Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:22][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]([OH:34])=O)=[CH:28][C:27]=1[O:35][CH3:36])[CH3:24].O[NH:38]/[C:39](=[N:56]\[H])/[C:40]1[CH:41]=[CH:42][CH:43]=[C:44]2[C:48]=1[NH:47][CH:46]=[C:45]2[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:24][CH:23]([O:25][C:26]1[N:31]=[CH:30][C:29]([C:32]2[O:34][N:56]=[C:39]([C:40]3[CH:41]=[CH:42][CH:43]=[C:44]4[C:48]=3[NH:47][CH:46]=[C:45]4[CH2:49][CH2:50][C:51]([O:53][CH2:54][CH3:55])=[O:52])[N:38]=2)=[CH:28][C:27]=1[O:35][CH3:36])[CH3:22]
Reactant: [H]/N=C(\NO)c1cccc2c(CCC(=O)OCC)c[nH]c12
Reactant: COc1cc(C(=O)O)cnc1OC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(OC)c4)n3)cccc12
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
EDCI (289 mg) and HOBT (220 mg) were added to a solution of 6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinecarboxylic acid (152 mg) in THF (3 mL) at RT. The resulting solution was stirred for 30 mins. Ethyl 3-{7-[(Z)-(hydroxyamino)(imino)methyl]-1H-indol-3-yl}propanoate (D35) (250 mg) in THF (3 mL) was added and the reaction mixture was stirred at RT for 2 hours. TBAF (910 mg) was then added. The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 120° C. for 90 mins. After cooling, the reaction was quenched with water, and extracted with EtOAc for 3 times. The combined organic solution was washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated. The residue was purified by column chromatography (20% EtOAc in hexane) to afford ethyl 3-(7-{5-[6-[(1-methylethyl)oxy]-5-(methyloxy)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D38) (286 mg) as a pale yellow solid. MS (ES): C24H26N4O5 requires 450; found 451.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2([C:23]#[N:24])[CH2:20][CH2:19][N:18](C#N)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(O)(=O)C>O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2([C:23]#[N:24])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: N#CN1CCC(C#N)(c2ccccc2Sc2ccc(Cl)cc2)CC1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: N#CC1(c2ccccc2Sc2ccc(Cl)cc2)CCNCC1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
A mixture of 1.2 g of 4-[2-(4-chlorophenylthio)phenyl]-1,4-dicyanopiperidine, Example 24, and 15 ml of a glacial acetic acid 3 N hydrochloric acid (1:2) solution is stirred at 110° C. for 24 hours. Thereafter, the solution is diluted with 80 ml of water before being evaporated to dryness. The solid residue is made strongly basic with ammonium hydroxide and the alkaline solution is extracted with ether. The combined ether extracts are successively dried, filtered and concentrated to dryness, leaving a white solid. The solid is dissolved in methylene chloride and this solution is chromatographed (silica gel/methylene chloride column, 10% methyl alcohol in methylene chloride as eluant). The desired fractions are concentrated to dryness. The resulting material is recrystallized from cyclohexane to provide 4-[2-(4-chlorophenylthio)phenyl]-4-cyanopiperidine.
Reaction SMILES: Cl.CS([O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:31])[C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)=[CH:18][CH:17]=3)=[C:13]([C:32]3[CH:37]=[CH:36][C:35]([O:38]S(C)(=O)=O)=[CH:34][CH:33]=3)[S:12][C:11]=2[CH:43]=1)(=O)=O.[OH-].[Na+]>CC(C)=O>[OH:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15](=[O:31])[C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)=[CH:20][CH:21]=3)=[C:13]([C:32]3[CH:33]=[CH:34][C:35]([OH:38])=[CH:36][CH:37]=3)[S:12][C:11]=2[CH:43]=1
Reactant: CS(=O)(=O)Oc1ccc(-c2sc3cc(OS(C)(=O)=O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12

Procedure:
A 4 g. portion of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy)-benzoyl]benzo[b]thiophene, hydrochloride, was combined with 100 ml. of denatured alcohol and 10 ml. of 5N sodium hydroxide, and stirred under reflux for 1.5 hours under a nitrogen atmosphere. The reaction mixture was then evaporated to dryness under vacuum, and the residue was dissolved in 200 ml. of water and washed with 300 ml. of diethyl ether. The water layer was degassed under vacuum, and then nitrogen was bubbled through it to remove all traces of ether. The mixture was then acidified with 1N hydrochloric acid, and then made basic with excess sodium bicarbonate. The precipitate was collected by filtration and washed with cold water to obtain 2.4 g. of crude product. It was purified on a 2×30 cm. column of silica gel, eluting first with 700 ml. of 55 methanol in chloroform, followed by 1 liter of 10% methanol in chloroform. The impurities came off first, and the product-containing fractions were combined and evaporated under vacuum to obtain 1.78 g. of yellow oil. The oil was dissolved in 6 m. of acetone, seeded and chilled in a freezer to obtain 1.2 g. of purified product, m.p. 143°-147° C. The identity of the product was confirmed as follows:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH:2]=1.[OH:17][CH2:18][C@H:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>S(Cl)(Cl)=O.N1C=CC=CC=1.C(Cl)Cl>[OH:17][CH2:18][C@H:19]([NH:26][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[N:16][C:8]=1[O:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](CO)c1ccccc1
Reactant: O=C(O)c1cccnc1Oc1cccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C(N[C@@H](CO)c1ccccc1)c1cccnc1Oc1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-(Pyridin-3-yloxy)-nicotinic acid (0.250 grams, 1.2 mmole) in thionyl chloride (10 ml) was heated to reflux. After 1 hour the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting residue was suspended in tetrahydrofuran (10 ml) and added dropwise to a solution of (R)-2-hydroxy-1-phenyl ethylamine (0.160 grams, 1.2 mmole) in pyridine (5 ml) at 0° C. After 30 minutes the mixture was warmed to room temperature, stirred at room temperature for 1 hour and concentrated to remove pyridine. The crude product was purified by chromatography on silica gel eluting with ethyl acetate to give a yellow oil. HRMS 336.1324; α=+63.9° 12.3 mg/ml in methylene chloride. 1H NMR (400 mhz, CDCl3) d 2.76 (bs, 1H), 3.95-4.02 (m, 2H), 5.31-5.36 (m, 1H), 7.16-7.40 (m, 1H), 8.19 (dd, J=2.1 Hz, 4.8 Hz, 1H), 8.48-8.61 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[O:30])[CH:24]=[C:25]([CH3:27])[CH:26]=1>>[CH3:20][C:21]1[CH:22]=[C:23]([NH:28][C:29](=[O:30])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:24]=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1cc(C)cc(N=C=O)c1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Product: Cc1cc(C)cc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)c1

Procedure:
61 mg of pale yellow solid 3-{4-[3-(3,5-dimethylphenyl)ureido]phenyl}-1H-pyrrolo[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 3,5-dimethylphenyl isocyanate.
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:27]=[CH:26][C:13]4[N:14]=[C:15]([NH:17][C@@H:18]5[CH2:23][CH2:22][CH2:21][C@@H:20]([OH:24])[C@H:19]5[OH:25])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I>[O:33]1[CH2:34][CH2:35][N:30]([C:2]2[CH:29]=[CH:28][C:5]3[N:6]([CH2:9][C:10]4[CH:27]=[CH:26][C:13]5[N:14]=[C:15]([NH:17][C@@H:18]6[CH2:23][CH2:22][CH2:21][C@@H:20]([OH:24])[C@H:19]6[OH:25])[S:16][C:12]=5[CH:11]=4)[CH:7]=[N:8][C:4]=3[CH:3]=2)[CH2:31][CH2:32]1
Reactant: C1COCCN1
Reactant: O[C@@H]1[C@H](O)CCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(I)ccc43)cc2s1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O[C@@H]1[C@H](O)CCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(N5CCOCC5)ccc43)cc2s1
Temperature: 110 °C
Yield: 0.8 %

Procedure:
A suspension of (1R,2S,3R)-3-((6-((5-iodo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (262 mg, 0.5 mmol) from Step 5 of Example 232, morpholine (264 μL, 3.0 mmol), L-proline (23 mg, 0.2 mmol), and K2CO3 (209 mg, 1.5 mmol) in DMSO (2.0 mL) was purged with argon for 5 min. Copper (I) iodide (19 mg, 0.02 mmol) was added, and the mixture was purged for an additional 5 min, then heated in a sealed tube at 110° C. for 2 h. The mixture was cooled to rt and filtered through Celite, and the filtrate was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase, followed by silica gel flash chromatography eluting with 5% MeOH in CH2Cl2 to afford (1R,2S,3R)-3-((6-((5-morpholino-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexane-1,2-diol (2 mg, 1%) as a white powder. 1H NMR (500 MHz, MeOH-d4) δ 8.19 (s, 1H), 7.50 (s, 1H), 7.31-7.39 (m, 2H), 7.16-7.23 (m, 2H), 7.05 (dd, J=2.0, 8.9 Hz, 1H), 5.44 (s, 2H), 3.95-4.06 (m, 2H), 3.80-3.88 (m, 4H), 3.50 (dd, J=2.6, 9.2 Hz, 1H), 3.06-3.14 (m, 4H), 2.09 (m, 1H), 1.77-1.86 (m, 2H), 1.48-1.53 (m, 2H), 1.33 (m, 1H); LCMS (ESI) m/z 480 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:17]2[C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:14]=[CH:13][C:12]=2[N:11]2[CH:27]([CH3:33])[CH2:28][N:29]([CH3:32])[C:30](=[O:31])[C:10]=12)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][N:15]2[C:16](=[O:18])[C:17]3[C:9]([OH:8])=[C:10]4[C:30](=[O:31])[N:29]([CH3:32])[CH2:28][CH:27]([CH3:33])[N:11]4[C:12]=3[CH:13]=[N:14]2)=[CH:21][CH:22]=1
Reactant: CC1CN(C)C(=O)c2c(OCc3ccccc3)c3c(=O)n(Cc4ccc(F)cc4)ncc3n21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CN(C)C(=O)c2c(O)c3c(=O)n(Cc4ccc(F)cc4)ncc3n21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 10-(benzyloxy)-2-(4-fluorobenzyl)-6,8-dimethyl-7,8-dihydropyrazino-[1′,2′:1,5]pyrrolo-[2,3-d]pyridazine-1,9(2H,6H)-dione (99 mg, 0.22 mmol) and Pearlman's catalyst (20 mg, 20% Pd(OH)2 on carbon) in methanol (2 mL) was stirred under an atmosphere of hydrogen gas (1 atm) at room temperature for one hour. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated under vacuum, and the residue triturated with diethyl ether. The solid precipitated was obtained by filtration to provide the titled product.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)[OH:21])=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33]>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([O:30][CH3:31])[CH:23]=2)=[O:21])=[CH:16][C:15]=1[N+:32]([O-:34])=[O:33]
Reactant: COc1ccc(C(O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(OC)c([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.8 %

Procedure:
Pyridinium chlorochromate (2.6 g, 12.2 mmol) and Celite (1 g) was added to a stirred solution of (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanol (2.6 g, 8.1 mmol) in CH2Cl2 (100 mL). The mixture was stirred for 4 h at room temperature then filtered through Celite. The filtrate was washed with water (2×40 mL), brine (40 mL) and dried (MgSO4). Solvent was removed and the residue was purified by flash chromatography (silica gel, CH2Cl2:EtOAc 95:5) to give (4-methoxy-3-nitro-phenyl)-(3,4-dimethoxy-phenyl)-methanone (2.0 g, 76%): 1H NMR (CDCl3) δ 8.29 (d, J=2 Hz, 1H), 8.07-8.03 (dd, J=2, 8 Hz, 1H), 7.34 (d, J=1 Hz, 1H), 7.35-7.26 (dd, J=2, 8 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 6.94 (d, J=8 Hz, 1H), 4.06 (s. 3H), 3.98 (s, 3H), 3.95 (s, 3H); 13C NMR (CDCl3) δ 192.10, 155.48, 153.34, 149.29, 139.01, 135.57, 130.35, 129.49, 127.60, 124.94, 113.14, 111.98, 109.96, 56.86, 56.13, 56.07.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2].Cl[C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=1)[C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].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]([C:3]1[CH:4]=[C:5]([C:18]2[CH:19]=[C:20]([CH:25]=[CH:26][N:27]=2)[C:21]([O:23][CH3:24])=[O:22])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]([CH3:13])[CH3:12])#[N:2]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: CC(C)COc1ccc(B(O)O)cc1C#N
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: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2ccc(OCC(C)C)c(C#N)c2)c1
Yield: 95.7 %

Procedure:
In a mixed solution of 50 ml of toluene and 30 ml of a 2M aqueous sodium carbonate solution were dissolved 1.46 g of (3-cyano-4-isobutoxyphenyl)boronic acid and 1.86 g of methyl 2-chloroisonicotinate, and the resulting solution was heated at 100° C. for 1 hour in the presence of 0.49 g of tetrakis(triphenylphosphine)palladium. The reaction solution was extracted with ethyl acetate and the organic layer was washed with brine and then dried and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate:chloroform=70:15:15) to obtain 1.98 g of methyl 2-(3-cyano-4-isobutoxyphenyl)isonicotinate. (2) Then, 1.98 g of the compound was dissolved in a mixed solution of 30 ml of methanol and 70 ml of THF, and 9 ml of a 1M aqueous sodium hydroxide solution was added thereto, followed by heating at 50° C. for 1 hour.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:5][NH:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([N:16]2[CH2:20][CH2:19][CH2:18][C@H:17]2[CH2:21][OH:22])[N:8]=1.[NH2:28][C:29]1[C:30]([CH3:36])=[N:31][N:32]([CH3:35])[C:33]=1[CH3:34].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>CN(C)C=O>[OH:22][CH2:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:9]1[N:8]=[C:7]([NH:6][CH2:5][C:4]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:13](=[O:15])[NH:28][C:29]2[C:30]([CH3:36])=[N:31][N:32]([CH3:35])[C:33]=2[CH3:34])=[CH:11][N:10]=1
Reactant: Cc1nn(C)c(C)c1N
Reactant: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CNc2nc(N3CCC[C@H]3CO)ncc2C(=O)Nc2c(C)nn(C)c2C)cc1Cl
Yield: 90.4 %

Procedure:
A mixture of (S)-4-(3-chloro-4-methoxybenzylamino)-5-carboxy-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine (100 mg) obtained in Example 1-(4), 4-amino-1,3,5-trimethylpyrazole (47.9 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58.7 mg), 1-hydroxybenzotriazole monohydrate (41.3 mg), and N,N-dimethylformamide (3 ml) is stirred at room temperature for 8 hours, and poured into aqueous sodium hydrogen carbonate solution. The mixture is extracted with ethyl acetate, and the organic layer is washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (solvent; chloroform:methanol=5:1) to give (S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine (115 mg), MS (m/z): 500 (MH+).
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=[O:6].Cl[Si](C)(C)[CH3:12]>CO.COC(OC)(C)C>[CH3:12][O:6][C:5](=[O:7])[C:4](=[O:8])[CH2:3][CH:2]([CH3:9])[CH3:1]
Reactant: CC(C)CC(=O)C(=O)O
Reactant: C[Si](C)(C)Cl
Solvent: CO
Solvent: COC(C)(C)OC
Product: COC(=O)C(=O)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methyl-2-oxo-pentanoic acid (3.4 g, 26 mmol) in methanol (12 mL) and 2,2-dimethoxypropane (48 mL) is added chlorotrimethylsilane (0.38 mL). The reaction mixture is stirred at ambient temperature overnight. The reaction mixture is concentrated under reduced pressure to give the title compound as an oil, (3.8 g, quant.). 1H NMR (400 MHz, CDCl3): δ 3.86 (s, 3H), 2.72 (d, 2H), 2.16 (m, 1H), 0.96 (d, 6H).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:17][C@@:11]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:12]([OH:27])[CH:13]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:34][C:35]([F:49])([F:48])[C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:39]Br.C(OCC)C>C1COCC1>[CH2:3]([N:10]1[C@@H:15]2[C@H:16]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:19])=[O:20])[CH2:17][C@@:11]1([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:12]([O:27][CH2:39][C:38]1[CH:41]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:43]=[C:36]([C:35]([F:34])([F:48])[F:49])[CH:37]=1)[CH:13]=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@@H](O)C=C[C@@H]1N2Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)[C@@H]1C[C@@]2(c3ccccc3)[C@@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)C=C[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (94 mg, 60% in oil, 2.45 mmol) was added to a stirred solution of (1R*,2S*,5S*,6R*)-8-benzyl-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]oct-3-en-2-ol (Description 5b; 256 mg, 0.6 mmol) and 3,5-bis(trifluoromethyl)benzyl bromide (0.8 ml) in dry THF (3 ml) at room temperature. The reaction mixture was stirred at +50° C. for 30 minutes, then cooled to room temperature and treated with diethyl ether (70 ml). The mixture was washed twice with water, brine. The combined organic extracts were dried (Na2SO4) and concentrated. The combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-30%) to give the title compound (400 mg, quant.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:24]3[CH:29]=[CH:28][C:27]([S:30][C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:38]([Si:40]([CH3:43])([CH3:42])[CH3:41])#[CH:39]>[Pd]>[CH3:41][Si:40]([C:38]#[C:39][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:24]3[CH:25]=[CH:26][C:27]([S:30][C:31]4[CH:36]=[CH:35][C:34]([C:39]#[C:38][Si:40]([CH3:43])([CH3:42])[CH3:41])=[CH:33][CH:32]=4)=[CH:28][CH:29]=3)([C:20]([F:22])([F:23])[F:21])[C:16]([F:17])([F:19])[F:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)([CH3:43])[CH3:42]
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)C(c1ccc(Sc2ccc(I)cc2)cc1)(c1ccc(Sc2ccc(I)cc2)cc1)C(F)(F)F
Agent: [Pd]
Product: C[Si](C)(C)C#Cc1ccc(Sc2ccc(C(c3ccc(Sc4ccc(C#C[Si](C)(C)C)cc4)cc3)(C(F)(F)F)C(F)(F)F)cc2)cc1

Procedure:
Compound 10 was prepared by treating Compound 9 with the palladium catalyst system and ethynyltrimethylsilane according to the general procedure described in Example 1, Section D herein.
Reaction SMILES: [F:1][C:2]([F:56])([F:55])[C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:27]=1[C:37]1[CH:42]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:40]=[CH:39][C:38]=1[O:46][CH3:47])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])=[CH:10][N:9]=1.Cl.O1CCOCC1.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:56][C:2]([F:1])([F:55])[C:3]1[CH:4]=[C:5]([CH:48]=[C:49]([C:51]([F:52])([F:53])[F:54])[CH:50]=1)[CH2:6][N:7]([CH2:25][C:26]1[CH:31]=[C:30]([O:32][C:33]([F:36])([F:35])[F:34])[CH:29]=[CH:28][C:27]=1[C:37]1[CH:42]=[C:41]([CH:43]([CH3:45])[CH3:44])[CH:40]=[CH:39][C:38]=1[O:46][CH3:47])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(OC(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)OC(C)(C)C)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)C)cc1-c1ccc(OC(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
To tert-butyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (57 mg) is added 4N-hydrogen chloride/dioxane solution (2 ml) and the mixture is stirred at room temperature overnight. To the reaction solution are added an aqueous saturated sodium hydroxide solution and chloroform, and the mixture is separated, dried over magnesium sulphate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→23:2) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethoxy-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butanoic acid (46.6 mg). MS (m/z): 746 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12].[Cl-].[Al+3].[Cl-].[Cl-].[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[CH3:1][C:2]1[CH:11]=[C:10]([C:17](=[O:19])[CH3:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[OH:12]
Reactant: Cc1ccc2ccccc2c1O
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C)c(O)c2ccccc12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To an ice-cooled solution of 2-methyl-l-naphthol (7.9 g, 0.05 mmol) in dichloromethane, anhydrous aluminum chloride (7.2 g) was slowly added with stirring, followed by slow addition of acetyl chloride (4.7 g) to start reaction. The reaction mixture was stirred at 10° C. or below for 1 h, then at room temperature for 3 h. Thereafter, the mixture was poured into ice water. Then, the reaction product was extracted with dichloromethane and the extracted layer was washed with water. Further, the extracted layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized with benzene, giving the desired compound, 2-methyl-4-acetyl-l-naphthol, in an amount of 3.9 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.[NH2:14][C:15]1[C:28]2[NH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[S:20][C:19]=2[CH:18]=[CH:17][CH:16]=1>[C].[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][C:15]2[C:28]3[NH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[S:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Nc1cccc2c1Nc1ccccc1S2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: [Pd]
Product: Nc1ccc(S(=O)(=O)Nc2cccc3c2Nc2ccccc2S3)cc1

Procedure:
4-Nitrobenzenesulfonyl chloride was reacted with 1-amino-10H-phenothiazine in the same manner as the one of Example 11. The product thus obtained was hydrogenated in the presence of palladium-carbon at room temperature under atmospheric pressure. Thus the title compound was obtained.