Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([NH2:15])[CH2:9]2.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>CN(C=O)C.CCOC(C)=O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH2:11][CH:10]([N:15]1[C:19](=[O:20])[C:18]3[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]1=[O:21])[CH2:9]2
Reactant: O=C1OC(=O)c2ccccc21
Reactant: COc1ccc2c(c1)CC(N)C2
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CC(N1C(=O)c3ccccc3C1=O)C2
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a suspension of 60% NaH (8 g; 0.240 mol) in DMF (250 mL), cooled to 0° C., is added 5-methoxyindan-2-ylamine hydrochloride (40.0 g; 0.2 mol) and the suspension stirred for 1 h at RT. Phthalic anhydride (30 g; 0.2 mol) is added in 1-portion and the suspension stirred for an additional 1-1.5 h at RT followed by stirring at 120° C. for 96 h. The reaction is cooled and diluted with EtOAc. The organic phase is washed with H2O, the resultant precipitate filtered, washed with EtOAc, MeOH and dried under vacuo to afford 25.2 g (43%) of 2-(5-methoxyindan-2-yl)isoindole-1,3-dione as a white solid. The organic phase is washed with H2O, evaporated under reduced pressure and the solid is triturated with MeOH, filtered, and dried to afford an additional 19.7 (33%) g of 2-(5-methoxyindan-2-yl)isoindole-1,3-dione as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]C(C)(C)C.[Sn:14](Cl)([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18]>CCOCC>[CH2:23]([Sn:14]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)[CH2:24][CH2:25][CH3:26]
Reactant: Fc1ccc(Br)cc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To 1-bromo-4-fluorobenzene (1.75 g, 10.0 mmol, 1.00 equiv) in Et2O (25 mL) at −78° C. was added tBuLi (1.7 M in pentane, 11.8 mL, 20 mmol, 2.0 equiv). The reaction mixture was stirred at −78° C. for 30 min before the addition of nBu3SnCl (3.26 g, 10.0 mmol, 1.00 equiv). The reaction mixture was warmed to 23° C. and stirred for 1.0 hr before being filtered through a plug of neutral alumina. The filtrate was concentrated in vacuo to afford 3.76 g of the title compound as a colorless oil (98% yield).
Reaction SMILES: [CH2:1]([C:3]([OH:36])([CH2:34][CH3:35])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:31][CH3:32])([C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]3)=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33])[CH3:2].[H][H]>CO.C(OCC)(=O)C.[C].[Pd]>[CH2:1]([C:3]([OH:36])([CH2:34][CH3:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:13][CH3:14])([C:15]2[CH:20]=[CH:19][C:18]([B:21]3[O:25][C:24]([CH3:26])([CH3:27])[C:23]([CH3:28])([CH3:29])[O:22]3)=[C:17]([CH3:30])[CH:16]=2)[CH2:31][CH3:32])=[CH:8][C:7]=1[CH3:33])[CH3:2]
Reactant: [H][H]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C)CC
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C
Yield: 98.2 %

Procedure:
10% palladium carbon (50 mg) was added to a solution of (E)-3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl-2-methyl-phenyl)-1-penten-3-ol (Example 28; 150 mg, 0.306 mmol) in methanol (6 mL) and ethyl acetate (1.5 mL), and the mixture was stirred in a hydrogen atmosphere at room temperature for three hours. Then, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50, 40 minutes) to give the target product as a colorless oil (148 mg, 98%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]#[N:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:15]=O>>[CH3:10][O:11][C:12]1[CH:13]=[C:14](/[CH:15]=[C:7](/[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)\[C:8]#[N:9])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCc1ccccn1
Product: COc1ccc(/C=C(\C#N)c2ccccn2)cc1OC
Yield: 77.4 %

Procedure:
2-Pyridineacetonitrile (1.18 g) was condensed with 3,4-dimethoxybenzaldehyde (1.66 g) through Method B (production step 2), to thereby yield the target product (yield: 2.06 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([N:25]=[C:26]=[O:27])[CH:22]=[CH:23][CH:24]=1>>[F:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:26]([NH:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=2)=[O:27])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: COc1ccc(N)cc1-c1c(F)cnn1C
Product: COc1ccc(NC(=O)Nc2cccc(C(F)(F)F)c2)cc1-c1c(F)cnn1C
Yield: 48 %

Procedure:
3-(4-Fluoro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine was treated with 3-trifluoromethylphenylisocyanate, in a similar manner as described in Example 1.69, providing 37 mg (48% yield) of Compound 90: LCMS m/z (%)=409 (M+H, 100). 1H NMR (400 MHz, acetone-d6) δ: 8.50 (s, 1H), 8.27 (s, 1H), 8.07 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 7.49 (m, 2H), 7.38 (d, JH,F=4.8 Hz, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.14 (d, J=8.8 Hz, 1H), 3.84 (s, 3H), 3.65 (s, 3H). 19F NMR (376 MHz, acetone-d6) δ: −63.85 (s, 3F), −177.42 (d, JH,F=4.1 Hz, 1F).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:17][CH:18]([C:20]1[CH:21]=[C:22]2[CH:28]=[CH:27][N:26](C(OC(C)(C)C)=O)[C:23]2=[CH:24][N:25]=1)[CH3:19].CCN(C(C)C)C(C)C>CCCCO>[NH:26]1[C:23]2=[CH:24][N:25]=[C:20]([CH:18]([NH:17][C:2]3[N:7]=[C:6]([NH:8][C:9]4[CH:13]=[C:12]([CH:14]5[CH2:16][CH2:15]5)[NH:11][N:10]=4)[CH:5]=[CH:4][N:3]=3)[CH3:19])[CH:21]=[C:22]2[CH:28]=[CH:27]1
Reactant: CC(N)c1cc2ccn(C(=O)OC(C)(C)C)c2cn1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1)c1cc2cc[nH]c2cn1
Temperature: 115 °C

Procedure:
A sealed-cap vial was charged with 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-pyrimidin-4-amine (60 mg, 0.25 mmol), tert-butyl 5-(1-aminoethyl)-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (93 mg, 0.36 mmol), DIPEA (0.16 mL) and n-BuOH (0.8 mL). The mixture was heated at 115° C. for 72 h. The reaction mixture was concentrated under reduced pressure. The crude mixture was purified by preparative HPLC to afford N2-(1-(1H-pyrrolo[2,3-c]pyridin-5-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine: MS (ESI) m/z: 361.2 [M+1]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.[H][H]>C(O)C.[Pd]>[ClH:2].[Cl:2][C:3]1[CH:4]=[C:5]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:6]=[CH:7][C:8]=1[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: [H][H]
Reactant: O=C(O)/C=C/c1ccc(Cn2ccnc2)c(Cl)c1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(O)CCc1ccc(Cn2ccnc2)c(Cl)c1

Procedure:
A mixture of (E)-3-[3-chloro-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoic acid hydrochloride (0.07 g) and 5% palladium on barium sulphate (0.01 g) in ethanol was stirred under an atmosphere of hydrogen until the theoretical amount of hydrogen had been consumed. The catalyst was then filtered off (Hyflo) and the reaction mixture was concentrated to affored a colourless oil. N.M.R. spectroscopy of the product showed that it was consistent with the proposed structure.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31])=[CH:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:36][CH3:37])C1C=CC=CC=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[C:21]([C:30]([O:32][CH2:33][CH2:34][CH3:35])=[O:31])=[CH:22][C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:36][CH3:37]
Reactant: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OCc3ccccc3)c(OC)cc12
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CCCOC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(O)c(OC)cc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
Propyl 3-(7-benzyloxy-6-methoxy-quinolin-4-yloxy)naphthalene-2-carboxylate (160 mg) was dissolved in trifluoroacetic acid (1.5 ml) to prepare a solution. Methanesulfonic acid (0.15 ml) was added to the solution, and the mixture was stirred at 70° C. for one hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. An aqueous sodium hydrogencarbonate solution was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give propyl 3-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-naphthalene-2-carboxylate (87 mg, yield 68%).
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[C:8]([O:17][C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][C:19]=2[N:25]2[CH:29]=[CH:28][CH:27]=[CH:26]2)=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1.C(N(CC)CC)C.[Cl:37][C:38]1[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][C:39]=1[C:40](Cl)=[O:41]>O>[Cl:6][C:7]1[C:8]([O:17][C:18]2[CH:24]=[CH:23][C:21]([NH:22][C:40](=[O:41])[C:39]3[CH:43]=[C:44]([N+:47]([O-:49])=[O:48])[CH:45]=[CH:46][C:38]=3[Cl:37])=[CH:20][C:19]=2[N:25]2[CH:29]=[CH:28][CH:27]=[CH:26]2)=[N:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(-n2cccc2)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(-n2cccc2)c1)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To 5 mL of a tetrahydrofuran solution comprising 320 mg of 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-3-(1-pyrrolyl)aniline and 110 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 200 mg of 2-chloro-5-nitrobenzoylchloride was dropwise added, followed by stirring for about 30 minutes, and then water was added, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and then dried to obtain 260 mg of N-(4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)-3-(1-pyrrolyl)phenyl)-2-chloro-5-nitrobenzamide (Compound No. 127) having a melting point of from 165 to 167° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH2:29][CH3:30])[N:3]=1.[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([C@H:43]2[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:44]2)=[C:36]2[C:40]=1[C:39](=[O:41])[N:38]([CH3:42])[CH2:37]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C@H:43]4[CH2:44][CH2:45][C@H:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:47][CH2:48]4)=[C:36]4[C:40]=3[C:39](=[O:41])[N:38]([CH3:42])[CH2:37]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH2:29][CH3:30])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOC(=O)[C@H]1CC[C@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@H](C(=O)OCC)CC3)c3c2C(=O)N(C)C3)n1

Procedure:
The title compound was prepared according to the procedure for Example 102 using of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-ethoxybenzyl)phosphonate (Compound 244A, 29.84 mg, 0.064 mmol) and ethyl trans-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (22.2 mg, 0.070 mmol). 31.2 mg (65%) of the desired product was isolated after work-up/chromatography. 1H NMR (400 MHz, MeOD) δ ppm 8.48 (d, J=7.83 Hz, 1H), 8.35 (s, 1H), 7.87 (d, J=8.08 Hz, 1H), 7.38 (d, J=8.84 Hz, 1H), 7.05 (s, 1H), 6.94 (dt, J=8.08, 2.27 Hz, 1H), 4.52 (s, 2H), 4.04-4.22 (m, 8H), 3.28 (s, 2H), 3.19 (s, 3H), 2.63 (t, J=11.62 Hz, 1H), 2.42-2.54 (m, 1H), 2.13 (d, J=14.15 Hz, 2H), 1.90-1.99 (m, 2H), 1.54-1.77 (m, 4H), 1.41 (t, J=6.95 Hz, 3H), 1.24-1.33 (m, 9H). MS (ES+): m/z 748.26/749.29 (100/98) [MH+]. HPLC: tR=1.80 min (Micromass TOF: polar—3 min).
Reaction SMILES: C(OC([N:8]1[C:12]2[N:13]=[CH:14][N:15]=[C:16]([N:17]3[CH2:24][C:21]4([CH2:23][CH2:22]4)[N:20]([S:25](=[O:29])(=[O:28])[NH:26][CH3:27])[CH2:19][CH2:18]3)[C:11]=2[CH:10]=[CH:9]1)=O)(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>CN(C=O)C>[CH3:27][N:26]([CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[S:25]([N:20]1[CH2:19][CH2:18][N:17]([C:16]2[C:11]3[CH:10]=[CH:9][NH:8][C:12]=3[N:13]=[CH:14][N:15]=2)[CH2:24][C:21]21[CH2:22][CH2:23]2)(=[O:29])=[O:28]
Reactant: BrCCCc1ccccc1
Reactant: CNS(=O)(=O)N1CCN(c2ncnc3c2ccn3C(=O)OC(C)(C)C)CC12CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCCc1ccccc1)S(=O)(=O)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 35 °C
Reaction time: 1.5 h

Procedure:
4-(4-Methylsulfamoyl-4,7-diaza-spiro[2.5]oct-7-yl)-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid tert-butyl ester (intermediate 4) (0.71 mmol) was dissolved in dry DMF (0.5 mL) and added Cs2CO3 (0.85 mmol) and (3-bromo-propyl)-benzene (0.085 mmol). Stirred at 35° C. for 1.5 h and then added H2O (2 mL). Extracted with EtOAc (3×2 mL) and the combined organic phases were concentrated in vacuo. The residual oil was treated with TFA (2 mL) at rt→45° C. for 1.5 h. The crude reaction mixture was concentrated in vacuo and redissolved in DMSO (0.5 mL). The pure compounds were obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [I:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25]S(C)(=O)=O)=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[OH-].[Na+].Cl>O1CCCC1.O>[I:1][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Oc1ccc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1
Reaction time: 18 h
Yield: 101.7 %

Procedure:
To a solution of methanesulfonic acid 4-(6-iodo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (1.00 g, 1.89 mmol) in tetrahydrofuran (5 mL) was added a 2.5 N aqueous solution of sodium hydroxide (6.0 mL) and the biphasic reaction mixture was heated at reflux for 5 hours and then heated in a sealed pressure tube at 110 C. for about 18 hours. The reaction mixture was diluted with water (100 mL), acidified with 10% hydrochloric acid and the organics were extracted with ether (2×100 mL). The extracts were combined, washed with water (100 mL), concentrated and chased with petroleum ether to give the title compound (0.869 g, over theoretical); NMR (DMSO-d6); δ 9.85 (s, 1H, OH), 8.15 (d, J=8 Hz, 1H), 8.02 (d, J=8 Hz, 1H), 7.73 (ddd, J=8, 7, 1 Hz, 1H), 7.69-7.44 (m, 3H), 7.21-7.16 (m, 3H), 7.09-7.06 (m, 2H), 6.68 (d, J=8Hz, 1H).
Reaction SMILES: B(Br)(Br)Br.[CH:5]([C:8]1[C:16]([O:17]C)=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11])([CH3:7])[CH3:6]>ClCCl>[OH:17][C:16]1[C:8]([CH:5]([CH3:7])[CH3:6])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: COc1cccc(C(=O)O)c1C(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)c1c(O)cccc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A solution of 1M boron tribromide in dichloromethane (15 mL, 15 mmol) was added dropwise to a solution of 2-isopropyl-3-methoxybenzoic acid in dichloromethane. After stirring for 2 hours, the reaction mixture was cooled to 0° C., quenched with water, and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by silica gel flash chromatography, eluting with dichloromethane/methanol and 1% acetic acid, gave 3-hydroxy-2-isopropylbenzoic acid as a white crystalline solid (1.32 g, 97.5%).
Reaction SMILES: CC(C)=O.[CH:5]1[C:15]2[CH:14]=[CH:13][C:12]3[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=3[C:10](=[C:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][O:29][C:30]([C:32]4[CH:37]([C:38]5[CH:43]=[CH:42][CH:41]=[C:40]([Cl:44])[CH:39]=5)[C:36]([C:45]([OH:47])=[O:46])=[C:35]([CH3:48])[NH:34][C:33]=4[CH3:49])=[O:31])[CH2:22][CH2:21]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.[N+]([O-])([O-])=O.[NH4+].[Ce]>O>[Cl:44][C:40]1[CH:39]=[C:38]([C:37]2[C:36]([C:45]([OH:47])=[O:46])=[C:35]([CH3:48])[N:34]=[C:33]([CH3:49])[C:32]=2[C:30]([O:29][CH2:28][CH2:27][CH2:26][N:23]2[CH2:22][CH2:21][C:20](=[C:10]3[C:9]4[CH:8]=[CH:7][CH:6]=[CH:5][C:15]=4[CH:14]=[CH:13][C:12]4[CH:16]=[CH:17][CH:18]=[CH:19][C:11]3=4)[CH2:25][CH2:24]2)=[O:31])[CH:43]=[CH:42][CH:41]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C(C(=O)OCCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)=C(C)N1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc(C)c(C(=O)OCCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)c(-c2cccc(Cl)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 ml of acetone was added to 132 mg (0.21 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid mono (3-(4-(5H-dibenzo[a,d] cyclohepten-5-ylidene) piperidine-1-yl) propan-1-yl) ester. 233 mg (0.43 mmol) of cerium ammonium nitrate suspended in 5 ml of water was added and stirred at room temperature for 2 hours. After acetone was evaporated under reduced pressure, ethyl acetate was added and precipitates were taken by the filtration and dried under reduced pressure to obtain the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.CN(C)C=O.[CH3:22][N:23]1[CH2:27][CH2:26][CH2:25][CH:24]1[C:28]1[CH:29]=[CH:30][C:31]([NH2:34])=[N:32][CH:33]=1>CCOCC>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:34][C:31]1[CH:30]=[CH:29][C:28]([CH:24]2[CH2:25][CH2:26][CH2:27][N:23]2[CH3:22])=[CH:33][N:32]=1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21
Reactant: CN1CCCC1c1ccc(N)nc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1CCCC1c1ccc(N/C=C2\C(=O)NC(=O)c3ccc(I)cc32)nc1
Temperature: 125 °C

Procedure:
A mixture of (E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione (696 mg, 2.12 mmole), dimethylformamide (15 mL), and 5-(1-methylpyrrolidin-2-yl)pyridin-2-amine (375 mg, 2.12 mmole) is heated at 125° C. for four hours. The reaction mixture is cooled, diluted with ether, filtered, washed with fresh ether and dried to give a yellow solid, 580 mg, (58%), mp 174-206° C. dec; MS (ES+): m/z 475.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][C:25]([CH2:30][CH3:31])([CH2:28][CH3:29])[CH:26]=[O:27])=[CH:22][CH:21]=1.[Cl-].[NH4+].Cl>C(OCC)C>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:24][C:25]([CH2:28][CH3:29])([CH2:30][CH3:31])[CH:26]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:27])=[CH:32][CH:33]=1
Reactant: CCC(C=O)(CC)Cc1ccc(Cl)cc1
Reactant: Brc1cccnc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCC(CC)(Cc1ccc(Cl)cc1)C(O)c1cccnc1
Temperature: -70 °C
Reaction time: 0.17 h

Procedure:
A solution of 15.8 g of 3-bromopyridine (0.10 mol) in 50 ml of diethyl ether is added dropwise to a mixture of 82 ml of a 1.6M n-butyllithium solution in n-hexane (0.13 mol) under a nitrogen atmosphere at -70° C. The mixture is stirred at -70° C. for 10 minutes and then a solution of 24.7 g of 2-(4-chlorobenzyl)-2-ethylbutanal (0.11 mol) in 50 ml of diethyl ether is added dropwise. After 1 h at -70° C., the mixture is allowed to warm slowly to room temperature and is hydrolyzed with saturated aqueous ammonium chloride solution. The mixture is acidified with dilute hydrochloric acid, and the aqueous phase is separated off and washed with ether and then adjusted to pH 10 to 11 with concentrated ammonia solution while cooling. It is extracted three times with dichloromethane, and the organic phase is dried over Na2SO4 and concentrated. The solid crude product is recrystallized from ethyl acetate/hexane (1:1). 19.2 g (63% of theory) of colorless crystals of melting point 128°-129° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4]O.NC(N)=S.Cl.C(=O)([O-])[O-].[K+].[K+].C[S:23]([C:26]1[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][N:27]=1)(=O)=O>O.O1CCOCC1>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][S:23][C:26]1[CH2:30][C:29]([CH3:32])([CH3:31])[O:28][N:27]=1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: OCc1c(F)cccc1F
Agent: Cl
Agent: NC(N)=S
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)CC(SCc2c(F)cccc2F)=NO1
Temperature: 140 °C
Reaction time: 0.17 h
Yield: 25.9 %

Procedure:
2,6-Difluorobenzyl alcohol (0.2 ml, 1.8 mmol), thiourea (165 mg, 2.2 mmol), aqueous hydrochloric acid (2M) (2.7 ml) and 1,4-dioxane (3 ml) were mixed and the mixture heated in a sealed vessel in the microwave at 140° C. for 10 minutes. Potassium carbonate (1.1 g, 8 mmol) and 3-methanesulfonyl-5,5-dimethyl-4,5-dihydroisoxazole (380 mg, 2.1 mmol) were added and the mixture was stirred in an open vessel for 10 minutes. The mixture was heated in a sealed vessel in the microwave at 150° C. for 10 minutes. The mixture was diluted with water and extracted with ethyl acetate. The organic extract was washed with water, dried over magnesium sulfate and concentrated. The crude material was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product as a white solid (120 mg, 26% yield). M.p. 85-87° C. 1H-NMR (400 MHz, CDCl3): 1.43 (6H, s, Me), 2.82 (2H, s, CH2), 4.36 (2H, s, CH2), 6.90 (2H, d, CH), 7.26 (1H, t, CH).
Reaction SMILES: [Li+].[Cl-].[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12]C)[CH:11]=1)[C:7]#[N:8].CCOC(C)=O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:7]#[N:8]
Reactant: COc1cc(Cl)cc(C#N)c1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(O)cc(Cl)c1
Temperature: 180 °C
Yield: 84.7 %

Procedure:
To a stirred solution of LiCl (84 g, 1980 mmol) in DMF (500 mL) was added 3-chloro-5-(methyloxy)benzonitrile (167 g, 1000 mmol). The reaction mixture was heated to 180° C. for 12 h. The reaction mixture was poured into ice (300 g) and EtOAc was added. The organic layer was separated, dried over MgSO4 and evaporated to dryness. The solid was recrystallized from EtOAc and petroleum ether (1:5) to afford the title compound (130 g, 67%) as a solid.