Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C@@H:14]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C)[CH2:15]2)[N:12]=[C:11]([C:30]([F:33])([F:32])[F:31])[CH:10]=1)=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:37]=[CH:36][CH:35]=[CH:34][C:4]=1[CH2:5][NH:6][C:7]([C:9]1[N:13]([C@@H:14]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][NH:21][CH3:22])[CH2:15]2)[N:12]=[C:11]([C:30]([F:31])([F:32])[F:33])[CH:10]=1)=[O:8]
Reactant: COc1ccccc1CNC(=O)c1cc(C(F)(F)F)nn1[C@@H]1CCN(CCN(C)C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCN1CC[C@@H](n2nc(C(F)(F)F)cc2C(=O)NCc2ccccc2OC)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.7 %

Procedure:
To a stirred solution of 77 (10 mg, 0.019 mmol) in CH2Cl2 (0.38 mL) was added TFA (0.073 mL, 0.951 mmol). The resulting solution was allowed to stir at room temperature for 2 h. The mixture was concentrated and the residue was purified by silica gel column chromatography with gradient of methanol (5-30%) in dichloromethane to afford 78 (10 mg, 80%) as a white solid. 1H NMR (DMSO-d6) δ(ppm): 9.11 (t, J=5.1 Hz, 1H), 7.38 (s, 1H), 7.27-7.19 (m, 2H), 7.00 (d, J=7.8 Hz, 1H), 6.91 (t, J=7.4 Hz, 1H), 5.83 (qi, J=9.0 Hz, 1H), 4.41 (q, J=6.1 Hz, 2H), 3.81 (s, 3H), 3.20-3.16 (m, 1H), 2.96-2.92 (m, 2H), 2.80-2.68 (m, 4H), 2.53 (d, J=2.2 Hz, 3H), 2.32-2.17 (m, 3H). LRMS (ESI): calc. 425.2; found 426.1 (MH)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=2)=[CH:5][N:4]=1.Cl.N1C=CC=CC=1>ClCCl>[F:19][C:16]([F:17])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[N:4][CH:5]=2)=[N:11][CH:12]=1
Reactant: COc1ccc(Oc2ccc(C(F)(F)F)cn2)cn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cn1
Temperature: 200 °C
Yield: 67.6 %

Procedure:
A mixture of 2-methoxy-5-(5-trifluoromethyl-pyridin-2-yloxy)-pyridine (0.28 g, 1.04 mmol) and pyridine hydrochloride (1.00 g, 8.65 mmol) was heated in a kugelrohr oven at 200° C. for 10 minutes. After cooling to room temperature, the reaction mixture is dissolved in dichloromethane and extracted with water, dried over sodium sulphate, filtered and evaporated in vacuo, yielding the title compound (180 mg, 68% yield) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.C([O:24][B:25](OCCC)[O:26]CCC)CC>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([B:25]([OH:26])[OH:24])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCOB(OCCC)OCCC
Reactant: Brc1cccc(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C

Procedure:
20 g (76 mmol) of 3-Benzyloxybromobenzene was dissolved in 200 mL of anhydrous THF and cooled to -78° C. under a nitrogen atmosphere. To the stirring solution, 90 mL of 1.6 M n-BuLi (83.6 mmol) was slowly added. After several minutes, 33.6 mL (83.6 mmol) tripropylborate was added and the reaction was allowed to slowly warm to ambient temperature over the next four hours. The reaction was quenched with the addition of 400 mL of 1N HCl. The reaction mixture was extracted three times with EtOAc. The EtOAc solution was washed twice with brine, dried with Na2SO4, and evaporated to dryness. The final product was crystallized from EtOAc-hexane. This yielded 10 g of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([N:33]([CH3:35])[CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([N:33]([CH3:35])[CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(-c2ccc(F)cc2)nc2ccccc12
Reactant: CN(C)c1ccc2c(c1O)CCNC2
Agent: Cl
Product: CN(C)c1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3ccccc13)C2
Yield: 5 %

Procedure:
Reaction of 2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-dimethylamino-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 4 (5% yield) as a brown solid. 1H NMR (300 MHz, CDCl3) δ 2.71 and 3.17 (2d, 6H), 2.85 and 3.09 (2t, 2H), 3.58 and 4.21 (2t, 2H), 4.48 and 5.09 (2s, 2H), 6.36 and 6.84 (2d, 1H), 6.96-7.25 (m, 3H), 7.57-8.15 (m, 5H), 8.62-8.69 (m, 2H); MS (ESI) m/z 443 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](OC1C=CC([N+]([O-])=O)=CC=1)=[O:19].[NH3:36]>O1CCCC1>[CH3:1][C:2]1[C:7](=[O:8])[C:6]([CH3:9])=[C:5]([CH3:10])[C:4](=[O:11])[C:3]=1[CH:12]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH2:36])=[O:19]
Reactant: N
Reactant: CC1=C(C)C(=O)C(C(CCCCCC(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)=C(C)C1=O
Solvent: C1CCOC1
Product: CC1=C(C)C(=O)C(C(CCCCCC(N)=O)c2ccccc2)=C(C)C1=O
Reaction time: 4 h
Yield: 87 %

Procedure:
To a stirred solution of p-nitrophenyl 7-(3,5,6-trimethyl-1,4-benzoquinon-2yl)-7-phenyl-heptanate (0.71 g, 1.5 mmoles) in tetrahydrofuran (7 ml) was added concentrated ammonia (1.0 ml) at room temperature and kept stirring for 4 hours. After the reaction was completed, the solvent was evaporated in a reduced pressure. To the residue was added aqueous potassium carbonate and then extracted with ethylacetate. The organic layer was washed with water, dried over magnesium sulfate. Evaporation of the solvent gave 7-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanamide (0.46 g, 87%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9](N)[CH:10]=1)[N:7]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([NH2:16])=[O:15])[CH2:6][CH2:5]2>CO.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[NH:16][C:14](=[O:15])[C:13]3[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=3[N:7]3[CH2:6][CH2:5][C:4]([CH:3]=1)=[C:8]23
Reactant: NC(=O)c1ccccc1N1CCc2cc(Cl)cc(N)c21
Solvent: CO
Solvent: ClCCl
Product: O=C1Nc2cc(Cl)cc3c2N(CC3)c2ccccc21
Reaction time: 2 h

Procedure:
2-(5-chloro-7-aminoindolin-1-yl)benzamide of Example 1c (28.7 g, 0.10 mole) was dissolved in methanol/dichloromethane (DCM) solution (1:9 v/v) at 35° C. Silica gel (510 gm) was added to absorb the starting material, then the solvent was removed as much as possible under vacuum (50° C., 25 mmHg pressure for 1 hr.) The reaction mixture was then heated at 145°-155° C. and mechanically stirred for 11/2 hours. The heating was stopped when the mixture started to turn brown. The combined material was placed onto a flash chromatography column (1 kg, silica gel 60, slurry packed with DCM), eluted with DCM (16 l) and 2% CH3OH in DCM (10 l). The fractions containing the desired product were pooled and concentrated to yield a solid, 16 gm, (59%), m.p. 252°-255° C.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[O:21]1[CH2:26][CH2:25][CH:24]([CH2:27][CH2:28][NH2:29])[CH2:23][CH2:22]1>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:29][CH2:28][CH2:27][CH:24]2[CH2:25][CH2:26][O:21][CH2:22][CH2:23]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Reactant: NCCC1CCOCC1
Product: COc1cc(CNCCC2CCOCC2)ccc1Oc1ccc(C(N)=O)cn1
Yield: 76.8 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-(tetrahydropyran-4-yl)ethylamine (0.0237 g, 0.84 mmol) gives the title compound (0.0545 g, 77.0%): TOF MS ES+ 386.2 (M+H)+, HRMS calcd for C2)H28N3O4 386.2080 (M+H)+, found 386.2076, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=4.3 min, 100% purity.
Reaction SMILES: C(NCCO[C:8]1[C:14]([CH3:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[CH3:16])(C)C.[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25])(=[O:20])=[O:19]>>[CH3:17][S:18]([NH:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([NH:12][C:11]1[CH:10]=[C:9]([CH3:16])[CH:8]=[C:14]([CH3:15])[CH:13]=1)=[O:25])(=[O:20])=[O:19]
Reactant: Cc1cc(N)cc(C)c1OCCNC(C)C
Reactant: CS(=O)(=O)Nc1ccccc1C(=O)Cl
Product: Cc1cc(C)cc(NC(=O)c2ccccc2NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.7 %

Procedure:
4-[2-(Isopropylamino)ethoxy]3,5-dimethylaniline (2.6 g) solution in dimethylformamido (15 ml) was added with 2-(methanesulfonamido)benzoyl chloride (3.0 g) and the mixture was stirred for 2 hours at room temperature. After being concentrated under vacuum, the reaction mixture was dissolved into chloroform (50 ml) and extracted with 1N sodium hydroxide (100 ml). Resultant aqueous layer was neutralized with 1N HCl (100 ml) and extracted with chloroform (150 ml). Chloroform layer obtained was concentrated and purified by silica-gel column chromatography (chloroform:methanol=10:1) to obtain 4′-[2-isopropylamino) ethoxy]-2-methanesulfonamido-3′,5′-dimethylbenzanilide (2.15 g) as white solid.
Reaction SMILES: F[C:2]1[CH:28]=[CH:27][C:5]2[N:6]=[C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)[S:8][C:4]=2[CH:3]=1.[Cl:29]C1SC2C=CC(Cl)=CC=2N=1>>[Cl:29][C:28]1[CH:2]=[CH:3][C:4]2[S:8][C:7]([C:9]3[C:10]([NH2:26])=[N:11][CH:12]=[C:13]([C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)[CH:19]=4)[CH:14]=3)=[N:6][C:5]=2[CH:27]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(F)cc2s1
Reactant: Clc1ccc2sc(Cl)nc2c1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2cc(Cl)ccc2s1

Procedure:
Same procedure as 3-(6-fluorobenzothiazol-2-yl)-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine except using 2,5-dichloro-1,3-benzothiazole in place of 2-chloro-6-fluorobenzothiazole to afford the title compound as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=2.10-2.22 (m, 2H), 2.22-2.30 (m, 2H), 3.12 (q, J=11.1 Hz, 2H), 3.42 (d, J=12.4 Hz, 2H), 4.47-4.55 (m, 1H), 7.56 (d, J=8.4 Hz, 1H), 8.03 (s, 1H), 8.19-8.24 (m, 2H), 8.26 (br. s., 1H), 8.35 (s, 1H), 8.52 (s, 1H), MS (ES+): m/z=411.09/413.10 (3:1) [MH+]. HPLC: tR=2.18 min (ZQ2, polar—5 min).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:29][N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:18]2[NH:19][C:20](=[O:21])[N:16]([C:12]3[CH:11]=[CH:10][C:9]([O:8][C:6]4[CH:5]=[CH:4][N:3]=[C:2]([C:33]5[CH:32]=[N:31][N:30]([CH3:29])[CH:34]=5)[CH:7]=4)=[C:14]([CH3:15])[N:13]=3)[N:17]=2)=[CH:23][CH:24]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1nc(-n2nc(-c3ccc(F)cc3)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
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: C1COCCO1
Solvent: O
Product: Cc1nc(-n2nc(-c3ccc(F)cc3)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 100 °C
Yield: 45.5 %

Procedure:
A suspension of Example A8 (0.300 g, 0.754 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.250 g, 1.202 mmol), K2CO3 (0.200 g, 1.447 mmol) in a mixture of dioxane/water (10:1) (11 mL) was degassed for 5 minutes with argon purge. The reaction mixture was treated with Pd(PPh3)4 (0.020 g, 0.017 mmol) and heated at 100° C. under argon over night. The solvent from the reaction mixture was completely evaporated and the residue was partitioned between DCM (30 mL) and water (30 mL). The organic layer separated and the aqueous layer extracted with dichloromethane (2×15 mL). The combined organics were dried and concentrated to a small volume and purified by silica gel chromatography (0-100% THF/DCM) to provide 3-(4-fluorophenyl)-1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5(4H)-one (0.152 g, 45%) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 12.71 (s, 1H), 8.38 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.98-7.94 (m, 4H), 7.74 (d, J=8.8 Hz, 1H), 7.40 (t, J=8.8 Hz, 2H), 7.23 (d, J=2.4 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.37 (s, 3H); MS (ESI) m/z: 444.2 (M+H+).
Reaction SMILES: [CH:1]1(Cl)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:7]=[CH:8][C:9]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[C:11]([OH:12])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([O:12][C:11]2[CH:10]=[C:9]([CH:17]=[CH:16][C:13]=2[O:14][CH3:15])[CH:8]=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ClC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 122.5 °C
Reaction time: 1.5 h

Procedure:
A mixture of cyclopentyl chloride (8.48 g, 0.08 moles), isovanillin (6.12 g, 0.04 moles) and potassium carbonate (1.1 g, 0.08 moles) in dimethylformamide (4.04 g) was stirred in the reactor (100 mL) at 120 to 125° C. for 1.5 hours. A sample was taken to verify the batch conversion. Result (GC): 0.5 area % isovanillin (target:≦1.0 area %). The mixture was cooled to 20° C. and filtered to remove the solid (potassium bicarbonate, potassium chloride). The wet cake was washed with methanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:7]=[CH:6][C:5]=1[F:22].Br[C:25]1[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=1>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:25]3[CH:26]=[N:27][N:28]([CH2:30][CH3:31])[CH:29]=3)[C:12]=2[CH3:21])[CH:7]=[CH:6][C:5]=1[F:22]
Reactant: COC(=O)c1cc(Sc2c(C)[nH]c3cc(Cl)ccc23)ccc1F
Reactant: CCn1cc(Br)cn1
Product: CCn1cc(-n2c(C)c(Sc3ccc(F)c(C(=O)OC)c3)c3ccc(Cl)cc32)cn1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 5-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-2-fluoro-benzoic acid methyl ester and 4-bromo-1-ethyl-1H-pyrazole.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](Cl)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].N1C=CC=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][C:11]1[O:12][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[N:14]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)Cc1cccc([N+](=O)[O-])c1
Reactant: Nc1ccccc1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1oc(Cc2cccc([N+](=O)[O-])c2)nc2ccccc12
Temperature: 120 °C

Procedure:
To a solution of commercially available (3-nitro-phenyl)-acetyl chloride (2.20 g, 11.05 mmol) in anhydrous DCM (9 mL) was added 2-aminobenzoic acid (0.76 g, 5.50 mmol). Pyridine (3 mL) was then added to the mixture and the reaction mixture was heated under microwave condition at 120° C. for 30 minutes, then diluted with dichloromethane and washed with NaHCO3 satured solution, then with water followed by brine. The organic phase was dried over Na2SO4, filtered and evaporated to give the 2-(3-nitro-benzyl)-benzo[d][1,3]oxazin-4-one intermediate as red oil. To a solution of 2-(3-nitro-benzyl)-benzo[d][1,3]oxazin-4-one in dry pyridine (10 mL) was added aminoguanidine hydrogencarbonate (0.90 g, 6.60 mmol) and the mixture was heated under microwave condition at 180° C. for 20 minutes. The solvent was then evaporated and the crude was purified by flash column chromatography on silica gel eluting with DCM/CH3OH 95/5 to afford the title compound as orange solid (0.35 g, 30% yield).
Reaction SMILES: [OH-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[C:9]1[CH:10]=[C:11]([C:15]([O:17]C)=[O:16])[CH:12]=[N:13][CH:14]=1>O1CCOCC1.CO>[N:3]1[CH:8]=[CH:7][CH:6]=[N:5][C:4]=1[C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[CH:12]=[N:13][CH:14]=1
Reactant: COC(=O)c1cncc(-c2ncccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)c1cncc(-c2ncccn2)c1
Reaction time: 0.5 h
Yield: 25 %

Procedure:
A 2 mol/L aqueous solution of sodium hydroxide (0.21 mL) was added to a solution mixture of the obtained methyl 5-(pyrimidin-2-yl)pyridine-3-carboxylate (30 mg) in dioxane (0.3 mL) and methanol (0.3 mL) at room temperature, followed by stirring at the same temperature for 1 hour and 30 minutes. The solvent was evaporated under reduced pressure, and water and toluene were added to the residue. The aqueous layer was separated and adjusted to a pH of 3.8 with 1 mol/L hydrochloric acid. The solid substance was collected by filtration to obtain 7.0 mg of 5-(pyrimidin-2-yl)pyridine-3-carboxylic acid as a white solid.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].Br[CH2:10][CH2:11][C:12]([F:15])([F:14])[F:13]>CO>[F:13][C:12]([F:15])([F:14])[CH2:11][CH2:10][S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: FC(F)(F)CCBr
Reactant: O=C(O)CCS
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCSCCC(F)(F)F
Temperature: 25 °C
Yield: 90.4 %

Procedure:
3-Mercaptopropanoic acid (3.2 g, 30.1 mmol) was dissolved in MeOH (20 mL) and stirred at RT. Powdered potassium hydroxide (3.72 g, 66.3 mmol) was added to the solution, followed by 3-bromo-1,1,1-trifluoropropane (6.14 g, 34.7 mmol). The solution was then stirred at 65° C. for 3 h and then it was quenched with 1N HCl until the pH of the solution was acidic. The mixture was extracted with DCM (3×30 mL), the combined organic phases were dried, concentrated and purified by silica gel chromatography (0-50% EtOAc/hexane) to give 3-((3,3,3-trifluoropropyl)thio)propanoic acid (5.5 g, 27.2 mmol, 90% yield) as colorless oil mixed with some white suspension: IR (Thin film) 2936, 1708 cm−1; 1H NMR (300 MHz, CDCl3) δ 2.86-2.78 (m, 2H), 2.78-2.58 (m, 4H), 2.52-2.25 (m, 2H); EIMS m/z 202.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([Se:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29]CC)=[O:28])=[CH:25][CH:24]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:19])([CH3:18])[C:16]=2[CH:17]=1)(=O)C.[OH-].[Na+]>C1COCC1.C(O)C>[OH:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([Se:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:32][CH:33]=2)=[CH:10][C:11]2[C:12]([CH3:21])([CH3:20])[CH2:13][CH2:14][C:15]([CH3:18])([CH3:19])[C:16]=2[CH:17]=1
Reactant: CCOC(=O)c1ccc([Se]c2cc3c(cc2OCCOC(C)=O)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CCC(C)(C)c2cc([Se]c3ccc(C(=O)O)cc3)c(OCCO)cc21

Procedure:
In a manner similar to that of Example 2, by reaction of 322 mg (0.62 mmol) of ethyl 4-[3-(2-acetoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthylselanyl]benzoate with 250 mg (6.2 mmol) of sodium hydroxide in a THF/ethanol mixture (3 ml/3 ml), 226 mg (81%) of a white powder are obtained. m.p.: 197° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[C:8]([CH2:47][CH2:48][CH3:49])[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]4[N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:26]=[N:25][N:24]=4)=[CH:13][CH:12]=3)[C:5]=2[C:4]([CH3:50])=[N:3]1.O>CC(O)=O>[CH3:1][N:2]1[C:6]2[N:7]=[C:8]([CH2:47][CH2:48][CH3:49])[N:9]([CH2:10][C:11]3[CH:12]=[CH:13][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]4[NH:24][N:25]=[N:26][N:27]=4)=[CH:15][CH:16]=3)[C:5]=2[C:4]([CH3:50])=[N:3]1
Reactant: CCCc1nc2c(c(C)nn2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCc1nc2c(c(C)nn2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reaction time: 2 h
Yield: 67.7 %

Procedure:
The material prepared in Step E (160 mg, 0.24 mmol) was dissolved in glacial HOAc (2.0 mL) at 50° C. and H2O was added dropwise until the solution just became cloudy (approx. 0.7 mL). The mixture was kept at 50° C. for 2 hours and then was evaporated to dryness under a stream of nitrogen. The residue so formed was purified by preparative tlc on 1000μ SiO2 plates developed with CHCl3 /MeOH/NH4OH (80:20:2) to give 67 mg (68%) of the title compound as its ammonium salt. 1H NMR (200 MHz, DMSO-d6)δ 6.82-7.80 (m), 5.21 (s), 3.66 (s), 2.70 (t, J=9 Hz), 1.93 (s), 1.52-1.76 (m), 0.89 (t, J=9 Hz). FAB-MS: 413 (M+ +1). Anal. Calcd for C23H24N8 ·NH3 ·0.6 H2O; C, 62.74; H, 6.46; N, 28.63; Found: C, 62.49; H, 6.24; N, 28.73.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20](=O)[CH2:21]Br)=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])[S:3][CH:21]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COC(=O)c1cccc(C(N)=S)c1
Product: COC(=O)c1cccc(-c2nc(-c3ccc(OC)cc3)cs2)c1
Yield: 74 %

Procedure:
In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 4-methoxyphenacyl bromide to obtain methyl 3-[4-(4-methoxyphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 74%. Pale yellow prisms. Melting point: 108 to 109° C.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCOCC>[C:2]1([CH:1]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: OC(c1ccccc1)c1ccccc1

Procedure:
Grignard reaction of benzaldehyde (300.0 mg; 2.83 mmol) with phenylmagnesium bromide in anhydrous ether afforded 0.5 grams of diphenylmethanol.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:6]([C:32]([F:35])([F:34])[F:33])=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([NH:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])=[C:10]([O:26][CH2:27][C:28]([F:31])([F:30])[F:29])[CH:9]=[CH:8]2.Cl[C:37]([O:39][CH3:40])=[O:38]>C1COCC1>[CH3:3][O:4][C:5]1[C:6]([C:32]([F:33])([F:34])[F:35])=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([N:17]([C:37]([O:39][CH3:40])=[O:38])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[O:16])=[C:10]([O:26][CH2:27][C:28]([F:29])([F:30])[F:31])[CH:9]=[CH:8]2
Reactant: COC(=O)Cl
Reactant: COc1ccc2c(C(=O)NCC(=O)OC(C)(C)C)c(OCC(F)(F)F)ccc2c1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)N(CC(=O)OC(C)(C)C)C(=O)c1c(OCC(F)(F)F)ccc2c(C(F)(F)F)c(OC)ccc12
Temperature: 55 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (80% by weight dispersion in mineral oil, 381 mg, 1.1 eq) was added to a stirred solution of N-[[6-methoxy-2-(2,2,2-trifluoroethoxy)-5-(trifluoromethyl)-1-naphthalenyl]carbonyl]glycine, 1,1-dimethylethyl ester (5.56 g, 11.5 mmol) in anhydrous THF (90 mL) at room temperature under a dry nitrogen atmosphere. The reaction was heated at 55° C. for 2 hours, then cooled to 0° C. in an ice bath. A solution of methyl chloroformate (1.21 mL, 1.36 eq) in anhydrous THF (30 mL) was slowly added to the 0° C. reaction mixture over 25 minutes. After 10 minutes, the reaction was warmed to room temperature. After 1 hour, the reaction was quenched with saturated aqueous ammonium chloride (1 mL), diluted with ether (100 mL) and preabsorbed onto silica gel. The product was flash chromatographed (4:1 petroleum ether:ethyl acetate, silica) to provide the title compound as white flakes (4.42 g, 71%), m.p. 53°-54° C.