Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[CH3:13][O:14][C:15](=[O:27])[CH:16]([NH2:26])[CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([O:24][CH3:25])[CH2:20][CH2:19]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[CH3:13][O:14][C:15](=[O:27])[CH:16]([NH:26][C:10](=[O:11])[CH2:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[CH3:1])[CH2:17][CH:18]1[CH2:19][CH2:20][N:21]([O:24][CH3:25])[CH2:22][CH2:23]1
Reactant: Cc1ccc(C)c(CC(=O)Cl)c1
Reactant: COC(=O)C(N)CC1CCN(OC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(CC1CCN(OC)CC1)NC(=O)Cc1cc(C)ccc1C
Reaction time: 0.5 h

Procedure:
2,5-Dimethylphenylacetyl chloride (2.1 g, 11.5 mmol) was added dropwise to a mixture of 2-amino-3-(1-methoxy-piperidin-4-yl)-propionic acid methyl ester (1.7 g, 7.8 mmol) and K2CO3 (2.1 g, 15.2 mmol) in 50 mL of THF at room temperature. After the addition, the mixture was stirred for 0.5 h and diluted with 50 ml of water. The mixture was extracted with EtOAc five times and the combined organic layers were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel. Yield: 1.2 g of 2-[2-(2,5-dimethyl-phenyl)-acetylamino]-3-(1-methoxy-piperidin-4-yl)-propionic acid methyl ester as a solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[C:4](=[O:14])[N:3]1[CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22]>O1CCOCC1.[Pd]>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([NH2:11])=[CH:8][CH:9]=2)[C:4](=[O:14])[N:3]1[CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22]
Reactant: O=C1CCC(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)C(=O)N1
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reaction time: 6.5 h
Yield: 69 %

Procedure:
A mixture of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-nitroisoindoline {alternatively named as N-(2,6-dioxopiperidin-3-yl)-4-nitrophthalimide} (1 g, 3.3 mmol) and 10% Pd/C (0.13 g) in 1,4-dioxane (200 mL) was hydrogenated at 50 psi for 6.5 hours. The catalyst was filtered through Celite and the filtrate concentrated in vacuo. The residue was crystallized from ethyl acetate (20 mL) to give 0.62 g (69%) of 1,3-dioxo-2-(2,6-dioxopiperidin-3-yl)-5-aminoisoindoline {alternatively named as N-(2,6-dioxopiperidin-3-yl)-4-aminophthalimide} as an orange solid. Recrystallization from dioxane/ethyl acetate gave 0.32 g of yellow solid: mp 318.5-320.5° C.; HPLC (nova Pak C18, 15/85 acetonitrile/0.1% H3PO4) 3.97 min (98.22%): 1H NMR (DMSO-d6) δ 11.08 (s, 1H), 7.53-7.50 (d, J=8.3 Hz, 1H), 6.94 (s, 1H), 6.84-6.81 (d, J=8.3 Hz, 1H), 6.55 (s, 2H). 5.05-4.98 (m, 1H), 2.87-1.99 (m, 4H); 13C NMR (DMSO-d6) δ 172.79, 170.16, 167.65, 167.14, 155.23, 134.21, 125.22, 116.92, 116.17, 107.05, 48.58, 30.97, 22.22; Anal. Calcd for C13H11N3O4: C, 57.14; H, 4.06; N, 15.38. Found: C, 56.52-H, 4.17; N, 14.60.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:10]([Mg]Cl)[CH3:11].C1COCC1.B(F)(F)F.CCOCC>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2([NH2:6])[CH2:11][CH2:10]2)[CH:7]=[CH:8][CH:9]=1
Reactant: N#Cc1cccc(Cl)c1
Reactant: CC[Mg]Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC1(c2cccc(Cl)c2)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-chlorobenzonitrile (1 g, 7.27 mmol) and titanium (IV) isopropoxide (2.34 mL, 8 mmol) in Et2O (35 mL) at −78° C. was added ethyl magnesium chloride in THF (5.71 mL, 15.99 mmol). The solution was stirred for 10 min at −78° C. then at 25° C. for 1 h. BF3.Et2O (1.82 mL, 14.54 mmol) was added and the solution was stirred for 1 h at 25° C. The reaction mixture was quenched with 1N HCl (22 mL) Et2O was added (100 mL). Then 10% aq. NaOH (70 mL) was added and the layers were separated. The organic layer was dried over Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC (Waters SunFire C18-ODB, 5 μm, 19×50 mm, 5% CH3CN/H2O 2.5 min, 5-100% CH3CN/H2O in 10 min, CH3CN/H2O containing 0.1% HCOOH flow: 20 mL/min) to give after lyophilization of the purified fractions the title compound. MS (UPLC-MS): 170 [M+H]+, 168 [M−H]−; tR (HPLC conditions f): 1.22 min.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:17][CH:18]=2)[CH2:13]1)=O)C1C=CC=CC=1.[H][H].[C:31]([OH:34])(=[O:33])[CH3:32]>[C].[Pd]>[C:31]([OH:34])(=[O:33])[CH3:32].[NH2:11][C@H:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])=[CH:17][CH:18]=2)[CH2:13]1
Reactant: [H][H]
Reactant: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](NC(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: CC(=O)O
Product: CN(C)C(=O)COc1ccc2c(c1)C[C@@H](N)CC2

Procedure:
(S)-2 -[2-(Benzyloxycarbonylamino)-1,2,3,4-tetrahydronaphthalen-7-yloxy]-N,N-dimethylacetamide (100 mg) and 20 mg of 10% palladium-carbon were suspended in 5 ml of acetic acid and the suspension was stirred at room temperature for 3 hours in an atmosphere of hydrogen. The catalyst was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was recrystallized from ethanoldiethyl ether to give 72 mg of (S)-2-(2-amino-1,2,3,4-tetrahydronaphthalen-7-yloxy)-N,N-dimethylacetamide acetate having a melting point of 135 to 142° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)[C:18]([NH2:21])=[N:19][CH:20]=2)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Si:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][C:42](Cl)=[O:43])=[CH:37][CH:36]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Si:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH2:41][C:42]([NH:21][C:18]2[C:17]([C:22]3[CH:26]=[CH:25][S:24][CH:23]=3)=[N:16][C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3])=[CH:14][CH:13]=3)=[CH:20][N:19]=2)=[O:43])=[CH:39][CH:40]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-c2cnc(N)c(-c3ccsc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Nc2ncc(-c3ccc(O[Si](C)(C)C(C)(C)C)cc3)nc2-c2ccsc2)cc1
Temperature: 50 °C
Reaction time: 15 h
Yield: 69 %

Procedure:
Under an argon atmosphere, to a mixture of 5-[4-(tert-butyldimethylsilyloxy)phenyl]-3-(thiophen-3-yl)pyrazin-2-amine (7g) (450 mg, 1.17 mmol) and 4-(dimethylamino)pyridine (15.5 mg, 127 μmol) dissolved in anhydrous pyridine (20 mL) was added 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) prepared above at 0° C. and the mixture was heated with stirring at 50° C. for 15 hours. After cooling to room temperature, to this was added water and the product was extracted with ethyl acetate (200 mL×3). The combined organic extract was washed successively with water (200 mL) and brine (200 mL), followed by drying over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by column chromatography (silica gel 50 g, n-hexane/ethyl acetate=3/1) to give Compound 11g (512 mg, 809 μmol, 69.0%) as a yellow solid. Rf=0.22 (n-hexane/diethyl ether=2/3); 1H NMR (400 MHz, DMSO-d6) δ 0.16 (s, 6H), 0.20 (s, 6H), 0.92 (s, 9H), 0.94 (s, 9H), 3.56 (s, 2H), 6.72-6.82 (AA′BB′, 2H), 6.93-7.02 (AA′BB′, 2H), 7.12-7.22 (AA′BB′, 2H), 7.50 (dd, 1H, J=2.9, 5.0 Hz), 7.59 (d, 1H, J=5.0 Hz), 7.81 (d, 1H, J=2.9 Hz), 8.04-8.12 (AA′BB′, 2H), 8.91 (s, 1H), 10.50 (s, 1H); 13C NMR (75.5 MHz, DMSO-d6) δ −4.6 (4C), 17.90, 17.95, 25.50 (3C), 25.54 (3C), 41.9, 119.6 (2C), 120.3 (2C), 125.7, 126.0, 127.7, 127.9, 128.2 (2C), 128.8, 130.5 (2C), 137.1, 138.2, 142.0, 143.5, 148.0, 153.9, 156.8, 169.9; IR (KBr, cm−1) 517, 669, 712, 741, 781, 806, 839, 914, 1007, 1082, 1105, 1169, 1261, 1341, 1362, 1441, 1472, 1508, 1605, 1665, 2857, 2886, 2930, 2955, 3057, 3227; HRMS (ESI+) m/z 654.2618 ([M+Na]+, C34H45N3NaO3Si2+ requires 654.2612).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[N:13]=[C:12](Cl)[N:11]([CH2:16][C:17]#[C:18][CH3:19])[C:10]=2[C:9](=[O:20])[N:8]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:7]1=[O:29])[CH3:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][N:41]([C:12]2[N:11]([CH2:16][C:17]#[C:18][CH3:19])[C:10]3[C:9](=[O:20])[N:8]([CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:7](=[O:29])[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:30])[C:14]=3[N:13]=2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC#CCn1c(Cl)nc2c1c(=O)n(CCc1ccccc1)c(=O)n2CC(=O)OCC
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)n(CCc1ccccc1)c(=O)n2CC(=O)OCC
Temperature: 150 °C
Yield: 86.9 %

Procedure:
A mixture of [7-(2-butynyl)-8-chloro-1-(2-phenylethyl)-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]acetic acid ethyl ester (273 mg) and piperazine-1-carboxylic acid tert-butyl ester (360 mg) was heated in an oil bath of 150° C. for 30 minutes. The reaction mixture was purified by silica gel column chromatography using 20–30% ethyl acetate/hexane to give 320 mg of the title compound.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1ccc(Cl)cc1Br
Product: CCSc1ncc(C(=O)c2cc(Cl)ccc2OC)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-4-chloroanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(5-chloro-2-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 324.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=3[CH3:23])[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][C@@H:29]1[CH2:33][S:32](=[O:35])(=[O:34])[NH:31][CH2:30]1>>[CH3:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:31]3[CH2:30][C@H:29]([CH3:28])[CH2:33][S:32]3(=[O:35])=[O:34])=[CH:3][C:4]=2[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4C[C@H](C)CS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 27.2 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (534 mg) described in Preparation Example 110 and (S)-4-methylisothiazolidine 1,1-dioxide (320 mg) described in Preparation Example 4 and by the reaction and treatment in the same manner as in Example 4, the title compound (163 mg) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[N:33][NH2:34])[C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:13]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:12]([Br:32])[CH:11]=1.[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36]>C1COCC1>[CH2:17]([O:16][C:15]1[CH:14]=[C:13]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]([Br:32])=[CH:11][C:10]=1[C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:35]([OH:36])=[N:34][N:33]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccccc1NC(=NN)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccccc1-n1c(O)nnc1-c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
1.7 A solution of 30.98 g of N-(2-methylphenyl)-3-bromo-4,6-dibenzyloxybenzamide hydrazone in 200 ml of THF is slowly added at 45-50° to a solution of 11.67 g of 1,1′-carbonyldiimidazole in 1 l of THF. The mixture is stirred at room temperature for 30 minutes, the solvent is removed, and the residue is subjected to conventional work-up, giving 26 g of 5-(2,4-dibenzyloxy-5-bromophenyl)-4-(2-methylphenyl)-3-hydroxy-4H-1,2,4-triazole, Rf 2.25.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:10]=2)[C:5](=[O:21])[N:4]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=2)[C:3]1=[O:32].[CH3:33][NH:34][CH3:35]>ClCCl.CCOCC>[CH3:33][N:34]([CH3:35])[C:27](=[O:28])[C:26]1[CH:30]=[CH:31][C:23]([CH2:22][N:4]2[C:5](=[O:21])[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([C:12]#[C:13][CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:7]=3)[N:2]([CH3:1])[C:3]2=[O:32])=[CH:24][CH:25]=1
Reactant: Cn1c(=O)n(Cc2ccc(C(=O)Cl)cc2)c(=O)c2cc(C#CCc3ccccc3)ccc21
Reactant: CNC
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C)C(=O)c1ccc(Cn2c(=O)c3cc(C#CCc4ccccc4)ccc3n(C)c2=O)cc1
Reaction time: 16 h

Procedure:
To a solution of 0.5 g (1.1 mmol) of compound obtained in Step 1 in 50 ml of dichloromethane, 10 ml of dimethylamine in ether were added and stirring was continued at room temperature for 16 hours. The reaction mixture was partitioned between 1 M HCl and dichloromethane. The organic layer was washed with saturated sodium bicarbonate, dried over magnesium sulfate, filtered, and concentrated to give 0.4 g of the desired product.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]([O:26]C)=[O:25])=[CH:21]3)=[CH:16][C:15]=1[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[CH2:9][CH2:8][CH2:7]2>CO.O>[Br:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C:14]1[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([C:24]([OH:26])=[O:25])=[CH:21]3)=[CH:16][C:15]=1[C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)[CH2:9][CH2:8][CH2:7]2
Reactant: COC(=O)c1ccc2cc(-c3ccc(F)cc3)c(N3CCCc4cc(Br)ccc43)cc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2cc(-c3ccc(F)cc3)c(N3CCCc4cc(Br)ccc43)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
Sodium hydroxide (39 mg, 0.97 mmol) was added to a solution of methyl 7-(6-bromo-1,2,3,4-tetrahydroquinolin-1-yl)-6-(4-fluorophenyl)naphthalene-2-carboxylate (120 mg, 0.24 mmol) in methanol (30 ml) and water (2 ml). The resulting solution was stirred overnight at room temperature and concentrated in vacuo. The residue was dissolved in water (20 ml) and adjusted to pH 4 with hydrochloric acid (3 N) to give the precipitation, which was collected by filtration to afford 7-(6-bromo-1,2,3,4-tetrahydroquinolin-1-yl)-6-(4-fluorophenyl)naphthalene-2-carboxylic acid as a yellow solid (80 mg, 69%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.CN(C)[N:15]=[CH:16][C:17]([F:20])=[CH:18][CH3:19]>C(Cl)(Cl)Cl>[F:20][C:17]1[CH:16]=[N:15][C:9]2[C:7](=[O:8])[C:5]3[C:4]([C:11](=[O:12])[C:10]=2[C:18]=1[CH3:19])=[CH:3][CH:2]=[CH:1][CH:6]=3
Reactant: CC=C(F)C=NN(C)C
Reactant: O=C1C=CC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cc1c(F)cnc2c1C(=O)c1ccccc1C2=O
Yield: 15 %

Procedure:
A solution of naphthoquinone (553 mg, 3.5 mmol) and 2-fluoro-2-butenal N,N-dimethylhydrazone was refluxed for 8 days in chloroform (15 ml.) After the solvent was evaporated at reduced pressure, the residue was chromatographed over silica gel column, eluting with petroleum ether-ethyl acetate (9:1) and yielded 63 mg (10%) of compound (I-k) and 90 mg (15%) of 3-fluoro-4-methyl-1-azaanthracen-9-10-dione. m.p. 190°-192° C. (CDCl3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[N:18]([CH3:29])[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[CH:21]=2)=[CH:11][C:10]=1[CH3:30])([CH3:7])[CH3:6])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:38](I)[CH3:39]>>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]([C:17]2[N:18]([CH3:29])[N:19]=[C:20]([C:22]3[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[CH:21]=2)[CH2:38][CH3:39])=[CH:11][C:10]=1[CH3:30])([CH3:6])[CH3:7])[CH3:2]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CNc2cc(-c3ccc(Cl)cc3)nn2C)cc1C
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C(C)(C)Oc1ccc(CN(CC)c2cc(-c3ccc(Cl)cc3)nn2C)cc1C
Temperature: 95 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
A solution of example 15 (1.8 g, 4 mmol) in MIK (50 mL) was treated with Cs2CO3 (5 g, excess) and Ethyl iodide (2 mL). The resulting mixture was stirred at 95° C. overnight under pressure. After cooling to rt the reaction mixture was filtered off and the filtrate was evaporated off. The residue was diluted with DCM, washed with water and drying over Na2SO4 and filtration evaporation to give the title compound (320 mg, 0.68 mmol) as oil in a 17% yield after purification by flash chromatography.
Reaction SMILES: [N:1]([C@@H:4]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:5]([O:10]CC1C=CC=CC=1)[C:6]([O:8][CH3:9])=[O:7])=[N+]=[N-].[CH3:24][OH:25]>[Pd]>[CH3:9][O:8][C:6](=[O:7])[C@H:5]([OH:10])[C@H:4]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[NH:1][C:24](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](OCc1ccccc1)[C@@H](N=[N+]=[N-])c1ccccc1
Reactant: CO
Agent: [Pd]
Product: COC(=O)[C@H](O)[C@@H](NC(=O)c1ccccc1)c1ccccc1
Reaction time: 48 h
Yield: 74 %

Procedure:
The azide 10 (10 g, 24 mmol) was hydrogenated with 10% Pd/C (2.5 g) in methanol under H2 (50 p.s.i.) for 4 h. The solution was filtered, stood at 23° C. for 48 h, and concentrated. The solid was recrystallized over chloroform-methanol (50:1) to give 16 (5.5 g, 74%):[a]D20=-49 (c 1, CH3OH), lit. [a]D20=-49.6° (c 1, CH3OH); 1H NMR (CD3OD) d 3.68 (s, 3H), 4.60 (d, J=3.8 Hz, 1 H), 5.58 (d, J 3.8 Hz, 1 H), 7.32-7.61 (m, 8 H), 7.98-8.11 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:42]=[C:41]([O:43][CH3:44])[CH:40]=[CH:39][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[CH:15]=[CH:14][N:13]([C@H:16]3[C@@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@@H:19]4[C@@H:18]([CH2:26][N:27]([CH2:37][CH3:38])[CH:28]4[CH2:31][CH:30]([CH2:32][CH2:33][C:34]([OH:36])=O)[CH2:29]4)[CH2:17]3)[C:9]=2[N:10]=[CH:11][N:12]=1.C(N(CC)C(C)C)(C)C.[C:54]([C:58]1[CH:59]=[C:60]([NH2:65])[C:61]([NH2:64])=[CH:62][CH:63]=1)([CH3:57])([CH3:56])[CH3:55]>CN(C)C=O>[NH2:65][C:60]1[CH:59]=[C:58]([C:54]([CH3:56])([CH3:55])[CH3:57])[CH:63]=[CH:62][C:61]=1[NH:64][C:34](=[O:36])[CH2:33][CH2:32][CH:30]1[CH2:29][CH:28]([N:27]([CH2:26][C@@H:18]2[C@@H:19]3[C@@H:20]([O:21][C:22]([CH3:24])([CH3:25])[O:23]3)[C@H:16]([N:13]3[C:9]4[N:10]=[CH:11][N:12]=[C:7]([NH:6][CH2:5][C:4]5[CH:39]=[CH:40][C:41]([O:43][CH3:44])=[CH:42][C:3]=5[O:2][CH3:1])[C:8]=4[CH:15]=[CH:14]3)[CH2:17]2)[CH2:37][CH3:38])[CH2:31]1
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCC(=O)O)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN(C[C@H]1C[C@@H](n2ccc3c(NCc4ccc(OC)cc4OC)ncnc32)[C@@H]2OC(C)(C)O[C@H]12)C1CC(CCC(=O)Nc2ccc(C(C)(C)C)cc2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
N,N,N′,N′-Tetramethyl-0-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.84 g, 2.2 mmol) added to a solution 3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(ethyl)amino)cyclobutyl)propanoic acid (0.89 g, 1.5 mmol) and N,N-Diisopropylethylamine (0.84 ml, 4.8 mmol) and 4-tert-butylbenzene-1,2-diamine (0.29 g, 1.8 mmol) in N,N-Dimethylformamide (9 ml). The reaction was stirred overnight at RT, partially concentrated to ca. 2 ml and then NaHCO3 (saturated) was added. The mixture was extracted with EtOAc (3×) and the combined organics were dried with MgSO4, filtered and concentrated. The residue was purified by flash chromatography (DCM I 7N NH3 in MeOH 94:6) to give the desired compound (0.88 g) as a colorless solid. Retention time C, 3.363 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][N:25]3S(C3C=CC=CC=3)(=O)=O)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:48][CH2:47][N:46]5[CH2:49][CH2:50][CH2:51][C@H:45]5[CH2:44]4)=[N:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:11])=[O:10].[OH-].[Na+]>O1CCOCC1.CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([O:52][CH3:53])=[N:15][CH:16]=[C:17]([C:19]2[CH:27]=[C:26]3[C:22]([CH:23]=[N:24][NH:25]3)=[C:21]([C:37]3[O:38][C:39]([CH2:42][N:43]4[CH2:48][CH2:47][N:46]5[CH2:49][CH2:50][CH2:51][C@H:45]5[CH2:44]4)=[N:40][N:41]=3)[CH:20]=2)[CH:18]=1)(=[O:11])=[O:10]
Reactant: COc1ncc(-c2cc(-c3nnc(CN4CCN5CCC[C@H]5C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: COc1ncc(-c2cc(-c3nnc(CN4CCN5CCC[C@H]5C4)o3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.5 %

Procedure:
2,4-Difluoro-N-[5-[4-{5-[(8aS)-hexahydropyrrolo[1,2-a]pyrazin-2(1H)-ylmethyl]-1,3,4-oxadiazol-2-yl}-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]benzenesulfonamide (84 mg, 0.110 mmol) was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 0.110 mmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was dried down under a stream of nitrogen and the residue partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml). The organic layer was separated, dried by passing through a hydrophobic frit and the solvent removed in vacuo to give a brown gum. This was dissolved in DMSO (1 ml) and purified by high pH MDAP (Method E, extended run). The product-containing fraction was dried under a stream of nitrogen to give the title compound as a cream solid (2.4 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]2[NH:6][CH:7]=[N:8][C:4]=2[CH:3]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][O:11]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: Brc1ccc2[nH]cnc2c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc2c(c1)ncn2C1CCCCO1
Temperature: 80 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
A mixture of 78 (4.5 g, 23 mmol), 3,4-dihydro-2H-pyran (9 mL, 0.1 mol), p-TsOH.H2O (1.0 g, 3.4 mmol) in THF (200 mL) was stirred under nitrogen at 80° C. for 18 h. The reaction mixture was concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with DCM/MeOH (100:1) to afford 6.0 g (100%) of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazole (80) as yellow oil: MS (ESI) m/z=281.0 (M+1).