-lactam) and 1650 and 1520 cm-1 (CONH), τ (D2O-sodium bicarbonate) 2.65 and 3.0 (thienyl, 3-proton complex), 3.7 (C(2) -H), broad s), 4.62 (C(2) -H, d, J 4.5 Hz), 4.74 (C(6) -H, d, J 4.5 Hz), 5.15 (C(4) -H, broad s), 5.8 (CH2OH, broad s) and 6.12(CH2CONH, s). (Found: C, 47.4; H, 4.05; N, 7.65; s 18.0; Calc. for C14H14N2O5S2 : C, 47.5; H, 3.9; N, 7.9; S, 18.1%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([CH2:11][Cl:12])[CH:3]=1.[Na].[CH2:14]([OH:16])[CH3:15]>C(OCC)C>[CH2:14]([O:16][C:2]1[N:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[N:5]=[C:4]([CH2:11][Cl:12])[CH:3]=1)[CH3:15]
Reactant: CC(C)c1nc(Cl)cc(CCl)n1
Reactant: CCO
Agent: [Na]
Solvent: CCOCC
Product: CCOc1cc(CCl)nc(C(C)C)n1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 9.6 g (0.047 mol) of 6-chloro-4-chloromethyl-2-isopropyl-pyrimidine (see Example 61) in 40 ml of absolute ethanol is treated dropwise during 3 hours at 0° C. with a solution of 1.24 g (0.054 mol) of sodium in ethanol and the mixture is stirred at 0° C. for 3 hours and then at room temperature for 16 hours. The mixture is then taken up in diethyl ether and the solution is washed neutral with sodium chloride solution, dried over anhydrous sodium sulphate and freed from solvent under reduced pressure. After distillation of the oily residue in a high vacuum there is obtained 6-ethoxy-4-chloromethyl-2-isopropyl-pyrimidine, b.p. 52° C./0.07 mmHg, nD21 1.4955.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1.[Na].[CH3:22][SH:23].CN(C=O)C>O>[CH3:22][S:23][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[CH:12]=1
Reactant: Fc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Reactant: CS
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1cnccc1-c1cc2cc(C(F)(F)F)ccc2o1
Yield: 95 %

Procedure:
A mixture of 0.30 g of 3-fluoro-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine, 75 mg of methyl mercaptan sodium salt and 4 ml of DMF was stirred under ice-cooling for 1 hour. To this mixture was added 37 mg of methyl mercaptan sodium salt, and the mixture was stirred under ice-cooling for further 1 hour. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.31 g of 3-methylthio-4-[5-(trifluoromethyl)benzofuran-2-yl]pyridine (hereinafter, referred to as “Present Active Compound 11”).
Reaction SMILES: C([O:8][C:9]1[CH:16]2[CH:12]([CH2:13][CH:14]([CH:17]=O)[CH2:15]2)[C:11](=[O:19])[C:10]=1[C:20]1[C:25]([CH2:26][CH3:27])=[CH:24][C:23]([CH3:28])=[CH:22][C:21]=1[CH2:29][CH3:30])C1C=CC=CC=1.[CH:31](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:32]([CH3:34])=[O:33]>ClC(Cl)Cl>[CH2:26]([C:25]1[CH:24]=[C:23]([CH3:28])[CH:22]=[C:21]([CH2:29][CH3:30])[C:20]=1[CH:10]1[C:9](=[O:8])[CH:16]2[CH:12]([CH2:13][CH:14]([CH2:17][CH2:31][C:32](=[O:33])[CH3:34])[CH2:15]2)[C:11]1=[O:19])[CH3:27]
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCc1cc(C)cc(CC)c1C1=C(OCc2ccccc2)C2CC(C=O)CC2C1=O
Solvent: ClC(Cl)Cl
Product: CCc1cc(C)cc(CC)c1C1C(=O)C2CC(CCC(C)=O)CC2C1=O

Procedure:
1.87 g (4.65 mmol) of 6-(benzyloxy)-5-(2,6-diethyl-4-methylphenyl)-4-oxo-1,2,3,3a,4,6a-hexahydropentalene-2-carbaldehyde (compound I-a-2) and 1.63 g (5.11 mmol) of acetonylidenetriphenylphosphorane in 40 ml of trichloromethane are stirred at room temperature for 12 h. The solvent is then removed, and the residue is purified chromatographically on silica gel (mobile phase ethyl acetate/hexane 1:5). This gives 1.37 g (66%) of 3-benzyloxy-2-(2,6-diethyl-4-methylphenyl)-5-(3-oxobut-1-enyl)-4,5,6,6a-tetrahydro-3aH-pentalen-1-one as a colourless oil.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>O1CCCC1>[Cl:14][CH2:15][CH2:16][CH2:17][C:18]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:19]
Reactant: O=C(Cl)CCCCl
Reactant: c1ccc(Nc2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(CCCCl)N(c1ccccc1)c1ccccc1

Procedure:
A solution 22.8 g (0.14 mole) of diphenylamine in 150 ml of tetrahydrofuran was added dropwise to a solution of 9.9 g (0.07 mole) of 4-chlorobutyryl chloride in 100 ml of tetrahydrofuran. The reaction mixture was stirred mechanically and the temperature maintained between 5° C. and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates and the filtrate was concentrated under reduced pressure to give a yellow solid. The solid was purified by column chromatography using 300 g of silica gel on a 65 cm×4 cm column, eluted with 10% ethyl acetate in hexane. The fractions containing the desired product were combined and concentrated under reduced pressure to yield 16.8 g (88%) of white, crystalline solid, mp 78°-79° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1.C(=O)(OC(C)(C)C)[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.C(N(CC)CC)C>C1COCC1>[C:23]([O:22][C:20]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1)=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(CN)cnc1C(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CNC(=O)OC(C)(C)C)cnc1C(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
Combine ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate hydrochloride (17.849 mmol, 4.760 g), THF (180 mL) and tert-butoxycarbonyl tert-butyl carbonate (21.419 mmol, 4.675 mL). Stir the mixture at room temperature for about 10 minutes. Add triethylamine (5.225 mL, 37.484 mmol), and stir at room temperature 16 hours. Remove the solids by vacuum filtration, and rinse with EtOAc. Concentrate the filtrate under reduced pressure. Purify the resulting yellow oil by silica gel chromatography (220 g RediSep® silica gel column) eluting with a gradient of 5-45% EtOAc gradient in hexane to give the title compound (3.62 g, 68% yield) as a light yellow crystalline solid. 1H NMR (399.80 MHz, d6-DMSO) δ 8.71 (d, J=2.1 Hz, 1H), 8.15-8.13 (m, 1H), 7.56-7.24 (m, 2H), 4.33 (q, J=7.1 Hz, 2H), 4.24-4.21 (m, 2H), 1.36 (s, 9H), 1.30 (t, J=7.1 Hz, 3H). LCMS (m/z) 331 (M+1).
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][C:15]([C:21]([OH:23])=O)=[CH:14][CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C(=O)C.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:43][C:44](=[NH:46])[CH3:45]>O>[CH:1]1([C:7]2[N:11]3[C:12]4[C:17]([NH:18][C:19](=[O:20])[C:10]3=[CH:9][N:8]=2)=[CH:16][C:15]([C:21]2[O:23][N:46]=[C:44]([CH3:45])[N:43]=2)=[CH:14][CH:13]=4)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=N)NO
Reactant: O=C(O)c1ccc2c(c1)[nH]c(=O)c1cnc(C3CCCCC3)n12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1noc(-c2ccc3c(c2)[nH]c(=O)c2cnc(C4CCCCC4)n23)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Cyclohexyl-4-oxo-4,5-dihydroimidazo[1,5-a]quinoxaline-7-carboxyic acid as synthesized in Example 58, 300 mg, N,N-dimethylacetamide 5 mL and 1,1′-carbonyldiimidazole 266 mg were mixed and stirred for 30 minutes at room temperature. To the reaction liquid 143 mg of N-hydroxyacetamidine was added, followed by 12 hours' stirring at 110° C. After returning it to the room temperature, water was added thereto and the precipitated matter was recovered by filtration. Drying the precipitate by heating under reduced pressure, 210 mg of the title compound was obtained.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][CH2:7][C@H:6]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:5]1)=[N+]=[N-].[H][H]>C(O)C.[Pt]=O>[C:13]([Si:10]([CH3:12])([CH3:11])[O:9][C@H:6]1[CH2:7][CH2:8][C@H:4]([NH2:1])[CH2:5]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N=[N+]=[N-])C1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N)C1

Procedure:
A mixture of (±)-trans-(3-azido-cyclopentyloxy)-tert-butyl-dimethyl-silane (400 mg, 1.66 mmol) (from Example 9b supra) and platinum oxide (38 mg, 0.17 mmol) (Aldrich) in ethanol (6 mL) was stirred under 1 atmosphere of hydrogen pressure for 2 hours. The reaction mixture was then filtered. The solids were washed with tetrahydrofuran (approx. 40 mL) and the combined organic layer was evaporated under reduced pressure to give (±)-trans-3-(tert-butyl-dimethyl-silanyloxy)-cyclopentylamine as a colorless liquid. (Yield 270 mg, 76%).
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[CH2:16][CH:17]([C:19]2[C:20]([CH3:31])=[N:21][O:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=2)[OH:18])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:45]=[CH:44][C:43](B3OC(C)(C)C(C)(C)O3)=[CH:42][CH:41]=2)[CH2:39][CH2:38]1)[CH3:33]>>[CH2:32]([O:34][C:35](=[O:55])[CH2:36][C:37]1([C:40]2[CH:41]=[CH:42][C:43]([C:27]3[CH:26]=[CH:25][C:24]([C:23]4[O:22][N:21]=[C:20]([CH3:31])[C:19]=4[CH:17]([OH:18])[CH2:16]/[CH:15]=[CH:14]/[C:11]4[CH:10]=[CH:9][C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:13][CH:12]=4)=[CH:29][CH:28]=3)=[CH:44][CH:45]=2)[CH2:38][CH2:39]1)[CH3:33]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccc(Cc2ccccc2)cc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccc(Cc5ccccc5)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 28, Step 1, using (E)-4-(4-benzyl-phenyl)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-but-3-en-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([OH:23])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:34][C:35]1([CH3:39])[CH2:38][NH:37][CH2:36]1>>[NH2:34][C:35]1([CH3:39])[CH2:38][N:37]([C:15]2[C:16]([F:18])=[CH:17][C:10]3[C:11]([CH:14]=2)=[N:12][C:13]2[N:4]([CH:1]4[CH2:2][CH2:3]4)[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[C:7](=[O:20])[C:8]=2[CH:9]=3)[CH2:36]1
Reactant: O=C(O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Reactant: CC1(N)CNC1
Agent: CS(=O)(=O)O
Product: CC1(N)CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)C1
Yield: 89 %

Procedure:
8-(3-Amino-3-methyl-1-azetidinyl)-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]-naphthyridine-3-carboxylic acid was prepared under the conditions described in Example 16, but starting with 1.58 g of 1-cyclopropyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid and 2.22 g of 3-amino-3-methylazetidine dimethanesulphonate. 1.7 g of 8-(3-amino-3-methyl-1-azetidinyl)-1-cyclopropyl-7-fluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 298° C.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]([CH3:16])=[N:14][C:13]2[C:8](=[C:9](B3OC(C)(C)C(C)(C)O3)[CH:10]=[CH:11][CH:12]=2)[N:7]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[NH:28][C:29]2[CH2:30][CH2:31][CH2:32][C:33](=[O:36])[C:34]=2[CH:35]=1>O1CCOCC1.O.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]>[C:1]([NH:5][C:6]1[C:15]([CH3:16])=[N:14][C:13]2[C:8]([N:7]=1)=[C:9]([C:27]1[NH:28][C:29]3[CH2:30][CH2:31][CH2:32][C:33](=[O:36])[C:34]=3[CH:35]=1)[CH:10]=[CH:11][CH:12]=2)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1CCCc2[nH]c(Br)cc21
Reactant: Cc1nc2cccc(B3OC(C)(C)C(C)(C)O3)c2nc1NC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCCC4=O)c2nc1NC(C)(C)C
Temperature: 105 °C
Yield: 77 %

Procedure:
A mixture of N-(tert-butyl)-3-methyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoxalin-2-amine (174b) (222.6 mg, 0.652 mmol), 2-bromo-6,7-dihydro-1H-indol-4(5H)-one (303a; 209 mg, 0.978 mmol), K2PO4 (415 mg, 1.957 mmol), (Strem Chemicals, Inc., 31.1 mg, 0.065 mmol), and Pd2dba3 (Aldrich, 29.9 mg, 0.033 mmol) in a mixture of dioxane (4.5 mL) and water (0.900 mL) was heated under argon at 105° C. for 1 h. The reaction mixture was subsequently cooled to RT and diluted with water (30 mL). The resulting mixture was extracted with 5% MeOH/DCM (3×30 mL), and the combined extracts were dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes) furnished 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-indol-4(5H)-one (175 mg, 0.502 mmol, 77% yield) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.52 (1H, br. s.), 7.96 (1H, dd, J=7.6, 1.0 Hz), 7.73 (1H, d, J=7.8 Hz), 7.40 (1H, t, J=7.8 Hz), 7.08 (1H, d, J=2.0 Hz), 4.89 (1H, s), 2.93 (2H, t, J=6.2 Hz), 2.60 (3H, s), 2.51-2.57 (2H, m), 2.23 (2H, quin, J=6.3 Hz), 1.68 (9H, s). m/z (ESI, +ve) 349.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[CH3:7][CH:8]([C:11](=O)[CH2:12][CH2:13][CH2:14][CH3:15])[C:9]#[N:10]>C1(C)C=CC=CC=1>[NH2:10][C:9]1[N:3]2[N:4]=[CH:5][CH:6]=[C:2]2[N:1]=[C:11]([CH2:12][CH2:13][CH2:14][CH3:15])[C:8]=1[CH3:7]
Reactant: Nc1cc[nH]n1
Reactant: CCCCC(=O)C(C)C#N
Solvent: Cc1ccccc1
Product: CCCCc1nc2ccnn2c(N)c1C
Temperature: 115 °C

Procedure:
A toluene solution (2.5 ml) containing 1.8 g of 3-aminopyrazole and 3 g of 2-methyl-3-oxoheptanenitrile was heated at 115° C. for 3.5 hours. Toluene was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate and washed with diethyl ether to provide 2.4 g of the title object compound as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:14][CH2:13][O:12][C:11]=12)[C:6]([OH:8])=O.Cl.[CH2:16]([O:18][CH2:19][CH2:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[C:22]1[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][C:39]2([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:43][CH2:42][NH:41][CH2:40]2)[CH2:33][CH2:32]1)[CH3:17]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[O:14][CH2:13][O:12][C:11]=12)[C:6]([N:41]1[CH2:42][CH2:43][C:39]([CH2:38][CH2:37][N:34]2[CH2:35][CH2:36][CH:31]([NH:30][C:22]3[N:21]([CH2:20][CH2:19][O:18][CH2:16][CH3:17])[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[N:23]=3)[CH2:32][CH2:33]2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:40]1)=[O:8]
Reactant: COc1cc(C(=O)O)cc2c1OCO2
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)c5c(c4)OCO5)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 3-methoxy-4,5-methylenedioxybenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[OH:13].[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21]([N+]([O-])=O)[CH:20]=[CH:19][N:18]=1>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:13][C:21]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:16])[CH:22]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: CCOC(=O)c1ccc(F)c(O)c1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1ccc(F)c(Oc2ccnc(Cl)c2)c1
Yield: 88.8 %

Procedure:
Using the method of Example 3, Step A, ethyl 4-fluoro-3-hydroxybenzoate (2.90 g, 15.8 mmol), 60% sodium hydride in mineral oil (631 mg, 15.8 mmol), and 2-chloro-4-nitropyridine (2.50 g, 15.8 mmol) were reacted to provide ethyl 4-fluoro-3-(2-chloropyridin-4-yloxy)benzoate (4.15 g, 89% yield) as a clear oil. 1H NMR-(CDCl3) δ 8.27 (d, 1H), 8.02 (m, 1H), 7.90 (d, 1H), 7.30 (t, 1H), 6.78-6.83 (m, 2H), 4.39 (q, 2H), 1.40 (t, 3H).