Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:41][C:42]4[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[CH:44][CH:43]=4)[CH:40]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].Cl[CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62].C(N(CC)CC)C>O1CCCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:57][O:58][CH2:59][CH2:60][Si:61]([CH3:64])([CH3:63])[CH3:62])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[C:26]([C:36]3[CH:37]=[N:38][N:39]([CH2:41][C:42]4[CH:43]=[CH:44][C:45]([O:48][CH2:49][C:50]5[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=5)=[CH:46][CH:47]=4)[CH:40]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cnn(Cc2ccc(OCc3ccccc3)cc2)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)ccc1-c1cnn(Cc2ccc(OCc3ccccc3)cc2)c1
Reaction time: 1 h

Procedure:
A mixture of EXAMPLE 4C (0.30 g) and (2-(chloromethoxy)ethyl)trimethylsilane (0.094 g) in tetrahydrofuran (4 mL) was treated with triethylamine (0.122 g) at room temperature. The reaction was stirred for 1 hour. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 5% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: CN(C)[C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C@@H:15]([CH3:25])[C@H:16]([OH:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:8][C:7]=1[N:26]([CH3:28])[CH3:27].Cl.[OH-:32].[Na+]>>[CH3:28][N:26]([CH3:27])[C:7]1[CH:8]=[C:9]([CH2:12][CH2:13][NH:14][C@@H:15]([CH3:25])[C@H:16]([OH:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:29])=[O:32]
Reactant: [OH-]
Reactant: C[C@H](NCCc1ccc(OCC(=O)N(C)C)c(N(C)C)c1)[C@H](O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Product: C[C@H](NCCc1ccc(OCC(=O)O)c(N(C)C)c1)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N,N-Dimethyl-2-[2-dimethylamino-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetamide (503 mg) was dissolved in 1N aqueous sodium hydroxide solution (6.0 ml), and the solution was stirred for 20 hours at room temperature. 1N Hydrochloric acid (6.0 ml) was added to the stirred reaction mixture under ice-cooling, and direct purification of the resulting mixture by medium pressure liquid column chromatography on ion exchange resin (Nippon Rensui Co. Ltd., DIAION® HP-20) (eluent:water/methanol=1/0 to 1/1) gave 2-[2-dimethylamino-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid (330 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:33]>C1COCC1>[Br:33][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(CO)ccc1C#N
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(CBr)ccc1C#N
Reaction time: 17 h

Procedure:
4-hydroxymethyl-2-methoxy-benzonitrile (from L-819,538, step 2, 2.0 g, 12.3 mmol) was dissolved in THF (61.5 ml) and treated with Ph3P (4.82 g, 18.4 mmol) followed by CBr4 (6.1 g, 18.4 mmol). The reaction was mixture stirred at room temp. for 17 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography (10% EtOAc/Hexane) to yield the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:16]=1)=[O:14])[CH2:8][CH2:7]2)([O-])=O.CO.[H][H]>[Pd].C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]([C:15]1[N:20]=[CH:19][N:18]=[C:17]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:16]=1)=[O:14])[CH2:8][CH2:7]2
Reactant: [H][H]
Reactant: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1)N1CCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc2c(c1)CCN2C(=O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1

Procedure:
Under a hydrogen atmosphere 30 mg (0.06 mmol) 1-{1-[6-(5-nitro-2,3-dihydro-indole-1-carbonyl)-pyrimidin-4-yl]-piperidin-4-yl}-1,3-dihydro-imidazo[4,5-b]pyridin-2-one and 10 mg palladium on charcoal (10%) were hydrogenated in a 1:1 mixture methanol:THF (5 mL each) at RT and 3 bar hydrogen pressure. Then the catalyst was removed by suction filtering and the filtrate was evaporated down i. vac. The residue was dissolved in 1 mL DMF, filtered through a syringe filter and purified by preparative HPLC. The product fractions were combined and lyophilised.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH2:18])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:19]1[CH2:24][CH2:23][S:22][CH2:21][C:20]1=[O:25]>C(O)C>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15][CH2:16][CH2:17][NH:18][C:20](=[O:25])[CH2:21][S:22][CH2:23][CH2:24][OH:19])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CSCCO1
Reactant: NCCCOc1cc(CN2CCCCC2)ccn1
Solvent: CCO
Product: O=C(CSCCO)NCCCOc1cc(CN2CCCCC2)ccn1
Yield: 87.5 %

Procedure:
A mixture of 0.38 g of 3-(4-piperidinomethyl-2-pyridyloxy)propylamine and 0.18 g of 1,4-oxathian-2-one was added to 10 ml of ethanol, and the resulting mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure. The concentrate was mixed with water, and the resulting aqueous mixture was extracted with ethyl acetate. The extract was concentrated by evaporation under reduced pressure, and the concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and methylene chloride as the eluent, to give 0.49 g (yield 88%) of the title compound as an oil.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:23])[F:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]([F:24])([F:22])[F:23])[CH:12]=2)[C:3]([OH:25])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.3 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid methyl ester (2.92 g, 7.72 mmol) in tetrahydrofuran/water (3:1, 88 mL) was treated with lithium hydroxide (647 mg, 15.43 mmol). The reaction was stirred at 25° C. for 3 d. The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (50 mL) and extracted with diethyl ether (25 mL). The aqueous layer was acidified to pH=1 with a 3N aqueous hydrochloric acid solution. The product was extracted into ethyl acetate (3×75 mL) and diethyl ether (1×50 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (2×100 mL), dried over magnesium sulfate and sodium sulfate, filtered, and concentrated in vacuo to give 3-cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-propionic acid (2.37 g, 84.5%) as a pale-yellow semi-solid: EI-HRMS m/e calcd for C16H19F3O4S (M+) 364.0956, found 364.0958.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][CH2:4][C@H:3]1[OH:13].C(N(CC)CC)C.[CH:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[C:24]1([S:27]([NH:1][C@@H:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][CH2:5][CH2:4][C@H:3]2[OH:13])(=[O:29])=[O:28])[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: N[C@@H]1c2ccccc2CCC[C@H]1O
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(N[C@@H]1c2ccccc2CCC[C@H]1O)c1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 71 %

Procedure:
To an ice-cold solution of trans-5-amino-6,7,8,9-tetrahydro-5H-benzocyclo hepten-6-ol (0.056 g, 0.32 mmol; example 15 a) in methylene chloride (10 ml) and triethylamine (1 ml) was added 4-benzene sulfonyl chloride (0.056 g, 0.32 mmol). The reaction mixture was stirred at 0° C. then allowed to come to room temperature for 72 hours. The reaction mixture was diluted with methylene chloride, then washed with 10% hydrochloric acid, saturated potassium hydrogen carbonate solution, dried over MgSO4, filtered and evaporated. Recrystallization from ethyl acetate/n-heptane yielded trans-5-(N-phenylsulfonylamino)-6,7,8,9-tetrahydro-5H-benzocyclo hepten-6-ol as white crystals (0.071 g, 71% yield), m.p. 128.0-128.2° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:11]=[C:9]([CH3:10])[CH2:8][C:4]1[CH:3]=[C:2](/[CH:14]=[CH:13]/[C:12]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6][CH:5]=1
Reactant: C=CC(=O)OC
Reactant: CC(=O)Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)/C=C/c1cccc(CC(C)=O)c1
Temperature: 25 °C
Yield: 105.9 %

Procedure:
A solution of 3-bromophenylacetone (50.0 g, 235 mmol), methyl acrylate (40.4 g, 469 mmol), palladium(II)acetate (7.9 g, 35.2 mmol), tri-ortho-tolylphosphine (21.4 g, 70.4 mmol) and triethylamine (82 ml) in acetonitrile (900 ml) was heated at reflux under a nitrogen atmosphere for a period of 16 hours. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. Purification by flash column chromatography eluting with pentane:ethyl acetate (90:10 changing to 70:30 by volume) gave the title compound as an orange oil (54.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.II.[Cl:15][C:16]1[C:21]([CH:22]=[O:23])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:24][C:25](=[O:27])[CH3:26].[NH4+].[Cl-]>C1COCC1>[Cl:15][C:16]1[C:21]([CH:22]([C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=2)[OH:23])=[CH:20][CH:19]=[CH:18][C:17]=1[NH:24][C:25](=[O:27])[CH3:26]
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Reactant: CC(=O)Nc1cccc(C=O)c1Cl
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(O)c2ccc(Cl)c(C(F)(F)F)c2)c1Cl
Temperature: 32.5 °C
Reaction time: 2.5 h
Yield: 74.5 %

Procedure:
A solution of 4-bromo-1-chloro-2-(trifluoromethyl)benzene (0.165 mol) in THF (30 ml) was added dropwise under N2 flow to a suspension of Mg (0.181 mol) and a crystal of I2 in THF (20 ml). The mixture was stirred at 30-35° C. for 2.5 hours and then cooled to 10° C. The mixture was added dropwise at 5° C. under N2 flow to a solution of N-(2-chloro-3-formylphenyl)acetamide (0.0788 mol) in THF (500 ml). The mixture was stirred at RT for 3 hours, poured out into ice and NH4Cl, and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography (eluent: CH2Cl2/CH3OH 98.5/1.5). The pure fractions were collected and the solvent was evaporated, yielding 22.2 g (74%) of (±)-N-[2-chloro-3-[[4-chloro-3-(trifluoromethyl)phenyl]hydroxymethyl]phenyl]acetamide (interm. 25).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
To a THF (200 mL) solution containing 3-(4-fluorophenyl)propanoic acid (33.6 g, 0.2 mol) was added a 1.0 M solution of LiAlH4 in Et2O (200 mL, 0.2 mol) over a period of 0.5 h. The resulting mixture was allowed to stir at RT for 18 h. The reaction was slowly quenched with H2O and the aqueous layer extracted (1×) with Et2O. The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The resulting oil was used in the next step without further purification. Isolated 31.4 g (0.2 mol, 100% yield).
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[NH:16]1[C:24]2[CH:23]=[CH:22][CH:21]=[C:20](B3OC(C)(C)C(C)(C)O3)[C:19]=2[CH:18]=[N:17]1>>[S:15]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]2[C:19]=1[CH:18]=[N:17][NH:16]2
Reactant: Brc1cc2c(s1)-c1ccccc1OCC2
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: c1ccc2c(c1)OCCc1cc(-c3cccc4[nH]ncc34)sc1-2

Procedure:
2-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine from Example 73 was reacted with indazole 4-boronic acid pinacol ester using standard Suzuki coupling procedure. Purification on prep HPLC and triturating with hexanes gave 140. 1H NMR (400 MHz, CDCl3): 3.34 (2H, t), 4.42 (2H, t), 7.07-7.11 (2H, m), 7.18-7.22 (1H, m), 7.35 (1H, s), 7.42-7.49 (3H, m), 7.79 (1H, dd), 8.50 (1H, s). MS: (ESI+) 319
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].[O-]S(C(F)(F)F)(=O)=O.F[N+:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][N:11]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccc(-c2nn[nH]n2)c1
Reactant: F[n+]1ccccc1
Agent: C[O-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CO
Product: Brc1cccc(-c2nnn(-c3ccccn3)n2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
5-(3-Bromophenyl)-2H-tetrazole (448 mg, 2.0 mmol) was stirred in anhydrous MeOH (15 mL) under argon at ambient temperature. To this was added NaOMe (4 mL of 0.5M solution in MeOH, 2.0 mmol), and the reaction flask was cooled to −78° C. A solution of N-fluoropyridinium triflate (331 mg, 1.0 mmol) in anhydrous MeOH (2 mL) was then added dropwise via syringe. The resulting reaction mixture was stirred at −78° C. for 30 min, then warmed to ambient temperature and stirred for an additional 3 h. The reaction mixture was partitioned between EtOAc (150 mL) and 10% aqueous NaHCO3 (50 mL). The EtOAc layer was washed with additional 10% aqueous NaHCO3 (2×50 mL), and the combined aqueous layers were back extracted with EtOAc (100 mL). The EtOAc layers were combined, dried (MgSO4), filtered and concentrated in vacuo. The crude material was then chromatographed on silica gel eluting with hexanes:EtOAc (3:1) to afford 2-[5-(3-bromophenyl)-2H-tetrazol-2-yl]pyridine as a white solid.
Reaction SMILES: N[C:2]1[N:3]=[C:4]([OH:19])[C:5]2[CH2:10][N:9]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8](=[O:18])[C:6]=2[N:7]=1.O.Cl.N([O-])=[O:23].[Na+]>>[CH2:11]([N:9]1[CH2:10][C:5]2[C:4]([OH:19])=[N:3][C:2]([OH:23])=[N:7][C:6]=2[C:8]1=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=N[O-]
Reactant: Nc1nc(O)c2c(n1)C(=O)N(Cc1ccccc1)C2
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C1c2nc(O)nc(O)c2CN1Cc1ccccc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-amino-6-benzyl-4-hydroxy-5H-pyrrolo[3,4-d]pyrimidin-7(6H)-one (8.721 g, 0.03403 mol) and water (510.7 mL, 28.35 mol) were mixed and the mixture was heated at 100° C. Conc. HCl was added slowly until the sample dissolved. The mixture was cooled at 90° C. then sodium nitrite (7.044 g, 0.1021 mol) in water (68.05 mL, 3.778 mol) was added dropwise. The reaction mixture was stirred at 90° C. for 1 hour then vacuum filtered hot to provide the product cv (3.187 g, 36%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([C:12]12[CH2:19][CH2:18][N:15]([CH2:16][CH2:17]1)[C:14](=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]2=[O:27])[CH:10]=[CH2:11].C[Si](Cl)(C)C.CN(P(N(C)C)(N(C)C)=O)C>[Cu].C1(C)C=CC=CC=1>[CH2:9]([C:12]12[CH2:17][CH2:16][N:15]([CH2:18][CH2:19]1)[CH:14]([CH:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:13]2=[O:27])[CH:10]=[CH2:11]
Reactant: C=CCC12CCN(CC1)C(=Cc1ccccc1)C2=O
Reactant: Br[Mg]c1ccccc1
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: C=CCC12CCN(CC1)C(C(c1ccccc1)c1ccccc1)C2=O
Temperature: 0 °C
Yield: 67.5 %

Procedure:
Copper(I) bromide dimethyl sulfide complex (1.06 g, 5.16 mmol) and 100 ml of toluene were placed in a reaction vessel, which was immersed into an dry-ice acetone bath. Phenylmagnesium bromide (3.0M in ether, 42 ml, 126 mmol) was slowly added to the copper catalyst keeping the inner temperature below -60° C. To this yellow-white suspension was added a solution prepared from 4-allyl-2-benzylidene-1-azabicyclo[2.2.2]octane-3-one (25.9 g, 103 mmol), trimethylsilyl chloride (31.4 ml, 247 mmol), HMPA (43 ml, 247 mmol) and toluene (120 ml) keeping below -60° C. After addition was completed, the reaction mixture was warmed up to 0° C. The reaction was quenched with 14.5 ml of acetic acid at -60° C. Water was added to the reaction mixture, which was neutralized with Na2CO3 (pH=6.5). The resulting solution was worked-up by an ordinal procedure (extraction with ether at pH=6.5, and then at pH=8.0, washing with brine, drying over Na2SO4, concentration by evaporation) to provide a crude product, which was triturated with ether to afford 4-allyl-2-diphenylmethyl-1-azabicyclo[2.2.2]octane-3-one, 58 (23.04 g, 68%).
Reaction SMILES: [C:1]1([C:6]2[S:14][C:13]3[C:12]([C:15]#[N:16])=[CH:11][N:10]=[C:9]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:8]=3[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.[OH-].[K+].C([OH:33])(C)(C)C>C(Cl)Cl>[C:1]1([C:6]2[S:14][C:13]3[C:12]([C:15]([NH2:16])=[O:33])=[CH:11][N:10]=[C:9]([NH:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[C:8]=3[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(C)O
Reactant: COc1ccc(CNc2ncc(C#N)c3sc(C4=CCCC4)cc23)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(CNc2ncc(C(N)=O)c3sc(C4=CCCC4)cc23)cc1

Procedure:
2-Cyclopent-1-enyl-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile 32 (0.020 g, 0.055 mmol), crushed KOH (0.10 g) and tert-butanol (1.5 mL) was brought to reflux for 45 minutes. The reaction mixture was diluted with CH2Cl2 (20 mL) and extracted with H2O (5 mL). The organic layer was concentrated in vacuo to provide 33. 1H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.34 (d, J=8 Hz, 2H), 6.91 (m, 3H), 6.24 (m 1H), 5.93 (bs, 2H), 5.37 (t, J=5 Hz,1H), 4.78 (d, J=5 Hz, 2H), 3.83 (s, 3H), 2.73 (m, 2H), 2.57 (m, 2H), 2.04 (p, J=7 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:21]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:15][CH:16]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 81.8 %

Procedure:
To a solution of 2-t-butoxycarbonyl-4'-methylbiphenyl (25.3 g, 95 mmol) in CCl4 (200 ml) were added freshly opened N-bromosuccinimide (17.6 g, 0.099 mole) and dibenzoyl peroxide (2.28 g, 0.0094 moles). the mixture was refluxed for 4 hours, cooled to room temperature and filtered. The filtrate was washed with sat. NaHSO3 (1×50 ml), sat. NaHCO3 (1×50 ml), water (1×50 ml), sat. NaCl (1×50 ml) and dried over MgSO4. The solution was filtered, and concentrated in vacuo. The residue was dissolved in 100 ml of hot hexane. Crystallization gradually took place as the solution cooled. The flask was finally cooled to -20° C. and the precipitate recovered by filtration. The solid was washed with ice cold hexanes and dried in vacuo to give 27 g (88%) of a white solid. 1H-NMR (CDCl3): 1.23 (s, 9H), 4.53 (s, 2H), 7.2-7.5 (m, 7H), 7.68 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[C:6]=2[N:13]=1.[CH2:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:17][CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:15]2)[C:5]2[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:15]3)[C:6]=2[N:13]=1
Reactant: Clc1nc(Cl)c2nc(Cl)nc(Cl)c2n1
Reactant: c1ccc2c(c1)CCNC2
Solvent: C1CCOC1
Product: Clc1nc(N2CCc3ccccc3C2)c2nc(Cl)nc(N3CCc4ccccc4C3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 7 %

Procedure:
To a solution of 2,4,6,8-tetrachloropyrimidopyrimidine (0.54 g, 8.0 mmol) in THF (50 ml) was added a solution of 1,2,3,4-tetrahydroisoquinoline (1.0 ml) in THF (15 ml) dropwise over 10 minutes. The mixture was stirred for 12 hours at 25° C., the resultant solid was removed by filtration. The filtrate was evaporated under reduced pressure to afford a brown solid. Chromatography on silica gel, employing petrol:EtOAc (8:2) as eluent, afforded the title compound as a pale brown powder (0.27 g, 7%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][C:7]([OH:16])=[CH:6][C:5]2=1.Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.[I-].[K+]>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]=[CH:11][C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][C:7]([O:16][CH2:18][CH:19]1[CH2:21][CH2:20]1)=[CH:8][CH:9]=3
Reactant: BrCC1CC1
Reactant: Oc1ccc2ccc3ccc(Br)cc3c2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Brc1ccc2ccc3ccc(OCC4CC4)cc3c2c1
Yield: 86.9 %

Procedure:
A mixture of 6-bromophenanthren-3-ol (0.823 g, 3.02 mmol) from Step 1 above, (bromomethyl)cyclopropane (0.5 mL, 5.4 mmol), potassium carbonate (2.5 g, 18 mmol) and potassium iodide (5 mg) in acetone (50 mL) was heated at reflux for 3 days. Water was then added and the reaction mixture extracted with ethyl acetate The organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography on silica (100% hexanes) to provide 3-bromo-6-(cyclopropylmethoxy)phenanthrene (0.859 g, 87%).