Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]=1[OH:18])[CH:2]=[CH2:3]>C(Cl)Cl.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:6]1[C:5]([OH:18])=[C:4]([CH:1]=[CH:2][CH3:3])[CH:9]=[CH:8][C:7]=1[Cl:10]
Reactant: C=CCc1ccc(Cl)c(-c2ccccc2Cl)c1O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Product: CC=Cc1ccc(Cl)c(-c2ccccc2Cl)c1O
Yield: 48.4 %

Procedure:
Treatment of 3-allyl-2′,6-dichloro-biphenyl-2-ol (6.2 g, 22.2 mmol) in methylene chloride (200 mL) with dichlorobis(acetonitrile)palladium (II) (0.86 g, 3.3 mmol) according to the procedure described for Example 69, Step 5 provided 3.0 g (48%) of 2′,6-dichloro-3-(prop-1-enyl)biphenyl-2-ol as a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:9]2)[CH:7]=1.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:31])[NH:26][CH2:25]2>>[C:17]([Si:14]([CH3:16])([CH3:15])[O:13][C@@H:10]1[CH2:11][CH2:12][N:8]([C:6]2[CH:7]=[C:2]([N:26]3[CH2:25][C:24]4[C:28](=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=4)[C:27]3=[O:31])[CH:3]=[N:4][CH:5]=2)[CH2:9]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C1NCc2cc(Cl)ccc21
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2cncc(Br)c2)C1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CCN(c2cncc(N3Cc4cc(Cl)ccc4C3=O)c2)C1

Procedure:
In analogy to the procedures described for the preparation of example 137, 3-bromo-5-[(R)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-pyridine (example 137 [B]) has been reacted with 5-chloro-2,3-dihydro-isoindol-1-one to give 2-{5-[(R)-3-(tert-butyl-dimethyl-silanyloxy)-pyrrolidin-1-yl]-pyridin-3-yl}-5-chloro-2,3-dihydro-isoindol-1-one, which was then deprotected with 4M HCl in dioxane to give the title compound as light yellow solid. MS: 330.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])=[CH:11][N:10]([C:25]([CH3:30])([CH3:29])[C:26](O)=[O:27])[N:9]=2)[CH:7]=1.[NH:33]1[CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[N:33]1([C:26](=[O:27])[C:25]([N:10]2[CH:11]=[C:12]([NH:13][C:14]([C:16]3[C:24]4[N:23]=[CH:22][N:21]=[CH:20][C:19]=4[NH:18][N:17]=3)=[O:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:31][CH3:32])=[N:9]2)([CH3:30])[CH3:29])[CH2:36][CH2:35][CH2:34]1
Reactant: C1CNC1
Reactant: COc1ccc(Cl)cc1-c1nn(C(C)(C)C(=O)O)cc1NC(=O)c1n[nH]c2cncnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1-c1nn(C(C)(C)C(=O)N2CCC2)cc1NC(=O)c1n[nH]c2cncnc12
Reaction time: 6 h
Yield: 58.8 %

Procedure:
A solution of 2-(3-(5-chloro-2-methoxyphenyl)-4-(pyrazolo pyrimidine-3-carboxamido)-1H-pyrazol-1-yl)-2-methylpropanoic acid (0.050 g, 0.11 mmol, 1 equiv), azetidine (18.5 μL, 0.275 mmol, 2.50 equiv), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazole-1-yl)uranium hexafluorophosphate (84 mg, 0.20 mmol, 2.00 equiv), and N,N-diisopropylethylamine (380 μL, 2.2 mmol, 20 equiv) in N,N-dimethylformamide (1 mL) was heated at 50° C. After 6 h, the reaction mixture was concentrated, and the resulting residue was partitioned between saturated aqueous sodium bicarbonate (5 mL) and ethyl acetate (5 mL). The aqueous was extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by preparative HPLC afforded product (32 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.70 (s, 1H), 9.34 (m, 1H), 8.77 (dd, J=4.2, 1.5 Hz, 1H), 8.64 (s, 1H), 8.36 (s, 1H), 7.52 (dd, J=8.9, 2.7 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H), 7.28-7.32 (m, 2H), 3.88 (s, 2H), 3.86 (s, 3H), 3.41 (m, 2H), 2.04 (m, 2H), 1.72 (s, 6H). LCMS (ESI): M+H=494.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[NH2:9][NH2:10]>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:9][NH2:10])[CH:2]=1
Reactant: NN
Reactant: O=Cc1cccnc1
Solvent: CO
Product: NNCc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of pyridine-3-aldehyde (5 g, 46.7 mmol) in methanol (100 mL) was added hydrazine (1.05 mL, 46.7 mmol). The reaction mixture was stirred at rt for 1 h. After purging with nitrogen, 10% Pd/C (200 mg) was added. The reaction mixture was purged with hydrogen and stirred under hydrogen at rt overnight. Solid material was removed, and the filtrate was concentrated to give a crude Example 85A. This material was used without further purification. Yield: 5.2 g (91%). MS (DCI): m/z 124 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[Cl:11][C:12]1[N:13]=[C:14](Cl)[C:15]2[CH:21]=[CH:20][CH:19]=[N:18][C:16]=2[N:17]=1.C(N(CC)C(C)C)(C)C>ClCCCl.O>[Cl:11][C:12]1[N:13]=[C:14]([NH:5][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[C:15]2[CH:21]=[CH:20][CH:19]=[N:18][C:16]=2[N:17]=1
Reactant: Clc1nc(Cl)c2cccnc2n1
Reactant: NCc1ccc(Cl)cc1Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: Clc1ccc(CNc2nc(Cl)nc3ncccc23)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54.5 %

Procedure:
2,4-Dichlorobenzylamine (211 mg, 1.2 mmol) was added to the stirred solution of 2,4 dichloro-pyrido[2,3-d]pyrimidine(200 mg, 1 mmol) and N,N-diisopropylethylamine (266 μL, 1.5 mmol) in 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature for 12 h and then diluted with water (10 mL). The aqueous layer was extracted with CH2Cl2 and the combined organic layer was washed with water (2×10 mL), dried (Na2SO4) and concentrated in vaccuo to give (2-Chloro-pyrido[2,3-d]pyrimidin-4-yl)-(2,4-dichloro-benzyl)-amine as a yellow oil (185 mg) and was used as such in the next reaction without further purification.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9])(=[O:3])[CH3:2].Br[C:11]1[CH:12]=[CH:13][C:14]([C:17]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:30]([CH:31]4[CH2:33][CH2:32]4)=[CH:29][C:28]([CH:34]4[CH2:36][CH2:35]4)=[CH:27][N:26]=3)[CH2:21][CH2:20]2)=[O:18])=[N:15][CH:16]=1>>[C:1]([N:4]1[CH2:8][CH2:7][N:6]([C:11]2[CH:16]=[N:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]4[C:30]([CH:31]5[CH2:33][CH2:32]5)=[CH:29][C:28]([CH:34]5[CH2:35][CH2:36]5)=[CH:27][N:26]=4)[CH2:21][CH2:20]3)=[O:18])=[CH:13][CH:12]=2)[C:5]1=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNC1=O
Reactant: O=C(c1ccc(Br)cn1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: CC(=O)N1CCN(c2ccc(C(=O)N3CCN(c4ncc(C5CC5)cc4C4CC4)CC3)nc2)C1=O
Yield: 12.8 %

Procedure:
Using 1-acetyl-2-imidazolidinone (462 mg) and (5-bromopyridin-2-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (1.4 g) described in Preparation Example 142 and by the reaction and treatment in the same manner as in Example 1, the title compound (199 mg) was obtained.
Reaction SMILES: Cl.[S:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl.[OH-].[Na+].[OH-].C[N+](C)(C)CC1C=CC=CC=1>C1C=CC=CC=1>[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N:7]1[CH2:8][CH2:9][C:10]2[S:2][CH:3]=[CH:4][C:5]=2[CH2:6]1
Reactant: c1cc2c(s1)CCNC2
Reactant: ClCc1ccccc1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: c1ccccc1
Product: Clc1ccccc1CN1CCc2sccc2C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 74.7 %

Procedure:
To a solution of 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (580 mg, 3.3 mmol) and 2-chlorobenzyl chloride (640 mg, 3.9 mmol) in benzene (5.0 ml) were added an aqueous 5M NaOH solution (5 ml), and trimethylbenzyl ammonium hydroxide (100 mg of 40% methanol solution). The mixture was stirred for 40 hours at room temperature. The reaction mixture was allowed to stand, thereby separating an aqueous layer from an organic layer The organic layer was washed with water and then with saturated NaCl solution, dried (over MgSO4) and concentrated. The residue was purified by silica gel column chromatography to prepare 650 mg (yield 74.7%) of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine as an oily product, b.p. 155.0°-158.0° C. (1.5 mmHg). This pyridine was dissolved in hydrogen chloride saturated ethyl alcohol (5 ml) and the solution was then concentrated and cooled. The precipitated hydrochloride was filtered off and dried. The yield 420 mg (42.4%), m.p. 190° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:7]2=[N:6][C:5]=1[CH3:17].[C:18]1([CH3:30])[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1.[ClH:31]>C1(C)C=CC=CC=1>[ClH:1].[ClH:31].[C:18]1([CH3:30])[CH:23]=[CH:22][CH:21]=[C:20]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:7]4=[N:6][C:5]=3[CH3:17])[CH2:28][CH2:29]2)[CH:19]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: Cc1cc(C)n2c(=O)c(CCCl)c(C)nc2c1
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1cccc(N2CCN(CCc3c(C)nc4cc(C)cc(C)n4c3=O)CC2)c1

Procedure:
A mixture of 2.5 g of 3-(2-chloroethyl)-2,6,8-trimethyl-4H-pyrido[1,2-a]pyrimidin-4-one, 5.3 g of 1-(m-tolyl)piperazine and 20 ml of toluene was refluxed for 24 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by means of column chromatography using alumina. The oil obtained from the eluate was converted into the hydrochloride, which was then recrystallized from ethanol to give 0.8 g of the desired compound as pale yellow powders, m.p. 274°C (decomp.).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][NH2:13].O>C(O)C>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([NH:13][CH3:12])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1Br
Reactant: CN
Solvent: O
Solvent: CCO
Product: CNc1cc(Br)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 2,4-dibromo-1-nitro-benzene (2.0 g, 7.14 mmol) in ethanol (50 mL) was added a 40% aqueous solution of methylamine (50 mL). The reaction mixture was stirred at 80° C. in a closed vessel for 3 h, then cooled to 0° C. Water was added and the precipitate was filtered, washed with water, and dried in vacuo to give 1.26 g of (5-bromo-2-nitro-phenyl)-methyl-amine as an orange solid (76% yield): 1H NMR (CDCl3) δ 3.04 (s, 3H), 6.79 (dd, 1H), 7.03 (d, 1H), 8.05 (d, 1H), 8.0-8.1 (broad s, 1H); MS (m/z) 231, 233 [M+H+]+.
Reaction SMILES: C(OC1C=CC(F)=C2C=1C(CCN(C)C)=CN2C)C1C=CC=CC=1.[CH3:25][N:26]([CH3:42])[CH2:27][CH2:28][C:29]1[C:37]2[C:36]([OH:38])=[CH:35][C:34]([F:39])=[CH:33][C:32]=2[N:31]([CH2:40][CH3:41])[CH:30]=1.[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50]Cl)=[CH:46][CH:45]=1>>[Cl:43][C:44]1[CH:49]=[CH:48][C:47]([CH2:50][O:38][C:36]2[CH:35]=[C:34]([F:39])[CH:33]=[C:32]3[C:37]=2[C:29]([CH2:28][CH2:27][N:26]([CH3:25])[CH3:42])=[CH:30][N:31]3[CH2:40][CH3:41])=[CH:46][CH:45]=1
Reactant: CCn1cc(CCN(C)C)c2c(O)cc(F)cc21
Reactant: ClCc1ccc(Cl)cc1
Agent: CN(C)CCc1cn(C)c2c(F)ccc(OCc3ccccc3)c12
Product: CCn1cc(CCN(C)C)c2c(OCc3ccc(Cl)cc3)cc(F)cc21

Procedure:
Following the procedure (step 7, scheme 1) used to prepare compound 1-8c, compound 1-9b and 1-chloro-4-(chloromethyl)benzene were used as starting material to obtain compound 1-10b.
Reaction SMILES: CO[NH:3][C:4]1[N:5]=[CH:6][CH:7]=[C:8]2[CH:12]=[CH:11][O:10][C:9]=12.C(O)(=O)C>C(Cl)Cl.[Zn]>[O:10]1[C:9]2=[C:4]([NH2:3])[N:5]=[CH:6][CH:7]=[C:8]2[CH:12]=[CH:11]1
Reactant: CONc1nccc2ccoc12
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Nc1nccc2ccoc12
Yield: 97.5 %

Procedure:
N-methoxyfuro[2,3-c]pyridin-7-amine (43.0 g, 0.26 mol) in DCM (200 mL) was cooled in a water bath. Zinc dust (36.0 g, 0.64 mol) was added in one portion and stirred for a few min. Acetic acid (18.8 g, 0.31 mol) was added slowly over 5-10 min and stirred for 30 min. The water bath was removed and the mixture was stirred at RT for 16 h. At this point, TLC analysis (5% MeOH in DCM) indicated complete consumption of the starting material. The mixture was diluted with 400 mL of DCM and washed with saturated NaHCO3 until the pH of the wash was about 8.5. The DCM layer was then washed with water (2×100 mL) and then brine. The solution was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude product was purified by flash chromatography (2% MeOH:DCM) to provide 34 g (97%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 4.89 (br s, 2H), 6.71 (d, J=1.8 Hz, 1H), 6.94 (d, J=5.4 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.84 (d, J=5.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19]C)=[O:18])[C:3]=1/[CH:21]=[CH:22]/[Si:23]([CH3:26])([CH3:25])[CH3:24].C1COCC1.O.O.[OH-].[Li+]>CO>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([OH:19])=[O:18])[C:3]=1/[CH:21]=[CH:22]/[Si:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1/C=C/[Si](C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[Si](C)(C)/C=C/c1c(C(=O)O)nc(-c2ccc(Cl)c(F)c2)c(F)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.4 %

Procedure:
(E)-methyl 4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-(2-(trimethylsilyl)vinyl)picolinate (169 mg, 0.426 mmol) was dissolved in methanol (2 mL), THF (2 mL) and Water (1 mL). Lithium hydroxide hydrate (93 mg, 2.216 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under vaccum. The resulting residue was partitioned between 1 N HCl and ethyl acetate. The aqueous phase was extracted three more times with ethyl acetate. The organic phases were combined, dried over magnesium sulfate, filtered, and concentrated under vacuum to provide the title compound as an off-white solid (146 mg, 0.381 mmol, 90% yield): 1H NMR (400 MHz, DMSO-d6) δ 0.17 (s, 9H), 6.26 (d, J=19.4 Hz, 1H), 6.49 (s, 2H), 6.93 (d, J=19.5 Hz, 1H), 7.68-7.83 (m, 2H), 7.88 (dd, J=10.9, 1.8 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ −145.32 , −116.04 . ESIMS m/z 384 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[C:18](=[O:19])[CH2:17][O:16][C:15]2[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:14]1=2.C(O)(=O)C>C1COCC1.[Fe]>[NH2:24][C:21]1[CH:22]=[CH:23][C:14]2[N:13]([C:4]3[CH:5]=[CH:6][C:7]([C:9]([F:12])([F:10])[F:11])=[CH:8][C:3]=3[O:2][CH3:1])[C:18](=[O:19])[CH2:17][O:16][C:15]=2[CH:20]=1
Reactant: COc1cc(C(F)(F)F)ccc1N1C(=O)COc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)ccc1N1C(=O)COc2cc(N)ccc21
Temperature: 70 °C
Yield: 74.4 %

Procedure:
4-(2-Methoxy-4-(trifluoromethyl)phenyl)-7-nitro-2H-benzo[b][1,4]oxazin-3(4H)-one (2.1 g, 5.70 mmol) was dissolved in THF (22.81 ml) and acetic acid (17.95 ml, 314 mmol) in a 250 mL rbf, and iron (3.18 g, 57.0 mmol) was added. The flask was sealed and heated to 70° C. for 1 hr until the reaction was complete by LCMS. The reaction was cooled to RT, diluted with THF (50 mL), and filtered through Celite, washing well with 200 mL of THF. The filtrate was concentrated via rotary evaporation, and partitioned between sat. aq. sodium bicarbonate solution (50 mL) and EtOAc (50 mL). The layers were separated, and the aqueous was then extracted two times with EtOAc (2×50 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated to a brown oil. The oil was loaded onto a silica column and purified by MPLC with a gradient Heptanes:EtOAc column (0-100%). Fractions were combined and concentrated to give 7-amino-4-(2-methoxy-4-(trifluoromethyl)phenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (1.434 g, 4.24 mmol, 74.3% yield) as an off-white foamy solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][O:29][Si](C(C)(C)C)(C)C)[C@@H:25]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C@H:24]([O:47][CH2:48][C:49]3[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=3)[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=3)[C@H:24]([O:47][CH2:48][C:49]3[CH:50]=[CH:51][C:52]([O:55][CH3:56])=[CH:53][CH:54]=3)[C@H:22]2[N:23]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: COc1ccc(CO[C@@H]2[C@H]3N=C(N(CCOCc4ccccc4)C(=O)OC(C)(C)C)S[C@H]3O[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CO[C@@H]2[C@H]3N=C(N(CCOCc4ccccc4)C(=O)OC(C)(C)C)S[C@H]3O[C@H](CO)[C@H]2OCc2ccc(OC)cc2)cc1
Yield: 89.8 %

Procedure:
A solution of 133 (7.5 g, 9.3 mmol) in THF (30 mL) was treated with TBAF (4.9 g, 18.6 mmol) for 3 hours at room temperature. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layer was washed with brine (2×30 mL), dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column, eluted with 3%-10% ethyl acetate in petroleum ether to afford 134 as a light yellow syrup (5.8 g, 90%). (ES, m/z) [M+H]+ 695.0; 1H NMR (300 MHz, CDCl3) δ 7.21-7.36 (m, 9H), 6.80-6.85 (m, 4H), 6.09 (d, J=6.3 Hz, 1H), 4.50-4.55 (m, 4H), 4.49 (s, 2H), 4.31-4.33 (m, 1H), 4.05-4.06 (m, 1H), 3.84-3.91 (m, 1H), 3.82 (s, 3H), 3.83 (s, 3H), 3.56-3.67 (m, 2H), 3.30-3.53 (m, 5H), 1.56 (s, 9H).
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(=O)(O)(O)O.OP=O.C(O[C:19]([CH2:21][O:22][C:23]([C:25]1[CH:26]=[C:27]([OH:36])[C:28]2[C:33]([CH:34]=1)=[CH:32][C:31]([CH3:35])=[CH:30][CH:29]=2)=[O:24])=O)C>O.C(Cl)Cl>[C:1]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:21]2[O:22][C:23](=[O:24])[C:25]3[CH:26]=[C:27]([OH:36])[C:28]4[C:33]([C:34]=3[CH:19]=2)=[CH:32][C:31]([CH3:35])=[CH:30][CH:29]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)COC(=O)c1cc(O)c2ccc(C)cc2c1
Agent: O=P(O)(O)O
Agent: O=PO
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(O)cc3c(=O)oc(C(c4ccccc4)c4ccccc4)cc3c2c1

Procedure:
Toluene, 1000 milliliters (mL), heptanes, i.e., a C7 distillate having a boiling range of from 82 to 98° C., (1000 mL), methylene chloride (1000 mL), phosphoric acid, 20.0 grams of an 85 weight percent solution, 5.0 grams of hypophosphorus acid and 625.0 grams of 3-(ethoxycarbonyl)methoxycarbonyl-1-hydroxy-6-methylnaphthalene were added to a reaction flask. The reaction flask was a 5 liter four necked round bottom reactor equipped with an overhead mechanical stirrer, thermometer, electric heating mantle, heavier than water Barrett water trap, Fredrich's condenser and bottom outlet. The mixture was heated to reflux (~55° C.) and about 2 mL of water was removed. 1,1-Diphenyl-2-propyn-1-ol, 903.25 grams of a 61 weight percent solution in methylene chloride, was added to the reactor and the mixture was heated at reflux (~57° C.) for about 8 hours. The hot mixture was filtered to separate the insoluble desired product from the other products of reaction. The crystals were washed with 1 liter of a 1:1:2 mixture of toluene:heptanes:methylene chloride and dried to yield 144 grams of 2-diphenylmethyl-6-hydroxy-9-methyl-4-oxo-4H-naphtho[2,1-c]pyran.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br.[CH3:25][O:26][C:27]1[CH:34]=[C:33]([O:35][CH3:36])[C:32]([C:37]2[S:38][CH:39]=[CH:40][CH:41]=2)=[CH:31][C:28]=1[CH:29]=O>ClCCl>[C:29]([C:28]1[C:27]([O:26][CH3:25])=[CH:34][C:33]([O:35][CH3:36])=[C:32]([C:37]2[S:38][CH:39]=[CH:40][CH:41]=2)[CH:31]=1)#[CH:1]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COc1cc(OC)c(-c2cccs2)cc1C=O
Agent: BrC(Br)(Br)Br
Solvent: ClCCl
Product: C#Cc1cc(-c2cccs2)c(OC)cc1OC
Temperature: -78 °C
Reaction time: 8 h
Yield: 67.1 %

Procedure:
Ex-1B: A solution of triphenylphosphine (8.64 g, 32.9 mmol) and CBr4 (5.4 g, 16.3 mmol) in 140 mL of dichloromethane was stirred at room temperature for 15 min. Then 2,4-dimethoxy-5-thiophen-2-yl-benzaldehyde (3.1 g, 12.5 mmol) from Ex-1A was added, and the mixture was stirred overnight. The solvent was reduced to 30 mL and then filtered through silica gel with hexanes as eluent. After evaporation of the solvents, the crude 2-[5-(2,2-dibromo-vinyl)-2,4-dimethoxy-phenyl]-thiophene was dissolved in THF (40 mL) and cooled to −78° C. Then n-butyllithium (25.6 mmol, 16 mL of a 1.6 M solution in hexanes) was added dropwise while maintaining an internal temperature below −70° C. After stirring the reaction mixture for 1 h at −78° C., the reaction was quenched with a saturated NH4Cl solution. This solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was chromatographed on silica gel (hexane/ethyl acetate, 1:1) to give 2.05 g (67%) of 2-(5-ethynyl-2,4-dimethoxy-phenyl)-thiophene as a yellow solid, m.p. 141–142° C. 1H-NMR (300 MHz, CDCl3) δ 7.73 (s, 1H), 7.38 (dd, 1H, J=3.7 and 1.3 Hz), 7.28 (dd, 1H, J=5.2 and 1.3 Hz), 7.06 (dd, 1H, J=5.2 and 3.7 Hz), 6.51 (s, 1H), 3.96 (s, 6H), 3.27 (s, 1H).
Reaction SMILES: [NH2:1][OH:2].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]=O)=[CH:6][CH:5]=1>CO>[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([CH:14]=[N:1][OH:2])=[CH:6][CH:5]=1
Reactant: NO
Reactant: O=Cc1ccc(Br)c2ccccc12
Solvent: CO
Product: ON=Cc1ccc(Br)c2ccccc12

Procedure:
Hydroxylamine (50% aqueous, 0.37 ml) is added to a solution of 4-bromo-naphthalene-1-carbaldehyde (0.7 g) in methanol (6 ml). After 16 hours at room temperature the reaction is concentrated in vacuo to yield crude 4-bromo-naphthalene-1-carbaldehyde oxime, which is used in the next step without further purification.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[CH2:3][C:4]1[N:5]([CH:11]=[C:12]3[C:17]=1[C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[C:13]3=[O:23])[CH2:6]2.[C:24](=O)([O-])[O-].[K+].[K+].IC>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C.ClCCl>[CH3:24][CH:3]1[C:2]2[C:7](=[CH:8][CH:9]=[CH:10][CH:1]=2)[CH2:6][N:5]2[CH:11]=[C:12]3[C:17]([C:16](=[O:18])[C:15]4[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=4[C:13]3=[O:23])=[C:4]12
Reactant: O=C([O-])[O-]
Reactant: O=C1c2ccccc2C(=O)c2c1cn1c2Cc2ccccc2C1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: CI
Product: CC1c2ccccc2Cn2cc3c(c21)C(=O)c1ccccc1C3=O
Temperature: 25 °C
Yield: 9.8 %

Procedure:
A mixture of 5,14-dihydrobenz[5,6]isoindolo[2,1-b]isoquinoline-8,13-dione (0.96 g) (Intermediate 1), benzyl triethylammonium chloride (0.16 g), potassium carbonate (2.20 g) and iodomethane (0.45 ml) in acetonitrile (100 ml) was stirred and heated under reflux for 4 h. A further portion of iodomethane (0.5 ml) was added and the mixture was stirred at 80° C. for 1 h. The mixture was cooled to room temperature, diluted with dichloromethane (250 ml) and filtered. The filtrate was concentrated in vacuo and the residue was purified on preparative plates eluting five times with chloroform to give the title compound (98 mg) m.p. 215°-218° C. λmax (in CHCl3) 246.5 nm (ε51,050), 266.5 nm (ε18,250) and 366.55 nm (ε3,700).