Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[O:11]CCCOC)C.[CH2:18]([O:20][C:21](=O)[C:22]1C=CC=N[C:23]=1[OH:28])C.COCCCBr>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:18][O:20][CH2:21][CH2:22][CH2:23][O:28][N:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([O:3][CH3:1])=[O:17])[C:6]1=[O:11]
Reactant: CCOC(=O)c1cccnc1OCCCOC
Reactant: CCOC(=O)c1cccnc1O
Agent: [Ag+2]
Agent: COCCCBr
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COCCCOn1cccc(C(=O)OC)c1=O

Procedure:
2-(3-Methoxypropoxy)-nicotinic acid ethyl ester: 2-Hydroxy-nicotinic acid ethyl ester (1.67 g), 3-methoxypropyl bromide (2.3 g) and silver carbonate (1.38 g) in toluene (80 ml) are reacted in accordance with the procedure described by Labaudiniere et al. (J. Med. Chem. 1992, 35, 4315-4324). Purification of the crude product by FC (dichloromethane-methanol-conc. ammonia 95:5:1) yields 1-(3-methoxypropoxy)-3-carbomethoxy-2(1H)-pyridinone (1.1 7 g), Rf (dichloromethane-methanol-conc. ammonia 95:5:1)=0.59, in the form of a pale-yellow oil, as well as the title compound (0.93 g), Rf (dichloromethane-methanol-conc. ammonia 95:5:1)=0.79, in the form of a yellowish oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[CH3:10][NH2:11]>CC(C)=O>[NH2:11][C:10]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:3][CH3:4])[N:1]=1
Reactant: Nc1nc(Cl)nc(Cl)n1
Reactant: CN
Solvent: CC(C)=O
Product: CNc1nc(N)nc(Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-4,6-dichloro-1,3,5-triazine (0.2 mole) in 200 ml reagent grade acetone was cooled to 0° C. Two equivalents of 40% aqueous methylamine were added dropwise keeping the temperature less than 10° C.; solids precipitated during the addition. The reaction was then warmed to room temperature and stirred overnight under N2.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1.C(OCC)C>O1CCCC1.O>[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])[OH:24])=[CH:21][CH:20]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: C#C[Si](C)(C)C
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CN(C)c1ccc(C(O)C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
Place lithium hexamethyldisilazane (12 mL of a 1M solution in tetrahydrofuran, 12 mmol) under an argon atmosphere and cool to 0° C. Add trimethylsilylacetylene (1.7 mL, 12 mmol) and stir for 1 hour at 0° C. Add 4-dimethylaminobenzaldehyde (1.49 g, 10 mmol) in tetrahydrofuran (25 mL). Allow to warm to room temperature and stir for 3 hours. Pour the mixture into ethyl ether and water, separate the organic phase and evaporate the solvent in vacuo. Filter the oil through silica gel (20% ethyl acetate/hexane) and evaporate the solvent in vacuo to yield 2.26 g of the title compound.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH2:17])[CH:14]([CH3:16])[CH3:15]>>[CH2:13]([NH:17][C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:14]([CH3:16])[CH3:15]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: CC(C)CN
Product: CCCCCCC/C=C/C(=O)NCC(C)C

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and isobutylamine as starting materials to give the aimed compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:20][CH3:21])=[C:11]([CH:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]3=[O:19])[N:12]=2)=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]3[C:17](=[O:18])[CH2:16][CH2:15][C:14]=3[O:19][CH3:22])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CCc1sc(-c2ccc(Cl)cc2)nc1C1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCc1sc(-c2ccc(Cl)cc2)nc1C1=C(OC)CCC1=O
Temperature: 40 °C
Yield: 58.3 %

Procedure:
To a solution of 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-cyclopentane-1,3-dione (650 mg, 2.03 mmol) in acetone (10 ml) was added potassium carbonate (553 mg, 4 mmol), followed by iodomethane (248 μl, 4 mmol), and the reaction heated to 40° C. for 6 hours. The solvent was then removed from the crude reaction mixture under reduced pressure and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dry loaded onto silica and purified by flash chromatography to give 2-[2-(4-Chloro-phenyl)-5-ethyl-thiazol-4-yl]-3-methoxy-cyclopent-2-enone (395 mg).
Reaction SMILES: C1C=CC2N(O)[N:8]=[N:7]C=2C=1.CCN=C=NCCCN(C)C.Cl.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([I:43])=[CH:29][N:30]2[S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:26][C:25]=1[C:44]([OH:46])=O.NN>O.CN(C=O)C>[F:23][C:24]1[CH:32]=[C:31]2[C:27]([C:28]([I:43])=[CH:29][N:30]2[S:33]([C:36]2[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=2)(=[O:35])=[O:34])=[CH:26][C:25]=1[C:44]([NH:7][NH2:8])=[O:46]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)O)c(F)cc32)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NN
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)c(F)cc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 245.2 %

Procedure:
HOBt (Aldrich, St. Louis, Mo., 303 mg, 2.24 mmol), EDC HCl (430 mg, 2.242 mmol) and 6-fluoro-3-iodo-1-tosyl-1H-indole-5-carboxylic acid (858 mg, 1.87 mmol) were weighed into a 250 mL round bottomed flask and treated with DMF (7 mL). The resulting solution was stirred at RT for 30 min. The reaction mixture was then treated with anhydrous hydrazine (0.29 mL, 9.34 mmol) and stirred at RT for 30 min. The reaction mixture was diluted with water resulting in precipitate formation. The solid was collected by filtration, washed with water, and dried under high vacuum for 3 h at 50° C., affording crude 6-fluoro-3-iodo-1-tosyl-1H-indole-5-carbohydrazide (2.17 g) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 473.9 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.59 (1H, br. s.), 8.17 (1H, s), 8.01 (2H, d, J=8.4 Hz), 7.97 (5H, s), 7.82 (1H, d, J=10.8 Hz), 7.50 (1H, d, J=6.5 Hz), 7.45 (3H, d, J=8.2 Hz), 4.56 (2H, br. s.), 4.11 (3H, br. s.), 2.36 (4H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].CC1C2C=C3[C:33]4([C:41]5[C:36](=CC=CC=5)NC4=O)[CH2:32][O:31][C:29]3=[CH:30]C=2ON=1.BrCC1CCCCO1.BrCC1OC(C(F)(F)F)=CC=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:30][CH:29]1[CH2:36][CH2:41][CH2:33][CH2:32][O:31]1)[C:10]3=[O:18]
Reactant: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Agent: FC(F)(F)c1ccc(CBr)o1
Product: COc1ccc2c(c1)OCC21C(=O)N(CC2CCCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)tetrahydro-2H-pyran to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 6-methoxy-1′-(tetrahydro-2H-pyran-2-ylmethyl)spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless foam; 1H NMR (300 MHz, CDCl3) δ 7.28 (dd, J=7.5, 7.5 Hz, 1H), 7.20-6.98 (m, 3H), 6.66-6.49 (m, 2H), 6.41-6.33 (m, 1H), 4.99-4.91 (m, 1H), 4.74-4.66 (m, 1H), 4.02-3.31 (m, 8H), 1.92-1.19 (m, 6H); MS (ES+) m/z 366.4 (M+1).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])(C)(C)C.[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([Cl:37])[C:28]3[C:38](=[O:46])[O:39][C:40]4([CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)[C:27]=3[C:26]1=2)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>O1CCCC1.CCCCC>[Si:17]([O:24][C@H:25]1[CH2:34][C:33]([CH3:36])([CH3:35])[CH2:32][C:31]2[N:30]=[C:29]([Cl:37])[C:28]3[C:38]([C:2]4[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=4)([OH:46])[O:39][C:40]4([CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)[C:27]=3[C:26]1=2)([C:20]([CH3:21])([CH3:22])[CH3:23])([CH3:19])[CH3:18]
Reactant: FC(F)(F)c1ccc(I)cc1
Reactant: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)OC3=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O[Si](C)(C)C(C)(C)C)C1)C1(CCOCC1)OC3(O)c1ccc(C(F)(F)F)cc1
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
2.31 g 1-Iodo-4-(trifluoromethyl)benzene are dissolved in 30 ml tetrahydrofurane, cooled to −65° C. and treated dropwise with 9.2 ml of a 1.6 M solution of tert.-butyllithium in n-pentan. The mixture is stirred for 30 minutes and then a solution of 1.9 g (S)-9-(tert-butyldimethylsilyloxy)-4-chloro-7,7-dimethyl-2′,3′,5′,6,6′,7,8,9-octahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3-one in 30 ml tetrahydrofurane is added dropwise. The mixture is stirred for 30 minutes at −65° C. and for 30 minutes at −50° C. Then the reaction is quenched by addition of 0.5 ml methanol. The mixture is partitioned between 0.1 M hydrochloric acid and ethylacetate. The aqueous phase is twice extracted with ethylacetate. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 80:20).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.C1(NN)CCCCC1.[CH:18]1([C:21]2[N:25]([CH:26](C)C)[N:24]=[CH:23][C:22]=2C=O)[CH2:20][CH2:19]1>>[CH:23]1([N:24]2[C:3]([CH3:5])=[C:2]([CH:1]=[O:7])[CH:26]=[N:25]2)[CH2:19][CH2:20][CH2:18][CH2:21][CH2:22]1
Reactant: CCOC(=O)CC(C)=O
Reactant: CC(C)n1ncc(C=O)c1C1CC1
Agent: NNC1CCCCC1
Product: Cc1c(C=O)cnn1C1CCCCC1

Procedure:
1-Cyclohexyl-5-methyl-1H-pyrazole-4-carbaldehyde was prepared from ethyl acetoacetate and cyclohexyl hydrazine (TCI) in the same manner as 5-cyclopropyl-1-isopropyl-1H-pyrazole-4-carbaldehyde (Example 49).
Reaction SMILES: Cl.[CH2:2]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[CH2:4][NH:3]1.[OH-].[Na+].[C-:12]#[N:13].[Na+]>P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[CH:2]1([C:12]#[N:13])[CH:6]2[CH2:7][CH2:8][CH2:9][CH:5]2[CH2:4][NH:3]1
Reactant: [C-]#N
Reactant: C1CC2CNCC2C1
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: N#CC1NCC2CCCC21
Reaction time: 24 h
Yield: 85.6 %

Procedure:
To a 50-mL 3-neck flask under air was added 25 mL of 100 mM pH 8.0 potassium phosphate buffer and 400 mg of octahydrocyclopenta[c]pyrrole hydrochloride, 500 mg of Na2S2O5 and the pH was adjusted to approximately 7.5 with 10 N NaOH. To the pH adjusted solution was added 30 pt of A. niger catalase suspension (Sigma Aldrich; catalog number C-3515) and 300 mg of monoamine oxidase powder (prepared by the method of Example 2 (with SEQ ID NO 10 in pH 8.0 potassium phosphate buffer. The resulting pale yellow solution was stirred under air for 24 hours during which time the pH was maintained at 7.5 via feedback controlled addition of 1 N NaOH in 1-5 μL portions. After stirring for 48 hours, 300 mg of NaCN was added to the reaction mixture raising the pH to ±9.9. After stirring at room temperature (about 21° C.) for an additional 1 hour, the mixture was extracted with ethyl acetate. After phase separation and solvent evaporation, 316 mg of octahydrocyclopenta[c]pyrrole-1-carbonitrile was isolated (82% yield). 1H-NMR showed ˜90% (1S,3aR,6aS), “trans” and ±10% of the (1R,3aR,6aS) epimer, “cis.” (1H-NMR (300 MHz, CDCl3) spectrum: δ 3.95 (d, J=6.6, cis aminonitrile methine H), 3.62 (d, J=1.2; trans aminonitrile methine H), 3.15 (m, 1H), 2.71 (m, 2H), 2.62 (m, 1H), 1.63-1.92 (m, 3H), 1.55 (m, 1H), 1.22-1.45 (m, 3H)).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH:23]([C:30](=O)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=O)=[CH:15][CH:14]=2)[N:10]=1.C([O-])(=O)C.[NH4+:43].C(O)(=O)C>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20]3[O:22][C:23]([CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:43]=3)=[CH:15][CH:14]=2)[N:10]=1
Reactant: [NH4+]
Reactant: COC(=O)CCC(OC(=O)Cc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)CCc1oc(Cc2ccc(OCc3nc(-c4ccco4)oc3C)cc2)nc1-c1ccccc1
Yield: 77.3 %

Procedure:
A mixture of methyl 4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]phenyl]acetoxy-5-oxo-5-phenylpentanoate (1.49 g), ammonium acetate (777 mg) and acetic acid (5 ml) was refluxed for 3 hrs. After cooling, ethyl acetate was added to the reaction mixture. The obtained ethyl acetate solution was washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[2-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzyl]-4-phenyl-5-oxazolyl]propionate (1.11 g, yield 77%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio).
Reaction SMILES: [CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2].N1C=CC=CC=1.[Cl:36][C:37](Cl)([O:39]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[CH2:1]([C:3]1[CH:29]=[CH:28][CH:27]=[CH:26][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@:12]([C@@H:20]1[CH2:25][CH2:24][CH2:23][N:22]([C:37]([Cl:36])=[O:39])[CH2:21]1)([OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:18])[CH3:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCNC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccccc1Oc1ccccc1[C@](O)(CCCCOC)[C@@H]1CCCN(C(=O)Cl)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-1-(2-(2-ethylphenoxy)phenyl)-5-methoxy-1-((R)-piperidin-3-yl)pentan-1-ol (19.9 mg, 0.05 mmol) and pyridine (20 μL, 0.15 mmol) in CH2Cl2 (2 mL) at 0° C. was added triphosgene (22.7 mg, 0.08 mmol) in CH2Cl2 (0.5 mL). The resulting solution was warmed to rt, and stirred for 1 h. The completion of reaction was confirmed by LC-MS, and the product was used for next step without workup.
Reaction SMILES: [C:1]([C:3]1(O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.NC1C=CC=CC=1>[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ru].[Ru].[Ru].ClCCl>[CH3:2][C:1]1[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: Nc1ccccc1
Reactant: C#CC1(O)CCCCC1
Agent: [Ru]
Agent: Cl
Agent: [C-]#[O+]
Solvent: ClCCl
Product: CC1=Nc2ccccc2C12CCCCC2
Temperature: 120 °C
Reaction time: 12 h
Yield: 1.2 %

Procedure:
1-Ethynyl-1-cyclohexanol (1.242 g, 10 mmol), aniline (0.931 g, 10 mmol), Ru3(CO)12 (32.0 mg, 0.05 mmol) and aniline hydrochloride (0.259 g, 2.0 mmol) were placed in a 10 ml round-bottomed flask, and the mixture was stirred at 120° C. for 12 hours. After cooling, dichloromethane (3 mL) was added, and the organic layer was washed twice with 1 M hydrochloric acid (2 mL) and once with water (2 mL). The organic layer was dried over sodium sulfate, and the solvent was distilled away, whereby 2-methyl-3H-indole-3-spiro-1′-cyclohexane (24 mg; 0.12 mmol; yield, 1.2%; purity, 95% or more) was obtained.
Reaction SMILES: Br[C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH3:11][NH:12][C:13]([C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.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]>[NH2:6][C:5]1[C:4]([F:10])=[CH:3][C:2]([C:18]2[CH:19]=[CH:20][C:15]([C:13]([NH:12][CH3:11])=[O:14])=[CH:16][CH:17]=2)=[C:8]([CH3:9])[CH:7]=1
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(N)c(F)cc1Br
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: CNC(=O)c1ccc(-c2cc(F)c(N)cc2C)cc1
Temperature: 130 °C

Procedure:
The mixture of 4-bromo-2-fluoro-5-methylaniline (203 mg, 1.0 mmol), 4-(methylcarbamoyl)phenylboronic acid (179 mg, 1.0 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (82 mg, 0.2 mmol), Pd2(dba)3 (91 mg, 0.1 mmol), and K3PO4 (424 mg, 2.0 mmol) in 5.0 mL of n-butanol is degassed and heated at 130° C. for 1 h. The reaction mixture is concentrated in vacuo. The crude product mixture is partitioned between EtOAc and brine, the collected organic extracts are dried (Na2SO4), concentrated and purified with silica gel chromatography (EtOAc/hexanes:1/4) to afford 4′-amino-5′-fluoro-N,2′-dimethylbiphenyl-4-carboxamide; ESMS m/z 259.1 (M+H+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:12]1[CH2:17][CH2:16][CH2:15][C@@:14]([CH2:19][OH:20])([CH3:18])[CH2:13]1.[OH-].[Na+].[C:23]([O:27][C:28](=[O:31])[CH2:29]Br)([CH3:26])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:23]([O:27][C:28](=[O:31])[CH2:29][O:20][CH2:19][C@@:14]1([CH3:18])[CH2:15][CH2:16][CH2:17][N:12]([CH2:11][C@@H:2]2[O:1][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[O:4][CH2:3]2)[CH2:13]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C[C@]1(CO)CCCN(C[C@H]2COc3ccccc3O2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)COC[C@@]1(C)CCCN(C[C@H]2COc3ccccc3O2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 68.1 %

Procedure:
To a stirred solution of {(S)-1-[(S)-1-(2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]-3-methylpiperidin-3-yl}methanol (0.516 g, 1.8 mmol) in toluene (4 ml) was added tetrabutylammonium bromide (0.12 g) and 50% NaOH (4 ml). The mixture was stirred at RT for 15 min and bromoacetic acid tert-butyl ester (0.53 g) was added. After vigorous stirring at RT overnight, the reaction was quenched by addition of brine (15 ml) and the aqueous phase extracted twice with toluene. The combined organic phases were extracted with 1 M HCl solution and the acidic water phase was basified by addition of NaOH. Extraction with toluene and evaporation afforded the title compound (0.48 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: CO
Reactant: O=C(O)c1cc(Br)ncc1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)ncc1F
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-bromo-5-fluoroisonicotinic acid (1.5 g, 6.82 mmol) in methanol (75 ml), thionyl dichloride (2.5 ml, 34.09 mmol) was added drop-wise. The reaction mixture was stirred overnight. The solvent was removed under high vacuum. The residual solid was distilled at 90° C. under vacuum to get 1.3 g (81%) of pure methyl 2-bromo-5-fluoroisonicotinate:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][O:12]C)=[CH:7][C:6]=2[C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[C:4]([F:26])[CH:3]=1.ClCCl.B(Br)(Br)Br.O>ClCCl>[Cl:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][OH:12])=[CH:7][C:6]=2[C:5]([C:14]2[C:15](=[O:25])[N:16]([CH3:24])[C:17]([C:20]([F:22])([F:21])[F:23])=[CH:18][CH:19]=2)=[C:4]([F:26])[CH:3]=1
Reactant: COCc1cc2c(-c3ccc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2o1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Cn1c(C(F)(F)F)ccc(-c2c(F)cc(Cl)c3oc(CO)cc23)c1=O
Temperature: -65 °C
Reaction time: 1 h
Yield: 99.2 %

Procedure:
0.20 g (0.51 mmol) of 3-(7-chloro-5-fluoro-2-methoxymethylbenzofuran-4-yl)-1-methyl-6-trifluoromethyl-2-(1H)-pyridone was dissolved in 10 ml of dichloromethane, and 1.54 ml (1.54 mmol) of a 1.0 M boron tribromide dichloromethane solution was added thereto at −65° C. The mixture was stirred at −65° C. for 1 hour and then poured into water, followed by stirring at room temperature for 30 minutes. Then, it was extracted with dichloromethane. After washing with water, the organic layer was dried over anhydrous magnesium sulfate. Dichloromethane was distilled off under reduced pressure. Then, the obtained crude crystals were washed with n-hexane to obtain 0.19 g (yield: 99%) of the desired product. Melting point: 145-147° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH3:15])[CH2:13][OH:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C)C=O>[Si:16]([O:14][CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:15])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: C[C@H](CO)NC(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Yield: 84.7 %

Procedure:
A procedure similar to that described in Preparation 8 was repeated, except that 12.54 g of (R)-2-benzyloxycarbonylaminopropanol (prepared as described in Preparation 23), 9.97 g of t-butyldimethylsilyl chloride, 4.90 g of imidazole and 150 ml of anhydrous dimethylformamide were used, to give 16.43 g of the title compound having an Rf value of 0.54 (on silica gel thin layer chromatography, using a 1:4 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=O)=[CH:24][C:23]=4OC)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=CC2[N:38](C)[C:39](=[O:52])C(F)(F)CN(C3CCCC3)C=2N=1.NC1C=C2C(CC(=O)N2)=CC=1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[C:29]5[C:25]([CH2:26][C:39](=[O:52])[NH:38]5)=[CH:24][CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Nc1ccc2c(c1)NC(=O)C2
Product: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc4c(c3)NC(=O)C4)ncc21

Procedure:
The title compound was synthesized using an analogous procedure to that described in connection with 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid from 2-Chloro-9-cyclopentyl-7,7-difluoro-5-methyl-8,9-dihydro-5H-pyrimido[5,4-b][1,4]diazepin-6(7H)-one and 6-aminoindolin-2-one. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45-1.86 (m, 6 H) 1.92-2.16 (m, 2 H) 3.39 (s, 3 H) 3.54 (s, 2 H) 3.87 (t, J=13.39 Hz, 2 H) 4.74 (quin, J=8.27 Hz, 1 H) 6.81 (d, J=8.34 Hz, 1 H) 7.00 (br. s., 1 H) 7.26 (s, 1 H) 7.50 (br. s., 1 H) 7.58 (s, 1 H) 7.97 (s, 1 H). [M+H] calc'd for C21H22F2N6O2, 429; found 429.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3[C:8](=[N:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:15])C(=O)[C:5]=2[N:4]=[CH:3][CH:2]=1.Cl>[OH-].[Na+]>[N:9]1[C:8]2[C:7](=[O:15])[C:5]3[C:14](=[CH:1][CH:2]=[CH:3][N:4]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C(=O)c2ncccc2-c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1c2ncccc2-c2cccnc21
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a solution of 200 ml of 10% sodium hydroxide was added 10 g (47 mmole) of 4,7-phenanthrolin-5,6-quinone. This was heated in a water bath at 70°-80° with magnetic stirring for 2 hours. Then the reaction was cooled in an ice bath and acidified with concentrated hydrochloric acid to pH 4-5, keeping the mixture below 20°. The precipitate of side product, 5,6-dihydroxy-4,7-phenanthroline was filtered off and the filtrate was extracted with 5×50 ml of chloroform. After drying with sodium sulfate, the solvent was evaporated, yielding 2.6 g of 1,8-diazafluoren-9-one, m.p. 233°-234.5°.