Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=1[F:22].[CH3:24][N:25](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:24]#[N:25])=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]=1[F:22]
Reactant: COC(=O)c1ccc(Cl)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1ccc(C#N)nc1Nc1ccc([Si](C)(C)C)cc1F

Procedure:
A degassed suspension of 6-chloro-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid methyl ester (4.8 g, 12.4 mmol), zinc cyanide (1.2 g, 10.2 mmol), and Pd(PPh3)4 (1.6 g, 1.36 mmol) in dimethylformamide (14 mL) was subjected to microwave irradiation at 190° C. for 20 minutes. This procedure was repeated seven times and all the reaction mixtures were combined and concentrated in vacuo. The resultant residue was dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium hydrogen carbonate. The aqueous layer was separated and extracted with ethyl acetate three times. The combined organic extracts were washed with water and then brine, dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was subjected to flash chromatography (silica, gradient 0% to 100%, diethyl ether in pentane) to afford the title compound as a yellow solid (18.2 g). LCMS (method B): RT=4.74 min, M+H+=344.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH2:44][CH2:45][CH:46]([OH:58])[CH2:47][N:48]1[CH2:57][CH2:56][C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH2:49]1>C(Cl)Cl>[CH2:49]1[C:50]2[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:56][CH2:57][N:48]1[CH2:47][CH:46]([OH:58])[CH2:45][NH:44][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: O=C(O)c1ccccc1-c1ccccn1
Reactant: NCC(O)CN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1ccccc1-c1ccccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.5 %

Procedure:
To a solution of 2-(pyridin-2-yl)benzoic acid (150 mg, 0.75 mmol) in DCM (6 mL) was added EDCI (215 mg, 1.1 mmol), HOBt (148 mg, 1.1 mmol), Et3N (228 mg, 2.25 mmol) and 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (185 mg, 0.9 mmol). The mixture was stirred at 25° C. for 16 h. The reaction solution was washed with water and extracted with DCM. The organic layer was then concentrated, and the residue was purified by prep-HPLC to give the title compound (80 mg, Yield 27.5%). 1H NMR (CD3OD, 400 MHz): δ 8.60-8.53 (m, 1H), 7.89-7.81 (m, 1H), 7.63-7.51 (m, 4H), 7.48-7.43 (m, 1H), 7.39-7.32 (m, 1H), 7.12-7.05 (m, 3H), 7.05-6.98 (m, 1H), 4.05-3.93 (m, 1H), 3.73-3.63 (s, 2H), 3.46-3.37 (m, 1H), 3.31-3.23 (m, 1H), 2.92-2.75 (m, 4H), 2.56 (s, 2H). LCMS (m/z): 388.2 (M+1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[CH2:23]([O:25][P:26]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([O:39][CH3:40])[CH:33]=1)(=[O:30])[O:27][CH2:28][CH3:29])[CH3:24]>>[CH2:28]([O:27][P:26]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)=[C:34]([O:39][CH3:40])[CH:33]=1)(=[O:30])[O:25][CH2:23][CH3:24])[CH3:29]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: CCOP(=O)(Cc1ccc(N)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(=O)NC)n2)c(OC)c1)OCC

Procedure:
Prepared according to the procedure described for Example 48 using (2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide and diethyl(4-amino-3-methoxybenzyl)phosphonate. 1H NMR (CD3OD, 400 MHz): δ=1.27 (t, J=7.07 Hz, 6H), 2.90 (s, 3H), 3.20-3.28 (m, 2H), 3.91 (s, 3H), 4.01-4.11 (m, 4H), 6.80 (dt, J=8.21, 2.21 Hz, 1H), 6.99 (t, J=2.15 Hz, 1H), 7.19 (td, J=7.58, 1.26 Hz, 1H), 7.48 (ddd, J=8.46, 7.20, 1.52 Hz, 1H), 7.64 (dd, J=7.83, 1.52 Hz, 1H), 7.96 (d, J=8.08 Hz, 1H), 8.30-8.36 (m, 2H). MS (ES+): m/z 568.1542 [MH+] (TOF, polar).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH:5]1[NH:14][C:15]([C:17]1[C:18](Cl)=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])[CH2:11]2>CC(N(C)C)=O.CCOC(C)=O>[CH:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH:5]1[NH:14][C:15]([C:17]1[C:18]([S:2][CH3:1])=[N:19][C:20]([Cl:23])=[CH:21][CH:22]=1)=[O:16])[CH2:11]2
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CSc1nc(Cl)ccc1C(=O)NC1C2CC3CC(C2)CC1C3
Temperature: 60 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
Sodium thiomethoxide (0.409 g, 5.84 mmol) was added to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (2 g, 6.15 mmol) in DMA (10 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 60° C. for 3 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with water (3×20 mL), and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product which was purified by crystallisation from EtOAc/isohexane to afford N-(2-adamantyl)-6-chloro-2-methylsulfanyl-pyridine-3-carboxamide (1.150 g, 55.5%) as a white solid
Reaction SMILES: S([O-])([O-])(=O)=O.[C:6]([C:11]1[CH:16]=[CH:15][C:14]([IH+:17])=[CH:13][CH:12]=1)([CH2:9][CH3:10])([CH3:8])[CH3:7].[C:18]([C:23]1[CH:28]=[CH:27][C:26]([IH+])=[CH:25][CH:24]=1)([CH2:21][CH3:22])([CH3:20])[CH3:19].[F:30][C:31]1[C:36]([S:37]([O-:40])(=[O:39])=[O:38])=[C:35]([F:41])[C:34]([F:42])=[C:33]([F:43])[C:32]=1[F:44].C[N+](C)(C)C>O>[F:30][C:31]1[C:36]([S:37]([O-:40])(=[O:39])=[O:38])=[C:35]([F:41])[C:34]([F:42])=[C:33]([F:43])[C:32]=1[F:44].[C:6]([C:11]1[CH:12]=[CH:13][C:14]([I+:17][C:26]2[CH:25]=[CH:24][C:23]([C:18]([CH2:21][CH3:22])([CH3:19])[CH3:20])=[CH:28][CH:27]=2)=[CH:15][CH:16]=1)([CH2:9][CH3:10])([CH3:7])[CH3:8]
Reactant: CCC(C)(C)c1ccc([IH+])cc1
Agent: C[N+](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: O=S(=O)([O-])c1c(F)c(F)c(F)c(F)c1F
Solvent: O
Product: CCC(C)(C)c1ccc([I+]c2ccc(C(C)(C)CC)cc2)cc1

Procedure:
60 g of t-amylbenzene, 39.5 g of potassium iodate, 81 g of acetic anhydride and 170 ml of dichloromethane were mixed together. Then 66.8 g of conc. sulfuric acid was slowly added dropwise thereinto under ice-cooling. After stirring under ice-cooling for 2 hours, the mixture was stirred at room temperature for additional 10 hours. 500 ml of water was added to the liquid reaction mixture under ice-cooling and the mixture was extracted with dichloromethane. The organic phase was washed with sodium hydrogencarbonate and water and then concentrated to give (4-t-amylphenyl)iodonium sulfate. This sulfate was added to a solution of tetramethylammonium pentafluorobenzenesulfonate in excess. After adding 500 ml of water, the solution was extracted with dichloromethane. Then the organic phase was washed with a 5% aqueous solution of tetramethylammonium hydroxide and water and then concentrated to give di(4-t-amylphenyl)iodonium pentafluorobenzenesulfonate (III-1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]([NH:19][O:20]C3CCCCO3)=[O:18])[C:10](=[O:32])[CH:9]=2)=[C:4]([F:33])[C:3]=1[F:34].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:31])([S:27]([CH3:30])(=[O:28])=[O:29])[C:17]([NH:19][OH:20])=[O:18])[C:10](=[O:32])[CH:9]=2)=[C:4]([F:33])[C:3]=1[F:34]
Reactant: C[C@@](CCn1ccc(-c2ccc(Cl)c(F)c2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: C[C@@](CCn1ccc(-c2ccc(Cl)c(F)c2F)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a heterogeneous mixture of (2R)-4-[4-(4-chloro-2,3-difluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (14500 mg, 26.94 mmol) in Ethanol (50 mL) and water (100 mL) was added a solution of PPTS (pyridinium p-touluenesulfonate) (7090 mg, 27.9 mmol). The mixture was stirred overnight at 70° C. and a solid formed. The solid was collected via filtration and dried to furnish the title compound as a white solid (5.7 g, 46.9%). The filtrate was concentrated to half the volume and more desired product formed and was collected via filtration to provide additional title compound (3.3 g, 27.1%). LCMS m/z 435.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 3H) 2.06-2.20 (m, 1H) 2.36-2.45 (m, 1H) 3.08 (s, 3H) 3.67-3.81 (m, 1H) 4.10 (ddd, J=12.20, 11.32, 4.78 Hz, 1H) 6.47 (dt, J=7.17, 1.98 Hz, 1H) 6.57-6.62 (m, 1H) 7.39-7.47 (m, 1H) 7.49-7.57 (m, 1H) 7.77 (d, J=7.22 Hz, 1H) 9.23 (br. s., 1H) 11.08 (s, 1H)19F NMR (376 MHz, DMSO-d6) 6 ppm −138.08 (dd, J=22.56, 7.52 Hz) −139.09 (dd, J=22.56, 7.52 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].CN(C1C=CC=CN=1)C.[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>ClCCl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:43]2[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:29])[N:22]=[C:23]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1
Reactant: CN1CCNCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCOc1ccc(S(=O)(=O)N2CCN(C)CC2)cc1-c1nn2c(C(CC)CC)nc(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.114 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-(1-ethylpropyl)-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride are initially charged in 5 ml of dichloromethane and a spatula tip of 4 dimethylaminopyridine is added, followed by 30 mg (0.342 mmol) of N-methylpiperazine. The mixture is stirred at room temperature overnight, diluted with dichloromethane, washed twice with saturated ammonium chloride solution, dried over sodium sulphate, concentrated and filtered through silica gel (methanol).
Reaction SMILES: C(OC([NH:11][NH:12][C:13]([C:15]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36]3[N:40]([C:41]([CH3:44])([CH3:43])[CH3:42])[N:39]=[CH:38][CH:37]=3)[N:30]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])=O)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[C:41]([N:40]1[C:36]([NH:35][C:31]2[N:30]=[C:29]([CH2:28][C:15]3([C:13]([NH:12][NH2:11])=[O:14])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH2:16]3)[CH:34]=[CH:33][CH:32]=2)=[CH:37][CH:38]=[N:39]1)([CH3:42])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(C(=O)NNC(=O)OCc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Cc2cccc(Nc3ccnn3C(C)(C)C)n2)(C(=O)NN)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 535 mg of tert-butyl 4-((2-((benzyloxy)carbonyl)hydrazino)carbonyl)-4-((6-((1-tert-butyl-1H-pyrazol-5-yl)amino)pyridin-2-yl)methyl)piperidine-1-carboxylate in 10 ml of methanol was added 200 mg of 20% palladium hydroxide on carbon, followed by stirring the reaction mixture at room temperature overnight under hydrogen atmosphere. Palladium catalyst was filtered off using Celite, washed with methanol, and the filtrate was concentrated in vacuo to give the title compound as a pale brown solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18]C)=[O:17])=[CH:12][C:11]=1[C:20]([F:23])([F:22])[F:21]>CCO>[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:11]=1[C:20]([F:21])([F:22])[F:23]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
Sodium hydroxide (5M; 10.2 mL; 51 mmol; 3 eq.) was added to a solution of methyl 2′-methyl-2-(trifluoromethyl)biphenyl-4-carboxylate (5 g; 17 mmol; 1 eq.) in EtOH (150 mL) and the reaction mixture was stirred at 60° C. for 2 hours. After concentration in vacuo, the residue was taken up in water (300 mL) and the aqueous phase was washed with ethyl acetate (2×100 mL). The pH was adjusted to 2 with conc. HCl and the solution was concentrated to ca. 150 mL. The precipitate was filtered off and dried to afford the title compound (3.33 g, 70%) as a beige solid.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][CH2:5][CH:6]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[N+:7]([O-:9])=[O:8].[CH3:17][N:18]1CN(C)CN(C)[CH2:19]1>>[CH:10]1([C:6]2([N+:7]([O-:9])=[O:8])[CH2:17][N:18]([CH3:19])[C:3](=[O:16])[CH2:4][CH2:5]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CN1CN(C)CN(C)C1
Reactant: COC(=O)CCC(C1CCCCC1)[N+](=O)[O-]
Product: CN1CC(C2CCCCC2)([N+](=O)[O-])CCC1=O
Temperature: 100 °C
Yield: 57.4 %

Procedure:
To 4.25 g (18.5 mmol) rac-4-cyclohexyl-4-nitro-butyric acid methyl ester were added 4.56 ml (32.5 mmol) 1,3,5-trimethylhexahydro-1,3,5-triazine and the mixture heated to 100° C. for 4 hours. The reaction mixture was cooled to ambient temperature and adsorbed on silica gel which was transferred on top of a silica gel column and purified by flash-chromatography with a gradient of heptane and 10 to 75% ethyl acetate: 2.55 g of title compound were isolated as colourless oil: MS (m/e): 240 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[N:7]([CH2:9][CH:10]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]=[C:23](Cl)[CH:22]=[C:21]([N:26]([CH3:33])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:20]=2)[CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[N:49]1[CH:54]=[CH:53][C:52](B(O)O)=[CH:51][CH:50]=1>O1CCOCC1.O.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>[C:1]([O:5][C:6](=[O:42])[N:7]([CH2:9][CH:10]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:20]=[C:21]([N:26]([CH3:33])[CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:22]=[C:23]([C:52]3[CH:53]=[CH:54][N:49]=[CH:50][CH:51]=3)[N:24]=2)[CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CC(COc1cccc(-c2nc(Cl)cc(N(C)C3CCOCC3)n2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccncc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CN(CC(COc1cccc(-c2nc(-c3ccncc3)cc(N(C)C3CCOCC3)n2)c1)O[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
To a solution of [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-chloro-6-[methyl-(tetrahydro-pyran-4-yl)-amino]-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (160 mg, 0.26 mmol) in degassed dioxane and H2O (4/1, 25 mL) was added Na2CO3 (83 mg, 0.78 mmol); Pd(PPh3)4 (30 mg, 0.026 mmol) and pyridin-4-ylboronic acid (64 mg, 0.52 mmol). The system was purged with N2 stream and the mixture was stirred 100° C. for 2 h., cooled down to room temperature, diluted with water (25 mL) and extracted with EtOAc (25 mL×2). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatographic column on silica gel (petroleum ether/EtOAc=10/1 to 1/1) to give [2-(tert-Butyl-dimethyl-silanyloxy)-3-(3-{4-[methyl-(tetrahydro-pyran-4-yl)-amino]-6-pyridin-4-yl-pyrimidin-2-yl}-phenoxy)-propyl]-methyl-carbamic acid tert-butyl ester (128 mg, 75% yield). ESI-LCMS (m/z): 664.4 [M+1]+.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[CH3:24].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36].O>CN(C=O)C>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:6][C:5]([CH3:15])=[CH:4][C:3]=1[CH2:16][NH:17][C:18]1[C:19]([CH3:26])=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:25][CH2:34][C:35]([O:37][CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: CC(C)OC(=O)CBr
Reactant: Cc1cc(CNc2c(C)ccc(O)c2C)c(F)c(-c2cccc(F)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)c(F)c(-c2cccc(F)c2)c1
Reaction time: 1 h
Yield: 74.4 %

Procedure:
To a solution of 3-[[2-fluoro-3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (114 mg, 0.32 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (158 mg, 0.48 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 30 min the isopropyl bromoacetate (70 mg, 0.39 mmol, 1.2 eq) was added. The reaction mixture was stirred a further 1 h then poured into water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc, 30:1 to 20:1) to give the title compound as colorless oil (108 mg, 76%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:16])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30].O>CCCCCC.C1(C)C=CC=CC=1>[Br:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:16][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Br:30]
Reactant: OCCCCCCCCCCCCO
Reactant: BrCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: BrCCCCCCCCCCCCOCCCCCCCCCCCCOCCCCCCCCCCCCBr
Temperature: 80 °C
Reaction time: 96 h
Yield: 56 %

Procedure:
Sodium hydride (60%, 652 mg, 16.3 mmol) washed with hexane was suspended in toluene (3 ml), 1,12-dodecanediol (1.50 g, 7.41 mmol) was added, 1,12-dibromododecane (6.08 g, 18.5 mmol) was added, and the mixture was stirred at 80° C. for 4 days. The reaction mixture was cooled to room temperature, and pure water (30 ml) was added dropwise thereto in a water bath to quench the reaction. The mixture was extracted with chloroform (100 ml), and washed 3 times with 1N hydrochloric acid (30 ml), 3 times with 5% aqueous sodium hydrogen carbonate solution (30 ml), and once with 20% aqueous sodium chloride solution (30 ml). The organic layer was dried over sodium sulfate and the solvent of the filtrate was evaporated. The residue was isolated and purified by silica gel column chromatography, and precipitated with methanol (50 ml) to give 1,12-bis-(12-bromododecyloxy)-dodecane (yield 56%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:18]([O:20]CC)=[O:19])[CH2:6][C:5]2=1.[Li+].[OH-]>C1COCC1.CCO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([C:15](=[O:17])[NH2:16])[CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([C:18]([OH:20])=[O:19])[CH2:6][C:5]2=1
Reactant: CCOC(=O)C1CCc2[nH]c3c(C(N)=O)cc(Br)cc3c2C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: NC(=O)c1cc(Br)cc2c3c([nH]c12)CCC(C(=O)O)C3
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of ethyl 6-bromo-8-carbamoyl-2,3,4,9-tetrahydro-1H-carbazole-3-carboxylate (0.9 g, 2.464 mmol) and LiOH (0.177 g, 7.39 mmol) in THF/EtOH/H2O (3/1/1) (25 mL) was stirred at room temperature for 72 hours The reaction mixture was concentrated and the residue was dissolved in water. Aqueous 1M HCl was added to this solution until pH=5 whereupon a light yellow solid precipitated. The solid was collected by filtration, washed with water, air-dried and used as such in the next reaction. LCMS: RT=0.96 min, m/z (M+H) 337.0/339.0.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:6])[CH2:2][CH3:3]>C1COCC1.CO.[OH-].[Na+].O>[CH2:22]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[C:15]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[CH:16]=1)[C:10]([OH:12])=[O:11])=[O:6])[CH2:23][CH3:24]
Reactant: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ccsc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCN(CCC)C(=O)c1cc(C(=O)O)cc(-c2ccsc2)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 3-[(dipropylamino)carbonyl]-5-(3-thienyl)benzoate (XLIX, step 3, 0.31 g, 0.88 mmol) in THF/methanol/sodium hydroxide (3/1/1, 5 mL) is stirred at 40 degrees C. for 2 hours. The reaction is cooled to 20–25 degrees C., diluted with water and extracted with ethyl acetate. The aqueous phase is acidified to pH=4 and extracted with ethyl acetate. The organic phase is washed with water and saline, dried over magnesium sulfate and concentrated under reduced pressure to give 3-[(dipropylamino)carbonyl]-5-(3-thienyl)benzoic acid (IX–L), ESI-MS (m/z) [M+H]+=332.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:19]([CH2:20][CH2:21][C@:3]12[CH3:4])[C@:16]1([CH2:17][OH:18])[C:11](=[CH:12][C:13](=[O:23])[CH2:14][C@@H:15]1[CH3:22])[CH2:10][CH2:9]3.[CH:24](S)([SH:26])[CH3:25].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(=O)C>[CH2:25]1[O:23][C:13]2([CH2:14][C@H:15]([CH3:22])[C@@:16]3([CH2:17][OH:18])[C:11]([CH2:10][CH2:9][C@@H:8]4[C@@H:19]3[CH2:20][CH2:21][C@@:3]3([CH3:4])[C@H:5]4[CH2:6][CH2:7][C@@H:2]3[OH:1])=[CH:12]2)[S:26][CH2:24]1
Reactant: C[C@H]1CC(=O)C=C2CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]3[C@]21CO
Reactant: CC(S)S
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Product: C[C@H]1CC2(C=C3CC[C@H]4[C@@H]5CC[C@H](O)[C@@]5(C)CC[C@@H]4[C@]31CO)OCCS2
Reaction time: 4 h

Procedure:
17β,19-Dihydroxy-1α-methyl-4-androsten-3-one in acetic acid is treated with ethanedithiol and p-toluenesulfonic acid. After 4 hours at room temperature, the solution is poured onto water and the mixture extracted with methylenechloride. The methylenechloride extracts are washed well with water, sodium hydroxide solution, water, dried over sodium sulfate and evaporated under reduced pressure to leave 17β,19-dihydroxy-1α-methyl-4-androsten-3-one 3-ethylenethioketal which is recrystallized once from a solution of acetone-hexane.
Reaction SMILES: [CH3:1][CH:2]1[NH:15][CH:14]=[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:15]2[CH:2]([CH3:1])[CH2:3][C:4]3[C:12]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[NH:6][C:5]=3[C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14]2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1=CNC(C)Cc2c1[nH]c1ccccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)C(C)Cc2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using ethyl 2-methyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylate and 4-fluorobenzoyl chloride; 1H-NMR (CDCl3): δ 10.44 (1H, br s), 8.01 (1H, s), 7.63 (2H, m), 7.52 (1H, d), 7.39 (1H, d), 7.24 (4H, m), 5.61 (1H, br s), 4.22 (2H, m), 3.43 (1H, dd), 3.10 (1H, dd), 1.19 (3H, t), 1.06 (3H, d); MS (ES): 393 (MH+).