Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([CH3:7])[N:6]=1.F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[F:18].C(=O)(O)[O-].[Na+].O>CS(C)=O>[F:18][C:10]1[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:9]=1[N:3]1[CH:4]=[C:5]([CH3:7])[N:6]=[C:2]1[CH3:1]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1c[nH]c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cn(-c2ccc([N+](=O)[O-])cc2F)c(C)n1
Temperature: 80 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
Step T (1): A mixture of 2,4-dimethyl-1H-imidazole (5.00 g, 52.0 mmol), 1,2-difluoro-4-nitrobenzene (8.27 g, 52.0 mmol), and sodium bicarbonate (4.37 g, 52.0 mmol) in DMSO (100 mL) was heated at 80° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The dark residue was dissolved in ethyl acetate (200 mL). Hexane (50 mL) was added to the solution. The resulting mixture was allowed to age for 72 h at rt. The resulting solid was collected by vacuum filtration. The solid was dried under high vacuum to afford 1-(2-fluoro-4-nitrophenyl)-2,4-dimethyl-1H-imidazole (6.68 g, 27.8 mmol, 54% yield) as a yellow crystalline solid. LC-MS (M+H)+=236.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.13-8.22 (m, 2 H), 7.51 (dd, J=8.9, 7.3 Hz, 1 H), 6.72 (s, 1 H), 2.28-2.36 (m, 3 H), 2.22-2.28 (m, 3 H).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])[CH:8]=1)C.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>>[Cl:25][C:26]1[CH:31]=[C:30]([C:19]2[CH:18]=[CH:17][C:16]([F:22])=[C:15]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=3)[O:6][CH2:5][C:4]([OH:3])=[O:24])=[O:23])[CH:20]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Product: O=C(O)COc1cccc(NC(=O)c2cc(-c3cccc(Cl)c3)ccc2F)c1

Procedure:
The phenyl bromide (139) (50 mg, 0.13 mmol) was coupled to 3-chloro-phenylboronic acid (20 mg, 0.13 mmol) using Method E. During this reaction, hydrolysis occurred and the residue was extracted using Work-up E1. The crude product was then triturated with TBME (2 ml), DCM (2 ml), and recrystallised from a hot 10% EtOH in H2O mixture to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28]([O:30]C)=O)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH3:37]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28]([NH2:37])=[O:30])=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1
Reactant: N
Solvent: CCO
Product: C[C@@H](c1ccc(-c2cncc(C(N)=O)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (30 mg, 0.1 mmol) was dissolved in anhydrous NH3 in EtOH (5 mL). Then the mixture was stirred at rt overnight. The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC to provide 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl) nicotinamide (10 mg, 34%). LC-MS Method 2 tR=1.022 min, m/z=478; 1H NMR (CD3OD): 1.31 (m, 1H), 1.56 (m, 3H), 1.59 (m, 1H), 1.91 (m, 2H), 2.17-2.28 (m, 1H), 2.33 (m, 1H), 2.44 (m, 1H), 3.14 (m, 1H), 3.44 (m, 2H), 5.60 (m, 1H), 7.04-7.17 (m, 4H), 7.29 (m, 2H), 7.49 (m, 2H), 8.41 (m, 1H), 8.86 (m, 1H), 8.97 (m, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]([O:5][CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1)=[O:4].[C:14]1([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCCl>[ClH:2].[N:8]12[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9]1)[C@@H:6]([O:5][C:3](=[O:4])[N:20]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:7]2
Reactant: O=C(Cl)OC1CN2CCC1CC2
Reactant: c1ccc(CNc2ccccc2)cc1
Agent: Cl
Solvent: ClCCCl
Product: O=C(O[C@H]1CN2CCC1CC2)N(Cc1ccccc1)c1ccccc1

Procedure:
To a suspension of 750 mg (2.58 mmol) of 3-quinuclidyl chloroformate hydrochloride in 20 mL of 1,2-DCE, a solution of 395 mg (2.15 mmol) of N-phenylbenzylamine in 5 mL of 1,2-DCE was added dropwise. Once completed the addition, the mixture was refluxed for three hours. The reaction crude was allowed to cool down and the solvent distilled off under reduced pressure. The residue was purified by column chromatography (SiO2, eluent: CHCl3-methanol 10:1) yielding 720 mg (1.95 mmol) of a hygroscopic foam corresponding to the title compound. IR (KBr, cm−1): 3400-3200, 2700-2300, 1700 cm−1. 1H-RMN (CDCl3): 12.30 (s, 1H), 7.20-6.90 (m, 10H), 5.10 (m, 1H), 4.83 (m, 2H), 3.52 (m, 1H), 3.18 (m, 4H), 2.80 (m, 1H), 2.34 (s, 1H), 1.92 (m, 2H), 1.60 (m, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[NH:23][N:24]=[C:25]([C:26](OC)=[O:27])[C:15]=3[N:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>O1CCCC1>[C:7]1([C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]3[NH:23][N:24]=[C:25]([CH2:26][OH:27])[C:15]=3[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1n[nH]c2c1nc(-c1ccccc1)c1ccccc12
Reaction time: 0.17 h

Procedure:
7.5 mg of lithium aluminum hydride were initially introduced into 1.5 ml of tetrahydrofuran and the mixture was stirred for 10 min. 6 mg of methyl 5-phenyl-1H-pyrazolo[4,3-c]isoquinoline-3-carboxylate (61) in 1.5 ml of tetrahydrofuran were then added dropwise. The mixture was stirred at 80° C. for 3 h, after which water was added and the whole was extracted with methylene chloride. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was purified by means of HPLC (Merk-Hibar-Lichrospher 100-RP-18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid) 80/20→10/90). The following was obtained: 62.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)[CH3:10]>C1(C)C=CC=CC=1>[CH3:10][C:9](=[N:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccccc1
Reactant: Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC(=Nc1ccc(C)cc1)c1ccccc1

Procedure:
p-Toluidine (0.20 mole), acetophenone (0.20 mole), and IRC-50 (weakly acidic) ion exchange resin (0.5 g.) are azeotropically refluxed in toluene (150 cc). The required amount of water is removed after 3 hrs. The solvent is removed on the rotary, and the residue is distilled under reduced pressure to give N-(methylbenzylidene)-p-toluidine. b.p. 129°-37° C./0.05 mm.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH:15]1[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH2:17][CH2:18]2)#[N:14].Br[CH2:24][CH:25]1[O:29][CH2:28][CH2:27][O:26]1>O1CCCC1>[C:13]([C:15]1([CH2:24][CH:25]2[O:29][CH2:28][CH2:27][O:26]2)[CH2:20][CH:19]2[CH2:21][CH2:22][CH:16]1[CH2:17][CH2:18]2)#[N:14]
Reactant: N#CC1CC2CCC1CC2
Reactant: BrCC1OCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: N#CC1(CC2OCCO2)CC2CCC1CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.6 %

Procedure:
84 ml of diisopropylamine are dissolved in 300 ml of absolute tetrahydrofuran. 39.9 ml of n-butyllithium (1.5 molar in hexane) are added at -20° C. under dry argon. After 30 minutes at room temperature, the mixture is cooled down to -78° C. and 8.1 g of 2-cyanobicyclo[2.2.2]octane in 30 ml of absolute tetrahydrofuran are stirred in, and, after 30 minutes at 0° C., the mixture is again cooled down to -78° C. and 10 g of 2-bromomethyl-1,3-dioxolane in 30 ml of tetrahydrofuran are added dropwise. The mixture is stirred for a further 45 minutes at -78° C., warmed up to room temperature and evaporated, and the residue is taken up in 2N acetic acid and ether, washed three times with water and dried over sodium sulfate and the solvent is removed. The crude product is chromatographed on silica gel with ethyl acetate/cyclohexane (1:6) as the mobile phase. 7.9 g of the title compound are obtained as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].[BrH:16]>C(O)(=O)C>[Br:16][C:11]1[S:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[N:12]=1
Reactant: N#CSCC(=O)c1cccc(Br)c1
Reactant: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Brc1cccc(-c2csc(Br)n2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
A suspension of 2-(3-bromophenyl)-2-oxoethyl thiocyanate (10.9075 g, 42.6 mmol), prepared in the previous step, in 64 mL of 30% hydrogen bromide in acetic acid was stirred under nitrogen at room temperature for 17 h. The yellow suspension was poured into 500 mL of 1 N NaOH (exotherm) and the mixture stirred at room temperature for 21 h. The solid present was collected by filtration, rinsed with water, ice-cold ethanol, hexane and then dried under high vacuum to give 2-bromo-4-(3-bromophenyl)-1,3-thiazole (11.3069 g, 83%) as a yellow solid, mp 88-90° C.; MS (ES) m/z 317.9 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=[CH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][O:4][N:3]=1.[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][CH:26]=2)[CH2:24][CH2:23]1)=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1([C:25]2[CH:26]=[CH:27][C:28]([C:11]3[CH:16]=[CH:15][C:14]([C:5]4[O:4][N:3]=[C:2]([CH3:1])[C:6]=4[CH:7]=[CH:8][CH2:9][CH2:10][C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[CH:13][CH:12]=3)=[CH:29][CH:30]=2)[CH2:23][CH2:24]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1nocc1C=CCCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C=CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 2, Step 2, using 5-4-bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][CH2:6][C:7]1([CH3:35])[CH2:12][CH2:11][C:10]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([OH:31])[C:23]=3[CH2:32][CH2:33][CH3:34])=[CH:16][C:9]=2[O:8]1)C.O1CCCC1.O.O.[OH-].[Li+]>O>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][CH2:19][CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:10]3[CH2:11][CH2:12][C:7]([CH3:35])([CH2:6][CH2:5][C:4]([OH:36])=[O:3])[O:8][C:9]=3[CH:16]=2)=[C:23]([CH2:32][CH2:33][CH3:34])[C:24]=1[OH:31])(=[O:30])[CH3:29]
Reactant: CCCc1c(OCCCOc2ccc3c(c2)OC(C)(CCC(=O)OCC)CC3)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCCCOc2ccc3c(c2)OC(C)(CCC(=O)O)CC3)ccc(C(C)=O)c1O
Yield: 95.7 %

Procedure:
To a mixture of 1.55 g of the ester from Example 3 and 35 ml of 1:1 tetrahydrofuran-water was added 2.3 g of lithium hydroxide monohydrate, with stirring. The mixture was stirred at room temperature for 22 hours then diluted with water and extracted 3 times with ether (ether extracts discarded). The aqueous solution was acidified to pH 1 by the addition of saturated aqueous oxalic acid and worked-up with ether in the usual manner. There was obtained 1.4 g (95.8%) of racemic-7-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]-3,4-dihydro-2-methyl-2H-1-benzopyran-2-propanoic acid as a viscous yellow oil.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16]3=[C:17]([CH2:19][S:20][CH2:21][CH2:22][N:15]3[C@H:14]3[CH2:23][CH2:24][N:25](C(OC(C)(C)C)=O)[CH2:26][C@@H:13]23)[CH:18]=1>>[CH2:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:16]3=[C:17]([CH2:19][S:20][CH2:21][CH2:22][N:15]3[C@H:14]3[CH2:23][CH2:24][NH:25][CH2:26][C@@H:13]23)[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCSC3
Product: c1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCSC3)cc1

Procedure:
Using benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 33, Part B was converted into the title compound of EXAMPLE 171. 1H NMR(CDCl3) δ: 7.42-7.25 (m, SH), 6.37 (d, 1H, J=1.8 Hz), 6.26 (d, 1H, J=2.2 Hz), 4.27 (s, 2H), 3.69 (ABq, 2H, JAB=15.2 Hz), 3.60-3.50 (m, 1H), 3.37-3.30 (m, 1H), 3.28-3.20 (m, 1H), 3.10-2.85 (m, 6H), 2.62 (dd, 1H, J=12.8, 9.1 Hz), 1.89-1.80 (m, 2H). LRMS (ES)+: 352.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([O:17]C(C)(C)C)=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]#[N:14])=[C:11]([C:15]([OH:17])=[O:16])[N:10]=[C:9]2[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1nc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 86.7 %

Procedure:
To a solution of tert-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-cyano-1H-imidazole-4-carboxylate (2.57 gram, 5.73 mmol) in dichloromethane (40 mL) is added trifluoroacetic acid and the resulting solution is stirred at room temperature for 20 hours and concentrated in vacuo. The residue is crystallised from diisopropyl ether to give pure 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (1.95 gram, 87% yield). Melting point: 200-202° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:25][C:26](=[O:28])[CH3:27]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:25][C:26](=[O:28])[CH3:27])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: CC(=O)CCl
Reactant: Cc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=O)COc1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.5 %

Procedure:
2-Methyl-8-hydroxyquinoline (0.80 g, 5 mmol), potassium carbonate (0.69 g, 5 mmol) and dry N,N-dimethylformamide (DMF) (40 ml) were stirred at room temperature for 30 min. To this solution was added chloroacetone (0.46 g, 5 mmol) in dry THF (10 ml) in one portion. The resulting mixture was stirred at room temperature for 24 h. (monitored by TLC) and then poured into ice water (100 ml). The pale yellow solid thus obtained was collected and crystallized from dichloromethane and ether to afford 2-methyl-8-(2-oxopropoxy)quinoline (10a) (0.77 g, 72%). mp: 99°-100° C.; 1H-NMR (CDCl3): δ2.35 (s, 3H, 2'-CH3), 2.79 (s, 3H, 2-CH3), 4.86 (s, 2H, OCH2), 6.88-7.44 (m, 3H, Ar--H), 7.33 (d, 1H, 3-H), 8.03 (d, 1H, 4-H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=S)[CH:13]=[CH:14][CH:15]=3)[CH:2]=1.[N:21]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][N:23]=[CH:22]1>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=[C:28]([NH2:29])[CH2:27][CH2:26][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:13]=[CH:14][CH:15]=3)[CH:2]=1
Reactant: NCCCn1ccnc1
Reactant: S=C1c2cccc3cccc(c23)N1Cc1cccnc1
Solvent: CCO
Product: NC(CCn1ccnc1)=c1c2cccc3cccc(c32)n1Cc1cccnc1
Yield: 73.8 %

Procedure:
A mixture of 2.75 g of 1-(3-pyridinylmethyl)-benz[cd]indole-2(1H)-thione (Cg), 1.4 g of 1H-imidazole -1-propanamine, 150 ml of ethyl alcohol and 3.5 g of mercuric acetate is reacted as described in Example 3, giving 2.7 g of the desired product, mp. 139°-141° C.
Reaction SMILES: [C:1]([O:5]/[N:6]=[C:7](\[C:16]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][N:17]=1)/[C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5]/[N:6]=[C:7](\[C:16]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[CH:18][N+:17]=1[O-:32])/[C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:9]=1[OH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)O/N=C(/c1cc(Br)ccc1O)c1ncccc1C#N
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)O/N=C(/c1cc(Br)ccc1O)c1c(C#N)ccc[n+]1[O-]
Yield: 32.9 %

Procedure:
A solution of (Z)-2-(5-bromo-2-hydroxybenzoyl)-3-cyanopyridine O-t-butyloxime (350 mg) and 50% m-chloroperbenzoic acid (710 mg) in chloroform (5 ml) was stirred for 6 hours at 50° C. The reaction mixture was cooled by aeration, which was poured into an aqueous solution of sodium sulfite. The mixture was stirred and subjected to extraction with chloroform. The extract solution was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give (Z)-2-(5-bromo-2-hydroxybenzoyl)-3-cyanopyridine N-oxide O-t-butyloxime (120 mg) (Compound 145).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.I[CH2:16][C:17](=[O:39])[C@@H:18]1[C@:35]2([CH3:36])[C@H:21]([C@H:22]3[C:32](=[CH:33][CH2:34]2)[C@:30]2([CH3:31])[C:25](=[CH:26][C:27](=[O:37])[CH:28]=[CH:29]2)[CH2:24][CH2:23]3)[CH2:20][C@H:19]1[CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:16][C:17](=[O:39])[C@@H:18]3[C@:35]4([CH3:36])[C@H:21]([C@H:22]5[C:32](=[CH:33][CH2:34]4)[C@:30]4([CH3:31])[C:25](=[CH:26][C:27](=[O:37])[CH:28]=[CH:29]4)[CH2:24][CH2:23]5)[CH2:20][C@H:19]3[CH3:38])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CI
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(CC(=O)[C@H]3[C@H](C)C[C@H]4[C@@H]5CCC6=CC(=O)C=C[C@]6(C)C5=CC[C@@]43C)CC2)cc1

Procedure:
Following the general procedure of EXAMPLES 1-6A, 7, 8, 11-19, 83, 126 and 139 and making non-critical variations but starting with 4 -(4-methoxyphenyl)piperazine (PREPARATION A-31) and 21-iodo-16αmethylpregna-1,4,9(11)-triene-3,20-dione (PREPARATION S-22), the title compound is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:8]2[C:16](=[O:17])[CH:15]3[CH:10]([CH:11]4[O:18][CH:14]3[CH:13]=[CH:12]4)[C:9]2=[O:19])[CH:7]=1>CO.[Pd]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:20][CH3:21])=[C:6]([CH:8]2[C:9](=[O:19])[CH:10]3[CH:15]([CH:14]4[O:18][CH:11]3[CH2:12][CH2:13]4)[C:16]2=[O:17])[CH:7]=1
Reactant: CCc1ccc(Br)cc1C1C(=O)C2C3C=CC(O3)C2C1=O
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(Br)cc1C1C(=O)C2C3CCC(O3)C2C1=O

Procedure:
A solution of (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-10-oxatricyclo[5.2.1.02,6]dec-8-en-3,5-dione (3.00 g, 8.6 mmol) in methanol (250 ml) is hydrogenated at 3.5 bar over 5% palladium on carbon for 2 hours at room temperature. The catalyst is removed by filtration through diatomaceous earth and the solvent is evaporated under reduced pressure to give (1RS,2SR,6RS,7SR)-4-(5-bromo-2-ethylphenyl)-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: CN(C=[CH:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])C.C1C[O:19]CC1>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]=[O:19])=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=1
Reactant: CN(C)C=Cc1ccc(F)cc1[N+](=O)[O-]
Reactant: C1CCOC1
Product: O=Cc1ccc(F)cc1[N+](=O)[O-]

Procedure:
N,N-Dimethyl-2-(4-fluoro-2-nitrophenyl)ethenylamine (6.72 g, 32 mmol) and NaIO4 (20.53 g, 96 mmol) were stirred in 50% aqueous THF (160 ml) at room temperature for 1.5 hours. The mixture was filtered in a celite pad and eluted with EtOAc. The organic layer was washed with NaHCO3 (saturated solution, 3×100 ml), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography (50% CH2Cl2 /hexane) affording 4-fluoro-2-nitro benzaldehyde as an orange oil.
Reaction SMILES: Cl.C([O:6][C:7]([C@:9]1([NH:28]C(OC(C)(C)C)=O)[CH2:14][C@H:13]([S:15][C:16]2[N:20]=[CH:19][NH:18][N:17]=2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:21]([O:23]C(C)(C)C)=[O:22])=[O:8])(C)(C)C>O1CCOCC1>[NH2:28][C@@:9]1([C:7]([OH:8])=[O:6])[CH2:14][C@H:13]([S:15][C:16]2[N:20]=[CH:19][NH:18][N:17]=2)[C@@H:12]2[C@H:10]1[C@H:11]2[C:21]([OH:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](Sc2nc[nH]n2)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@]1(C(=O)O)C[C@H](Sc2nc[nH]n2)[C@H]2[C@H](C(=O)O)[C@H]21

Procedure:
Add 4M hydrogen chloride in 1,4-dioxane (20 mL) to a solution of ditert-butyl(1R,2S,4S,5R,6R)-2-tert-butoxycarbonylamino-4-(1H-[1,2,4]triazol-3-ylsulfanyl)-bicyclo[3.1.0]hexane-2,6-dicarboxylate (1.64 g, 3.30 mmol) in 1,4-dioxane (20 mL) and shake mixture at 50° C. overnight. Concentrate to dryness. Purify by cationic ion exchange (DOWEX® Marathon C, Na+ Form strongly acidic). Dissolve the residue in a minimum amount of water to solubilize the material and load onto the resin. Wash the resin successively with 2 column volume of water, then 2 column volume of water: tetrahydrofuran (1:1) and 2 column volumes of water. Elute the desired product with 2 column volumes of 10% pyridine in water to give the title compound as a white solid. MS (m/z): 285 (M+1). 1H NMR (300 MHz, D2O): 4.25 (d, J=7.3 Hz, 1H), 2.53-2.38 (m, 3H), 2.23 (dd, J=8.1, 16.1 Hz, 1H), 1.95 (t, J=3.3 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27](I)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([F:31])[CH:37]=3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(I)cc2)n1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3cccc(F)c3)cc2)n1-c1ccc(Cl)cc1
Temperature: 170 °C
Yield: 53.5 %

Procedure:
A microwave reaction tube charged with 5-(4-chloro-phenyl)-6-(4-iodo-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (74.9 mg, 0.143 mmol), 3-fluorophenylboronic acid (39.9 mg, 0.285 mmol), and Pd(PPh3)4 (16.5 mg, 0.014 mmol) is purged with nitrogen. Toluene (3.5 mL) and Na2CO3 aqueous solution (2.0M, 0.75 mL) are added via syringe. The reaction mixture is heated in a microwave at 170° C. for 20 min, and is partitioned between water and ethyl acetate. The organic phase is washed with brine, dried over MgSC4, concentrated, and purified by silica gel chromatography to provide the title compound (37.7 mg, 54% yield) as a white solid product; 1H NMR (CDCl3, 400 MHz) δ 8.34 (s, 1H), 8.16 (dd, 2H), 7.52 (t, 2H), 7.48 (d, 2H), 7.43-7.33 (m, 7H), 7.25 (dt, 1H), 7.13 (d, 2H), 7.07 (td, 1H); HPLC-MS calculated for C29H18ClFN4O (M+H+) 493.1. Found: 493.1.