Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:36]=[CH:37][C:38]=1[OH:39])[O:7][CH2:8][CH2:9][N:10](CC1C=CC=CC=1)[CH2:11][CH:12]([OH:28])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:17][CH:16]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[C:1]([C:4]1[CH:5]=[C:6]([CH:36]=[CH:37][C:38]=1[OH:39])[O:7][CH2:8][CH2:9][NH:10][CH2:11][CH:12]([OH:28])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:23][CH2:24][CH:25]2[CH2:27][CH2:26]2)=[CH:17][CH:16]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(CCOCC3CC3)cc2)ccc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNCC(O)COc2ccc(CCOCC3CC3)cc2)ccc1O

Procedure:
A solution of 30 g of crude 1-[N-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethyl]-benzylamino]-3-[4-[2-(cyclopropylmethoxy)ethyl]-phenoxy]-2-propanol in 600 ml of methanol is hydrogenated, with the addition of 4 g of a Pd/C catalyst (5%), under normal conditions until 1 mol-equivalent of hydrogen has been absorbed. By the addition of dioxane and by heating, the product which has already crystallised out is taken into solution; the catalyst is filtered off and the filtrate is concentrated by evaporation. Recrystallisation from isopropanol and then from methanol yields pure 1-[2-(3-carbamoyl-4-hydroxy-phenoxy)-ethylamino]-3-[4-[2-(cyclopropylmethoxy)-ethyl]-phenoxy]-2-propanol, m.p. 149°-150°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-])=O)[CH:15]=2)=[O:11])=[CH:6][C:5]=1[Br:23]>O.C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=2)=[O:11])=[CH:6][C:5]=1[Br:23]
Reactant: COC(=O)c1ccc(C(=O)NCc2cccc([N+](=O)[O-])c2)cc1Br
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(C(=O)NCc2cccc(N)c2)cc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8.7 %

Procedure:
Iron powder (135 mg, 2.4 mmol) was added to a suspension of 2-bromo-4-[[(3-nitrobenzyl)amino]carbonyl]benzoic acid methyl ester (Example 85; 125 mg, 3.18 mmol) in water (530 μL) and acetic acid (111 μL) at 25° C. The reaction was heated to reflux for 30 min and then cooled to 25° C. The suspension was diluted with water (20 mL), stirred 15 min, filtered over Celite® and washed well with water (100 mL). The filtrate was washed with ethyl acetate (50 mL) followed by ethyl acetate containing 2% methanol (50 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated. The residue was diluted with 10% methanol in dichloromethane and stirred with Celite®. After 1 h, the suspension was filtered and washed well with 10% methanol in dichloromethane and the combined filtrates were evaporated to dryness to give 2-bromo-4-[[(3-aminobenzyl)amino]carbonyl]benzoic acid methyl ester (100 mg, 87% yield) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([NH:13][C@@H:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:15]([OH:17])=O)=[O:12])[NH:8][C:5]2=[CH:6][N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:50]1[O:59][C:53]2([CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)[O:52][CH2:51]1.CCN(C(C)C)C(C)C>CN(C=O)C>[O:52]1[C:53]2([CH2:58][CH2:57][N:56]([C:15](=[O:17])[C@@H:14]([NH:13][C:11]([C:9]3[NH:8][C:5]4=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]4[CH:10]=3)=[O:12])[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH2:55][CH2:54]2)[O:59][CH2:50][CH2:51]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)c1cc2cc(Cl)ncc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC2(CC1)OCCO2)c1cc2cc(Cl)ncc2[nH]1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(S)-[(5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carbonyl)amino]-3-(4-fluorophenyl)propionic acid (EXAMPLE 228, 40 mg, 0.11 mmol) in DMF (4 mL) was added HATU (50 mg, 0.13 mmol) and the reaction stirred for 10 min. 4-Piperidone ethylene ketal (19 mg, 0.13 mmol) was added, followed by DIPEA (23 μL, 0.13 mmol) and the reaction stirred at rt for 16 h. Solvent was removed in vacuo and the crude material partitioned between ethyl acetate (15 mL) and water (15 mL). The organic layer was washed with 1M HCl solution (15 mL), sodium bicarbonate solution (2×20 mL) then brine (2×20 mL), dried (MgSO4) and the solvent removed in vacuo. Purification by chromatography using dichloromethane/methanol (9:1) as the eluent gave the title compound as a pale yellow powder. (ES+)=487.30 [M+H]+; RT=3.28 min.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][O:16][C:17]([C:19]1[C:23]([N+:24]([O-:26])=[O:25])=[C:22]([C:27]([O:29][CH3:30])=[O:28])[NH:21][N:20]=1)=[O:18].[CH2:31]([O:34][CH2:35][CH2:36]O)[CH2:32][CH3:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N+:24]([C:23]1[C:19]([C:17]([O:16][CH3:15])=[O:18])=[N:20][N:21]([CH2:36][CH2:35][O:34][CH2:31][CH2:32][CH3:33])[C:22]=1[C:27]([O:29][CH3:30])=[O:28])([O-:26])=[O:25]
Reactant: COC(=O)c1n[nH]c(C(=O)OC)c1[N+](=O)[O-]
Reactant: CCCOCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)OC
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
Diisopropyl azodicarboxylate (14.2 mL, 70 mmol) was added to an ice-cooled solution of 4-nitro-1H-pyrazole-3,5-dicarboxylic acid dimethyl ester (EP 1241170, prep 10) (15 g, 60 mmol), 2-propoxyethanol (8.2 mL, 70 mmol) and triphenylphosphine (18.9 g, 70 mmol) in tetrahydrofuran (150 mL), and the reaction stirred at 0° C. for 2.5 hours, then allowed to stir at room temperature for a further 18 hours. The reaction was concentrated in vacuo and the residue purified by column chromatography on silica gel using ethyl acetate:pentane as eluant, and then re-columned using dichloromethane as eluant to afford the title compound as a solid, 14 g.
Reaction SMILES: [CH3:1][CH:2]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([Cl:20])[C:6]([Cl:19])=[C:7]([O:17][CH3:18])[CH:8]=2)[C:3]1=[O:21].[CH3:22]I.C[O-].[Na+]>CN(C)C=O>[CH3:1][C:2]1([CH3:22])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:9]2[C:4](=[C:5]([Cl:20])[C:6]([Cl:19])=[C:7]([O:17][CH3:18])[CH:8]=2)[C:3]1=[O:21]
Reactant: CI
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)C2c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C)C2c1ccccc1

Procedure:
2-Methyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone (9.63 g., 0.03 mole) and methyl iodide (18.7 ml., 0.3 mole) dissolved in dimethylformamide (100 ml.) at 25° C under nitrogen are treated portionwise with sodium methoxide (4.2 g., 0.036 mole) over a 45 minute period. Sodium iodide is filtered off, and the yellow filtrate is added to water (500 ml.) to precipitate 6.57 g. of 2,2-dimethyl-3-phenyl-5-methoxy-6,7-dichloro-1-indanone which melts at 146°-148° C. after crystallization from cyclohexane.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])[N:9]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=2)=[CH:21][N:20]=1)([O-])=O>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][N:30]=[C:29]([O:33][CH3:34])[CH:28]=3)=[CH:21][N:20]=2)[N:9]=1)[CH3:1]
Reactant: CN(C)Cc1nc(CSCCN)cs1
Reactant: COc1cc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)ccn1
Solvent: CCO
Product: COc1cc(Cc2cnc(NCCSCc3csc(CN(C)C)n3)[nH]c2=O)ccn1

Procedure:
Following the procedure of Example 1, a reaction mixture was prepared from 1.62 g. of 2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethylamine and 1.94 g. of 2-nitroamino-5-(2-methoxy-4-pyridyl)methyl-4-pyrimidone and 30 ml. of ethanol. The reaction mixture was stirred and heated at refluxing temperature for about 42 hours. The volatile constituents were removed by evaporation and the residue purified by high pressure liquid gradient elution chromatography (silica-ethanol/ethyl acetate/ammonium hydroxide). Fractions containing 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(2-methoxy-4-pyridyl)methyl-4-pyrimidone were combined and the solvent removed therefrom. Recrystallization of the resulting residue from a cyclohexane-ether solvent mixture gave 2-[2-(2-dimethylaminomethyl-4-thiazolylmethylthio)ethyl]amino-5-(2-methoxy-4-pyridyl)methyl-4-pyrimidone melting at 79°-80° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[C:28]12([NH2:38])[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH2:29]1)[CH2:35]2>C(Cl)(Cl)Cl>[C:28]12([NH:38][C:12]([C:9]3[C:8](=[O:15])[N:7]4[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]4=[N:11][CH:10]=3)=[O:14])[CH2:35][CH:34]3[CH2:33][CH:32]([CH2:31][CH:30]([CH2:36]3)[CH2:29]1)[CH2:37]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cccc2ncc(C(=O)NC34CC5CC(CC(C5)C3)C4)c(=O)n12
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
A mixture containing 4.08 (0.02 mole) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 3.1 ml (0.022 mol) of triethylamine in 120 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 2.52 ml (0.026 mol) of methyl chloroformate in 10 ml of chloroform is dropped to the above mixture at -15° C. during 10 minutes. After stirring for 5 minutes, 3.33 g (0.022 mol) of 1-adamantanamine dissolved in 20 ml of chloroform are dropped to the above solution at -15° C. during 15 minutes. The reaction mixture is stirred below -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 70 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 70 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 4.4 g (65.2%) of the named product as pale yellow crystals after recrystallization from ethanol, m.p.: 190°-193° C.
Reaction SMILES: [NH2:1][C:2](=[S:14])[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.Br[CH2:16][C:17](=O)[C:18]([OH:20])=[O:19]>C(#N)C>[CH2:12]([O:11][C:9]([C:7]1[CH:6]=[N:5][N:4]([CH2:3][C:2]2[S:14][CH:16]=[C:17]([C:18]([OH:20])=[O:19])[N:1]=2)[CH:8]=1)=[O:10])[CH3:13]
Reactant: O=C(O)C(=O)CBr
Reactant: CCOC(=O)c1cnn(CC(N)=S)c1
Solvent: CC#N
Product: CCOC(=O)c1cnn(Cc2nc(C(=O)O)cs2)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution (9 mL) of the compound (2.0 g, 9.38 mmol) obtained in Example 1b in acetonitrile was added 3-bromo-2-oxopropanoic acid (1.9 g, 11.3 mmol), and the mixture was stirred at 80° C. for 2 hr. The resulting crystals were collected by filtration and washed with hexane to give the title compound (2.56 g, 97%) as pale-brown crystals.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=1[CH3:31]>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[C:23]([CH3:31])[CH:24]=2)=[CH:7][C:6]=1[F:8]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Product: COc1ccc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)cc1C

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 3-methyl-4-methoxyphenylboronic acid (Step 2) to give 1,2-difluoro-4-(4-methoxy-3-methylpheny)-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 160.5-161.5° C.; NMR (CDCl3) δ 2.11 (S, 3H), 3.04 (S, 3H), 3.79 (S, 3H), 6.63 (d, J=9 Hz, 1H), 6.74 (dd, J=2, 9 Hz, 1H), 6.85 (d, J=2 Hz, 1H), 7.15-7.27 (m, 3H), 7.30 (d, J=8 Hz, 1H), 7.80 (d, J=8 Hz, 2H); MS (FAB) m/z 395 (M+Li)+; HRMS calc'd for M+ 388.0945, found 388.0940. Anal. for C21H18F2O3S: C, 64.94; H, 4.67; F, 9.78. Found: C, 64.59; H, 4.84; F, 9.52.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][NH:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:24](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:24][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[N:11]=2)[C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8]1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCOC(=O)c1c[nH]c2nc(C)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(N)c2nc(C)ccc2c1=O
Reaction time: 17 h
Yield: 63.1 %

Procedure:
A mixture of 9.7 g (0.0417 m) of ethyl 1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate, 11.5 g (0.0834 m) of potassium carbonate and 200 ml of dimethylformamide was slurried at room temperature, and 8.3 g (0.0417 m) of O-(2,4-dinitrophenyl)hydroxylamine was added. The reaction mixture was stirred for 17 hours and then concentrated in vacuo. The residue was dissolved in 1 liter of warm water and extracted with 800 ml of chloroform. The extracts were filtered, dried over anhydrous magnesium sulfate, decolorized with charcoal and concentrated in vacuo. The residue was recrystallized from ethanol and chromatographed on silica gel, using isopropyl alcohol-chloroform (1:9) for elution, to give 6.5 g of ethyl 1-amino-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate, buff-colored solid, m.p. 173°-174° C. when recrystallized from ethanol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][C:11]([O:14]CC2C=CC=CC=2)=[CH:10][CH:9]=1>CO.[OH-].[OH-].[Pd+2]>[CH3:1][O:2][C:3](=[O:23])[CH2:4][CH2:5][NH:6][C:7](=[O:22])[C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1
Reactant: COC(=O)CCNC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCNC(=O)c1ccc(O)cc1
Temperature: 40 °C

Procedure:
A mixture of 3-(4-benzyloxy-benzoylamino)-propionic acid methyl ester (11.26 g, 35.93 mmol) and Pd(OH)2/C (20%, 3.19 g) in MeOH was heated at 40° C. for 12 h. The mixture was filtered through celite to yield 7.89 (98%) of the title compound. The following compound was made in a similar manner:
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5]1.[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([O:3][C@@H:4]1[CH2:9][CH2:8][CH2:7][C@H:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:5]1)[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: O[C@@H]1CCC[C@H](OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1CCC[C@H](OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under an atmosphere of argon, 12 g of sodium hydride (55-65%) are initially charged in 200 ml of abs. DMF, and the mixture is stirred at RT for 10 min. With ice-cooling, 54 g of benzyl (1S,3R)-3-hydroxycyclohex-1-yl ether in 70 ml of DMF are added dropwise. The mixture is stirred at RT for 90 min. With ice-cooling, 50 g of allyl bromide are slowly added dropwise. After the addition has ended, the mixture is stirred at 45° C. for 1 h. According to TLC, the reaction is complete. The reaction solution is quenched with 15 ml of iPrOH, diluted with water and sat. NaCl solution and extracted with MTBE. The combined organic phases are washed with water and NaCl solution, dried over MgSO4 and concentrated. This gives 60 g of benzyl (1S,3R)-3-allyloxycyclohex-1-yl ether as a light-beige oil. C16H22O2 (246.35), MS (ESI): 247 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH:19]C(=O)C(F)(F)F)=[CH:14][C:13]=2[F:26])[N:4](COCC[Si](C)(C)C)[CH:3]=1.Cl.[OH-].[Li+]>O1CCOCC1.O>[Br:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[O:11][C:12]2[C:17]([F:18])=[CH:16][C:15]([NH2:19])=[CH:14][C:13]=2[F:26])[NH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCn1cc(Br)c2c(Oc3c(F)cc(NC(=O)C(F)(F)F)cc3F)ccnc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(F)c(Oc2ccnc3[nH]cc(Br)c23)c(F)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 201 mg of N-{4-[(3-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)oxy]-3,5-difluorophenyl}-2,2,2-trifluoroacetamide (280 μmol) in 4.00 ml of a mixture of hydrogen chloride in dioxane (4N) is stirred at RT overnight, and the precipitated crystals are filtered off and washed with diethyl ether. The solid residue (131 mg) is dissolved in 20 ml of THF. 2.7 ml of a 5% strength solution of lithium hydroxide in water (5.62 mmol) are then added, and the mixture is stirred at RT for 60 h. The reaction mixture is diluted with water and extracted twice with ethyl acetate. After drying over magnesium sulfate, the combined organic phases are concentrated and the residue is purified by preparative HPLC.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[Br-].[CH2:31]([Zn+])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3](=[O:29])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: [Zn+]Cc1ccccc1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Br)ccc21
Agent: [Br-]
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4Cc3ccccc3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromo-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and benzylzinc bromide following a procedure analogous to that described in Step 6 of Intermediate 1. LC (method 3): tR=0.94 min; Mass spectrum (ESI+): m/z=505 [M+Na]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[ClH:11].[OH:12][CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:14](=O)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18].C([BH3-])#N.[Na+]>CO>[ClH:11].[ClH:11].[CH3:18][CH:17]([CH3:19])[CH2:16][CH2:15][CH:14]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:12]
Reactant: NCCCN1CCCCC1
Reactant: CC(C)CCC(=O)C(O)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)CCC(NCCCN1CCCCC1)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 28 %

Procedure:
To a solution of 1-(3-aminopropyl)piperidine (285 mg, 2 mmol) in methanol (6 ml) was added 0.1 ml of 6.8N-HCl in MeOH, 1-hydroxy-5-methyl-1-phenylhexan-2-one (413 mg, 2 mmol) and sodium cyanoborohydride (126 mg, 2 mmol). The reaction mixture was stirred for 19 hours at room temperature. The mixture was concentrated under reduced pressure and to the residue was added lN-HCl and ether. The aqueous layer was separated, basified with a 10% NaOH aqueous solution and then extracted three times with ether. The combined ethereal extract was washed twice with water, dried over anhydrous sodium sulfate and then evaporated under reduced pressure. The residue was dissolved in ethanol (12 ml). To the solution was added 0.70 ml of 6N-HCl in EtOH and the resulting mixture was allowed to stand. Precipitated crystals were collected by filtration to obtain 228 mg of the title compound (yield: 28%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9](I)=[CH:10][C:5]2=[CH:4][CH:3]=1.[Cu][C:13]#[N:14]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:13]#[N:14])=[CH:10][C:5]2=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: Clc1ccc2cc(I)sc2n1
Solvent: CN(C)C=O
Product: N#Cc1cc2ccc(Cl)nc2s1
Temperature: 130 °C

Procedure:
A mixture of 6-Chloro-2-iodothieno[2,3-b]pyridine (80 mg, 0.27 mmol) and Copper (I) Cyanide (36 mg, 0.41 mmol) in DMF (3 mL) was heated to 130° C. for 16 hrs. LC showed formation of the title product. The crude reaction was adsorbed onto silica gel, and purified by flash chromatography to obtain the title product. LC-MS (IE, m/z): 195 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].C([O:28]C(C1C=NN(C2NC(=O)C3C(=CC=C(SC)C=3)N=2)C=1)=O)C>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[NH:7][C:8]([N:12]3[CH:16]=[C:15]([C:17]([OH:19])=[O:18])[CH:14]=[N:13]3)=[N:9]2)=[CH:4][C:3]=1[S:21]([C:22]([F:24])([F:23])[F:25])=[O:28]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(SC)cc3c(=O)[nH]2)c1
Reactant: O=C(O)c1cnn(-c2nc3cc(Cl)c(SC(F)(F)F)cc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc3cc(Cl)c(S(=O)C(F)(F)F)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 157 using 1-(7-chloro-4-oxo-6-trifluoromethanesulfanyl-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid (Intermediate from Example 159, product from Step A) for 1-(6-methylsulfanyl-4-oxo-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester in step A. MS (ESI/Cl): mass calcd. for C13H6ClF3N4O4S, 406.0; m/z found, 407.0 [M+H]+; 405.0 [M−H]−. 1H NMR (400 MHz, DMSO-d6): 13.46 (br s, 1H), 13.12 (s, 1H), 8.97 (d, J=0.6 Hz, 1H), 8.54 (s, 1H), 8.33 (s, 1H), 8.03 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([C:15]([CH:17]2[CH2:23][CH2:22][C:21]3([C:25]4([CH3:30])OCC[O:26]4)[CH2:24][CH:18]2[C:19](=[O:31])[O:20]3)=[O:16])[CH:4]=1.Cl.[CH3:33][OH:34]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([C:15]([CH:17]2[CH2:23][CH2:22][C:21]([C:25](=[O:26])[CH3:30])([OH:20])[CH2:24][CH:18]2[C:19]([O:34][CH3:33])=[O:31])=[O:16])[CH:4]=1
Reactant: COc1cc(C(=O)C2CCC3(C4(C)OCCO4)CC2C(=O)O3)c(OC)c2ccccc12
Reactant: CO
Agent: Cl
Product: COC(=O)C1CC(O)(C(C)=O)CCC1C(=O)c1cc(OC)c2ccccc2c1OC

Procedure:
Operating as described in Example 5, the treatment of 2-(1,4-dimethoxy-3-naphthylcarbonyl)-5-(2-methyldioxolan-2-yl)-6-oxa-bicyclo[3,2,1]octan-7-one, prepared as described in Example 10, with a solution of hydrogen chloride in methanol afforded 1-(1,4-dimethoxy-3-naphthylcarbonyl)-2-methoxycarbonyl-4-acetyl-4-hydroxy-cyclohexane (X, R=H) in almost quantitative yield. m/z 414 (M+.): IR (film): 3460 cm-1 (OH), 1730 cm-1 (C=O ester), 1710 cm-1 (C=O ketone) and 1670 cm-1 (C=O, benzylic ketone). PMR (CDCl3): inter alia: δ2.3 (s, CH3CO), 2.9-3.6 (m, two H), 3.7-3.9 (s, three OCH3), 6.9 (s, aromatic H) and 7.4-8.4 (m, four aromatic H).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([CH3:13])[CH2:8][CH2:7]1)=[O:5].C(N(CC)C(C)C)(C)C.[F:23][C:24]([F:30])([F:29])[S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:13][CH:9]1[CH2:8][CH2:7][C:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])=[C:11]([O:12][S:25]([C:24]([F:30])([F:29])[F:23])(=[O:27])=[O:26])[CH2:10]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CCOC(=O)C1CCC(C)CC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1=C(OS(=O)(=O)C(F)(F)F)CC(C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of ethyl 4-methyl-2-cyclohexanone-1-carboxylate (50 g, 0.27 mol) in dichloromethane (500 ml) at −10° C. was added N,N-diisopropylethylamine (52 ml, 0.3 mol) followed by dropwise addition of trifluoromethanesulphonyl chloride (57 ml, 0.3 mol) keeping the temperature between −5 and −100° C. The reaction mixture was allowed to warm to room temperature and stirred for 3 hours. TLC showed 80% reaction, it was cooled to −5° C. and more N,N-diisopropylethylamine (14 ml, 0.1 mol) was added followed by trifluoromethanesulphonyl chloride (15.5 ml, 0.1 mol) and the reaction mixture was stirred for 15 hours at room temperature. The mixture was washed with cold water (2×200 ml), cold saturated sodium bicarbonate (2×200 ml) and brine (1×200 ml). The organic layer was dried (MgSO4), filtered and evaporated to give the required product (85 g) as a colourless oil. 1H NMR (250 MHz, CDCl3) δ 1.04 (3H, d, J=6.5 Hz), 1.43 (3H, m), 1.73-2.09 (4H, m), 2.39-2.63 (3H, m), 4.25 (2H, m).