Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:37][CH2:36][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]4[C:18]([F:34])=[CH:19][CH:20]=[CH:21][C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:7]2)=[C:4]([C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[C:3]=1[CH3:49].[CH3:50]OC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.CB(O)O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:45]([O:44][C@@H:39]([C:4]1[C:3]([CH3:49])=[C:2]([CH3:50])[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]=1[N:6]1[CH2:7][CH2:8][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]2[C:18]([F:34])=[CH:19][CH:20]=[CH:21][C:22]=2[C:23]2[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=2)[CH2:36][CH2:37]1)[C:40]([O:42][CH3:43])=[O:41])([CH3:46])([CH3:47])[CH3:48]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1c(F)cccc1-c1cccc-3c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Methyl(2S)-2-[(22S)-5-bromo-19-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate (0.070 g, 0.095 mmol, 1.0 equiv), Pd(OAc)2 (0.013 g, 0.057 mmol, 0.6 equiv), Sphos (0.047 g, 0.114 mmol, 1.2 equiv), methylboronic acid (0.057 g, 0.095 mmol, 10.0 equiv) and cesium carbonate (0.124 g, 0.380 mmol, 4.0 equiv) were mixed in DMF (1.73 mL) and water (0.17 mL). The solution was degassed for five minutes by N2. Then it was stirred at 80° C. for 2 hours. It was diluted by ethyl acetate (15 mL), washed by water, dried over MgSO4 and concentrated to afford the pure enough product for the next reaction. LCMS (ESI, M+1): 658.4.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:19]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:20][N+:21]([O-])=O.CCOCC>CCOCC.C1COCC1>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]=1[CH:19]([S:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:20][NH2:21]
Reactant: COc1ccc2ccccc2c1C(C[N+](=O)[O-])Sc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2ccccc2c1C(CN)Sc1ccccc1
Temperature: 0 °C
Yield: 70 %

Procedure:
To a vigorously stirred suspension of lithium aluminum hydride (76 mg. 20 mmol) in anhydrous ether - THF 2:1 solvent mixture (80 ml) a solution of 1-(2-methoxynaphth-1-yl)-1-(phenylthio)-2-nitroethane (3394 mg, 10 mmol) in ether- THF 2:1 (40 ml) is added dropwise. The reaction mixture is heated at reflux for 24 h and then cooled to 0° C. Ether is added and the excess of LiAlH4 is destroyed by the cautious successive addition of water (2 ml) and 2N NaOH solution (4 ml). The aluminum salts are filtered off and the organic layer evaporated in vacuo. The residue is dissolved in ether and the ethereal solution extracted with 2N HCl solution. The aqueous acidic layer is brought to pH 9 by addition of 2N NaOH and extracted with ether. The ethereal layer is dried with Na2SO4 and then evaporated to dryness in vacuo to give almost pure title compound in 70 % yield (2165 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=2)[C:10]([O:12]C)=O)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl.[CH3:21][NH2:22].C[Al](C)C.Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[N:1]1([C:7]2[CH:8]=[C:9]([CH:14]=[C:15]([N+:17]([O-:19])=[O:18])[CH:16]=2)[C:10]([NH:22][CH3:21])=[O:12])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Reactant: CN
Agent: C[Al](C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CNC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
A stirred solution of 3-(4-morpholinyl)-5-nitro-benzoic acid, methyl ester (Example 86c; 0.53 g, 2 mmol) in toluene (5 mL) under an argon atmosphere, is treated with a mixture of methylamine hydrochloride (0.27 g, 4 mmol), trimethylaluminium (2 mL of a 2 M solution in toluene, 4 mmol) in toluene (5 mL) and heated at 60° C. for 18 h. The cooled mixture is then treated with hydrochloric acid (10 mL of 2 M), stirred for 5 min and then treated with aqueous sodium hydroxide (5 mL of 4 M). The mixture is then treated with water (100 mL) and extracted with ethyl acetate (3×100 mL). The combined extacts are washed with brine (2×50 mL), dried (MgSO4) and the solvent is evaporated off under reduced pressure to give the crude product which is purified by recrystallisation from ethyl acetate to afford the title compound as yellow crystalline solid, m.p. 204–207° C.
Reaction SMILES: [CH2:1]([CH:3]1[N:12]([C:13]2[CH:14]=[N:15][NH:16][CH:17]=2)[C:11]2[N:10]=[C:9]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:8]=[CH:7][C:6]=2[N:5]([CH3:30])[C:4]1=[O:31])[CH3:2].[C:32]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cl-].[Na+].O>[CH2:1]([CH:3]1[N:12]([C:13]2[CH:14]=[N:15][N:16]([CH3:32])[CH:17]=2)[C:11]2[N:10]=[C:9]([N:18]3[CH:22]=[CH:21][N:20]=[C:19]3[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[N:8]=[CH:7][C:6]=2[N:5]([CH3:30])[C:4]1=[O:31])[CH3:2]
Reactant: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(F)cc3)nc2N1c1cn[nH]c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCC1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(F)cc3)nc2N1c1cnn(C)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 13.4 %

Procedure:
7-ethyl-2-(2-(4-fluorophenyl)-1H-imidazol-1-yl)-5-methyl-8-(1H-pyrazol-4-yl)-7,8-dihydropteridin-6(5H)-one (Example 331, 55 mg, 0.131 mmol) was dissolved in 3 mL of dioxane and Me3PO4 (37 mg, 0.262 mmol) and K2CO3 (90 mg, 0.655 mmol) were added and the reaction mixture was stirred for 18 h at 90° C. The reaction mixture was diluted with brine and extracted with EtOAc. The organic phase was dried with Na2SO4, filtered, concentrated under vacuum and purified by HPLC to give the title compound (7.6 mg). 1H-NMR (CDCl3, 400 MHz): δ: 7.91 (s, 1H), 7.71 (s, 1H), 7.50-7.60 (m, 3H), 7.12 (s, 1H), 7.08-7.10 (m, 2H), 7.01 (s, 1H), 4.57-4.61 (m, 1H), 3.79 (s, 3H), 3.46 (s, 3H), 1.82-1.98 (m, 1H), 1.78-1.82 (m, 1H), 0.82 (t, 3H, J=7.4 Hz); LCMS: 433.2 m/z (M+H)+; ret. Time: 4.36 min (Analytical Method C).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([Cl:16])=[C:11]([NH2:17])[CH:10]=1.N1C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:8][C:9]1[CH:10]=[C:11]([NH:17][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])[C:12]([Cl:16])=[CH:13][C:14]=1[Cl:15]
Reactant: Nc1cc(N)c(Cl)cc1Cl
Reactant: O=C(Cl)CCCCl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1cc(NC(=O)CCCCl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
14.1 g (0.10 mol) of γ-chlorobutyryl chloride in 50 ml of chloroform are added dropwise in the course of 1 hour, at 10°-15° C., to a solution of 17.7 g (0.10 mol) of 1,3-diamino-4,6-dichlorobenzene and 8.7 g (0.11 mol) of pyridine in 500 ml of chloroform. The mixture is then stirred for 2 hours at room temperature, the solution is washed with water and filtered through 40 g of silica gel and the filtrate is concentrated. The resulting product is recrystallised from hexane/toluene. Yield: 13.5 g; melting point 125°-128° C.
Reaction SMILES: [N:1]1([C:7]2[C:8](=[O:25])[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:26].N1(C2C(=O)N(CCOC3C=C(F)C(F)=CC=3F)C=CN=2)CCNCC1.Br[CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[ClH:26].[C:55]1([CH2:54][CH2:53][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:8](=[O:25])[N:9]([CH2:13][CH2:14][O:15][C:16]4[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=4[F:24])[CH:10]=[CH:11][N:12]=3)[CH2:2][CH2:3]2)[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: O=c1c(N2CCNCC2)nccn1CCOc1cc(F)c(F)cc1F
Reactant: BrCCc1ccccc1
Agent: Cl
Product: O=c1c(N2CCN(CCc3ccccc3)CC2)nccn1CCOc1cc(F)c(F)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 60 starting from 3-(1-piperazinyl)-1-[2-(2,4,5-trifluorophenoxy)ethyl]-2(1H)-pyrazinone (0.71 g, 2.0 mmol; from the free base of Example 3) and (2-bromoethyl)benzene (0.41 g, 2.2 mmol). Yield: 0.20 g (20%). HPLC purity: 96%. HRMS calc for C24H25F3N4O2 (M)+ 458.1930, found 458.1928.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:5]=1.Cl[Sn]Cl>CO>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=2)[CH:7]=[C:8]([NH2:10])[CH:9]=1
Reactant: COC(=O)c1cc(-c2ccc(C)cn2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CO
Product: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Yield: 4 %

Procedure:
To a solution of 3-(5-Methyl-pyridin-2-yl)-5-nitro-benzoic acid methyl ester (410 mg, 36.9 mmol) in methanol was added SnCl2 (1.36 g, 6.03 mmol) at room temperature. The reaction mixture was refluxed for 3 hours and then cooled. Solvent was removed in vacuo and the residue was dissolved in H2O and basified by Na2CO3 to pH=9. The mixture was extracted with CH2Cl2, and the organic phase was washed with water, brine, and dried over Na2SO4. The solvent was removed under vacuum to give 3-amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (362 mg, 100%) as yellow oil. MS (M+H)=244.
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[F:29][C:30]1[CH:53]=[CH:52][C:33]([CH2:34][N:35]2[CH2:39][CH2:38][N:37]([C:40]3[S:41][C:42]([C:46]([O:48]CC)=[O:47])=[C:43]([CH3:45])[N:44]=3)[C:36]2=[O:51])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:34][N:35]2[CH2:39][CH2:38][N:37]([C:40]3[S:41][C:42]([C:46]([OH:48])=[O:47])=[C:43]([CH3:45])[N:44]=3)[C:36]2=[O:51])=[CH:52][CH:53]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Yield: 80 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid in 80% yield: 1H NMR (300 MHz, DMSO-d6) δ 7.39-7.34 (m, 2H), 7.22-7.17 (m, 2H), 4.43 (s, 2H), 4.01-3.98 (m, 2H), 3.48-3.43 (m, 2H), 2.50 (s, 3H); MS (ES+) m/z 336.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:23])[NH:6]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:34]([C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=1)=[C:35]=[O:36]>C1COCC1>[F:44][C:43]([F:45])([F:46])[C:39]1[CH:38]=[C:37]([NH:34][C:35]([N:6]2[C:7]3[C:3](=[C:2]([F:1])[C:10]([O:11][C:12]4[CH:17]=[C:16]([CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[N:15]=[CH:14][N:13]=4)=[CH:9][CH:8]=3)[CH:4]=[C:5]2[CH3:23])=[O:36])[CH:42]=[CH:41][CH:40]=1
Reactant: Cc1cc2c(F)c(Oc3cc(CS(C)(=O)=O)ncn3)ccc2[nH]1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc2c(F)c(Oc3cc(CS(C)(=O)=O)ncn3)ccc2n1C(=O)Nc1cccc(C(F)(F)F)c1
Temperature: -78 °C

Procedure:
4-Fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-1H-indole (250 mg, 0.745 mmol) in THF (10 mL) is cooled to −78° C. and a 1 M solution of LiHMDS in THF (1.86 mL, 1.86 mmol) is added. After 12 min 1-isocyanato-3-(trifluoromethyl)-benzene (0.12 mL, 0.895 mmol) is added and the reaction is allowed to stir at −78° C. After 1 h the reaction is quenched with saturated aqueous NH4Cl and then extracted with (3×100 mL) EtOAc, The organic phases are combined and washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue is purified FCC (0-3% MeOH/DCM) to provide 4-fluoro-5-(6-methanesulfonylmethyl-pyrimidin-4-yloxy)-2-methyl-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 523.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.99 (s, 1 H), 8.77 (d, J=1.01 Hz, 1 H), 8.12 (s, 1 H), 7.91 (s, 1 H), 7.66 (s, 1 H), 7.53 (d, J=9.35 Hz, 2 H), 7.36 (d, J=1.01 Hz, 1 H), 7.20 (d, J=7.33 Hz, 1 H), 6.64 (s, 1 H), 4.73 (s, 2 H), 3.13 (s, 3 H), 2.59 (s, 3 H).
Reaction SMILES: [C:1]([O:6]CC)(=O)[CH:2]([CH3:4])[OH:3].[CH2:9]([NH2:12])[CH2:10][CH3:11]>>[CH2:9]([NH:12][C:1](=[O:6])[CH:2]([CH3:4])[OH:3])[CH2:10][CH3:11]
Reactant: CCCN
Reactant: CCOC(=O)C(C)O
Product: CCCNC(=O)C(C)O
Temperature: 60 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
A mixture of 35.4 gm (0.3 mole) of ethyl lactate and 19.4 gm (0.33 mole) of propylamine were stirred together at 60° C. for 16 hours and subsequently distilled under reduced pressure. 30 gm (76% of theory) of N-propyl-lactic acid amide of boiling point 152° C./9 torr and of refractive index (nD20) 1.4563 were obtained.
Reaction SMILES: [O:1]=[C:2]([NH:14][CH2:15][C:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.O>P(Cl)(Cl)(Cl)=O>[F:24][C:23]([F:26])([F:25])[C:19]1[CH:18]=[C:17]([C:16]2[O:1][C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)=[N:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cnn(CC(=O)NCC(=O)c2cccc(C(F)(F)F)c2)c1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)c1cnn(Cc2ncc(-c3cccc(C(F)(F)F)c3)o2)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
The compound (0.73 g) obtained in Example 124a was dissolved in phosphorus oxychloride (10 mL), and the mixture was stirred at 110-130° C. overnight with heating. The reaction mixture was cooled to room temperature, slowly poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: petroleum ether-ethyl acetate) to give the title compound (0.50 g) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][CH3:17])=[O:15])#[N:2].[C:18]([O-])([O-])=O.[K+].[K+].IC.[H-].[Na+]>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[F:13])[O:9][CH2:8][CH2:7][C:6]2([CH3:18])[C:14]([O:16][CH3:17])=[O:15])#[N:2]
Reactant: COC(=O)C1CCOc2cc(F)c(C#N)cc21
Reactant: O=C([O-])[O-]
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CC#N
Product: COC(=O)C1(C)CCOc2cc(F)c(C#N)cc21
Temperature: 60 °C
Yield: 33.4 %

Procedure:
Methyl 6-cyano-7-fluoro-3,4-dihydro-2H-chromene-4-carboxylate (from Example 3, Step E; 28 mg, 0.12 mmol) was diluted with acetonitrile (1 mL) followed by the addition of K2CO3 (49 mg, 0.36 mmol) and iodomethane (0.023 mL, 0.36 mmol). The reaction was then heated at 60° C. for 1 hour, then cooled and NaH (8.6 mg, 0.36 mmol) was added. The reaction was deemed complete by LC. The reaction was loaded onto a Biotage 25 samplet and purified running a gradient 5% ethyl acetate/hexane to 100% ethyl acetate/hexane to yield the title compound (10 mg, 34% yield).
Reaction SMILES: C(SC1C=C(O)C(=O)NC=1)C1C=CC=CC=1.COC[O:20][C:21]1[C:22](=[O:40])[N:23](COC)[CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH:26]=1>>[OH:20][C:21]1[C:22](=[O:40])[NH:23][CH:24]=[C:25]([S:27][CH2:28][C:29]2[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=2)[CH:26]=1
Reactant: COCOc1cc(SCc2ccc(OC)nc2)cn(COC)c1=O
Agent: O=c1[nH]cc(SCc2ccccc2)cc1O
Product: COc1ccc(CSc2c[nH]c(=O)c(O)c2)cn1

Procedure:
Prepared as described for 5-(benzylsulfanyl)-3-hydroxypyridin-2(1H)-one (Example 12) from 3-(methoxymethoxy)-1-(methoxymethyl)-5-{[(6-methoxypyridin-3-yl)methyl]sulfanyl}pyridin-2(1H)-one (Intermediate 30).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH:25]=O)=[C:15]1[CH2:27][CH2:28][O:29][Si:30]([C:43]([CH3:46])([CH3:45])[CH3:44])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([NH:56][CH3:57])=[CH:52][CH:51]=1>>[CH3:47][O:48][C:49](=[O:58])[C:50]1[CH:55]=[CH:54][C:53]([N:56]([CH2:25][CH2:24][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[N:14]([CH:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:15]=2[CH2:27][CH2:28][O:29][Si:30]([C:43]([CH3:44])([CH3:46])[CH3:45])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH3:57])=[CH:52][CH:51]=1
Reactant: CNc1ccc(C(=O)OC)cc1
Reactant: CC(C)(C)[Si](OCCc1c(CC=O)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)c1ccc(N(C)CCc2c(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 73 %

Procedure:
Crude {1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-acetaldehyde from step 7, example 142 was treated with 4-Methylamino-benzoic acid methyl ester according to the procedure in Example 142 step 8 to yield the desired 4-[(2-{1-Benzhydryl-2-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-5-chloro-1H-indol-3-yl}-ethyl)-methyl-amino]-benzoic acid methyl ester in 73% yield.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[CH:4]=[C:3]1[C:10]([OH:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Pd].C1COCC1>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][S:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:27])=[O:26])[CH:4]=[C:3]1[C:10]([OH:12])=[O:11]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(NS(=O)(=O)c2ccccc2)cc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
1-Methyl-4-nitro-1H-pyrrole-2-carboxylic acid (Int. 15) (350 mg, 2.057 mmol) was dissolved in aqueous 1M sodium carbonate (15 ml, 15.00 mmol); 10% Pd/C (219 mg) was added, and the mixture was hydrogenated in a Parr apparatus at 40 psi for 2 hours. The catalyst was filtered off maintaining the mixture under nitrogen flow and the filtrate was collected in a cooled flask (ice bath). THF (20 ml) and benzenesulfonyl chloride (0.318 ml, 2.469 mmol) were added to the cooled solution and the resulting mixture was stirred at 0° C. for 0.5 hours and then at RT for 1 hour. The reaction mixture was extracted with Et2O and the organic layer was discarded. The aqueous layer was cautiously acidified by addition of solid KHSO4 to pH=3 and extracted twice with DCM. The combined organic layers were dried over Na2SO4 and the solvent was removed under vacuum to afford 1-methyl-4-(phenylsulfonamido)-1H-pyrrole-2-carboxylic acid (Int. 16) (540 mg, 1.927 mmol, MS/ESI+280.9 [MH]+), which was used without purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[Cl:25])[C:21]([O:26]CC2C=CC=CC=2)=[N:20][CH:19]=[CH:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C>CO>[Cl:25][C:24]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][NH:20][C:21]2=[O:26])=[CH:16][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc3ccnc(OCc4ccccc4)c3cc2Cl)CC1
Solvent: CO
Product: O=c1[nH]ccc2cc(OC3CCNCC3)c(Cl)cc12
Yield: 39.3 %

Procedure:
254 mg (0.52 mmol) of 4-(1-benzyloxy-7-chloro-isoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl-ester (53) were stirred in methanol/2 N HCl (1:1) at room temperature overnight. The solvent was removed i. vac. and the residue was purified by preparative HPLC. The product fractions were evaporated and dissolved in 2 N HCl. Lyophilization results in 57 mg of the desired compound as hydrochloride. Rt=0.95 min (Method B). Detected mass: 279.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](=O)[CH3:21])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(O)C.Cl.[NH2:34][OH:35].[OH-].[K+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[O:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20](=[N:34][OH:35])[CH3:21])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)CCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(CCN1CCN(CCOC(c2ccc(F)cc2)c2ccc(F)cc2)CC1)=NO

Procedure:
630 mg (1 mM) of 1-(2-(bis-(4-fluorophenyl)-methoxy)-ethyl)-4 -(3-ketobutyl)piperazine (prepared as described in example 19) was suspended in 2 5 ml of ethanol at room temperature. A solution of hydroxylamine hydrochloride in 1 ml of water was added, followed by the dropwise addition of 240 mg of potassium hydroxide dissolved in 1 ml of water. The mixture was heated at reflux for 1 h, the solvent was evaporated, and the residue was dissolved by the addition of 5 ml of water and 5 ml of methylene chloride. The aqueous phase was extracted three times with methylene chloride, and the organic extract was washed with water, dried, and evaporated in vacuo. The residual oil was dissolved in ethanol, and a crude dimaleate salt was precipitated by addition of an ethanolic solution of 417 mg of maleic acid. The crude salt (405 mg) was recrystallized from 50 ml of hot ethanol to yield the dimaleate salt of the title compound as colourless crystals, melting at 161°-162° C. Analytical data were in accordance with the proposed structure. H-NMR spectrum indicated the presence of two stereoisomers in the ratio of 2.5:1.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:5][NH:4][C:3]1=[O:14].Cl[C:16]1[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[CH:6]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[CH2:5][N:4]([C:16]2[N:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][N:17]=2)[C:3]1=[O:14]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CN1C(=O)NCC1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)N(c2nccc(C(F)(F)F)n2)CC1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 2-chloro-4-(trifluoromethyl)pyrimidine (547 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.49 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated at reflux under argon for 6 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated. The residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in isohexane to give 1,1-dimethylethyl 3-methyl-2-oxo-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-imidazolidinecarboxylate (506 mg, 49%). LC/MS [M+H]+=347. (ii) A solution of 1,1-dimethylethyl 3-methyl-2-oxo-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-imidazolidinecarboxylate (506 mg, 1.46 mmol) in TFA/DCM (1:2, 9 ml) was stirred at room temperature for 16 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 3-methyl-2-oxo-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-imidazolidinecarboxylic acid (assume ˜1.5 mmol) which was used in the next step. LC/MS [M+H]+=291.