Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].N1C=CC=CC=1.[CH2:30]([O:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)[C:31]#[C:32][CH3:33]>C(Cl)(Cl)Cl.CCOCC>[C:20]([O:19][C:17]([NH:16][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C@@H:2]([NH:1][S:41]([C:38]2[CH:37]=[CH:36][C:35]([O:34][CH2:30][C:31]#[C:32][CH3:33])=[CH:40][CH:39]=2)(=[O:43])=[O:42])[C:3]([O:5][CH3:6])=[O:4])=[CH:12][CH:11]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@H](N)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC#CCOc1ccc(S(=O)(=O)N[C@@H](C(=O)OC)c2ccc(OCCNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.8 %

Procedure:
To a solution of 0.682 g (2.10 mmol) of methyl (2R)-amino(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)ethanoate dissolved in 10 mL of chloroform and 2.2 mL of pyridine was added 0.566 g (2.315 mmol) of 4-but-2-ynyloxy-benzenesulfonyl chloride. The reaction was stirred at room temperature for 15 h and then diluted with ether. The organics were washed with water, 5% HCl solution and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to provide 0.691 g of methyl (2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl)({[4-(2-butynyloxy)phenyl]sulfonyl}amino)ethanoate as a white foam Electrospray Mass Spec 533.1 (M+H)+
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[O:12])[CH2:7][CH2:6]2)[CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[F:49][C:50]1[CH:55]=[CH:54][C:53]([N:56]2[C:60]3[CH:61]=[CH:62][C:63]([C:65](O)=[O:66])=[CH:64][C:59]=3[N:58]=[CH:57]2)=[CH:52][CH:51]=1>C(Cl)Cl.O>[F:49][C:50]1[CH:51]=[CH:52][C:53]([N:56]2[C:60]3[CH:61]=[CH:62][C:63]([C:65]([N:1]4[CH2:2][CH:3]([N:5]5[CH2:6][CH2:7][N:8]([C:11]([C:13]6[S:14][CH:15]=[CH:16][N:17]=6)=[O:12])[CH2:9][CH2:10]5)[CH2:4]4)=[O:66])=[CH:64][C:59]=3[N:58]=[CH:57]2)=[CH:54][CH:55]=1
Reactant: O=C(O)c1ccc2c(c1)ncn2-c1ccc(F)cc1
Reactant: O=C(c1nccs1)N1CCN(C2CNC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc2c(c1)ncn2-c1ccc(F)cc1)N1CC(N2CCN(C(=O)c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5e (0.058 g, 0.178 mmol) and HATU (0.081 g, 0.214 mmol) in CH2Cl2 (3 mL) was added Et3N (0.099 mL, 0.713 mmol). The mixture was stirred at room temperature for 30 min, and then 60f (0.050 g, 0.196 mmol) was added. The reaction mixture was stirred at room temperature overnight. Water (6 mL) was added and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product Cpd 1167 was purified by preparative reverse phase chromatography. MS m/z (M+H+) 491.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:10][N:11]1[C:15]([C:16](Cl)=[O:17])=[CH:14][C:13]([CH3:19])=[N:12]1>CN(C)C(=O)C>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[NH:1][C:16]([C:15]1[N:11]([CH3:10])[N:12]=[C:13]([CH3:19])[CH:14]=1)=[O:17]
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cc(O)ccc1Cl
Solvent: CC(=O)N(C)C
Product: Cc1cc(C(=O)Nc2cc(O)ccc2Cl)n(C)n1
Yield: 70.3 %

Procedure:
In the same manner as in Reference Example 23 and using 3-amino-4-chlorophenol (920 mg, 6.4 mmol), 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1170 mg, 7.4 mmol) and N,N-dimethylacetamide (13 mL) as starting materials, N-(2-chloro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1190 mg, 4.5 mmol) was obtained. Using lithium aluminum hydride (1060 mg, 22 mmol), N-(2-chloro-5-hydroxyphenyl)-1,3-dimethyl-1H-pyrazole-5-carboxamide (1190 mg, 4.5 mmol) and tetrahydrofuran (40 mL) as starting materials, the title compound (810 mg, 72%) was obtained as a brown solid.
Reaction SMILES: Cl.C(OC(=O)[C@H](C)N[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1.N1C=CN=C1.C(N1C=CN=C1)(N1C=CN=C1)=[O:33].C(NCCN(C)C)CC(C)C.[CH2:55]([C@H:62]([NH:72][C:73]([N:75]([CH2:81][CH2:82][N:83]([CH3:85])[CH3:84])[CH2:76][CH2:77][CH:78]([CH3:80])[CH3:79])=[O:74])[CH2:63][O:64][CH2:65][C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)C1C=CC=CC=1>O1CCCC1.C(Cl)(Cl)Cl>[CH2:65]([O:64][C:63]([C@@H:62]([NH:72][C:73]([N:75]([CH2:81][CH2:82][N:83]([CH3:85])[CH3:84])[CH2:76][CH2:77][CH:78]([CH3:80])[CH3:79])=[O:74])[CH2:55][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:17][CH:18]=1)=[O:33])[C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)CCN(CCN(C)C)C(=O)N[C@H](COCc1ccccc1)Cc1ccccc1
Reactant: C[C@H](Nc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: CC(C)CCNCCN(C)C
Agent: Cl
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)CCN(CCN(C)C)C(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 4-biphenylyl-L-alanine benzyl ester hydrochloride (270 mg) in anhydrous tetrahydrofuran (2 ml), there were added imidazole (50 mg) and 1,1′-carbonyl diimidazole (155 mg) in the nitrogen gas atmosphere and the resulting mixture was stirred at room temperature for 10 minutes. Then a solution of N-isopentyl-2-(dimethylamino) ethylamine (Reference Compound 2-2, 589 mg) in anhydrous tetrahydrofuran (3 ml) was added to the mixture, followed by the reflux with heating for 1.5 hour. Chloroform was added to this reaction liquid under ice cooling, the reaction liquid was washed with saturated sodium hydrogen carbonate aqueous solution and then with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting oily product was purified through the silica gel column chromatography to give the title compound (Compound 4-1, 402 mg).
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2](OCC)=O.[K].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1C)([O-:14])=[O:13]>CCOCC>[CH3:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:15]([N+:12]([O-:14])=[O:13])[C:16]=1[CH2:2][C:1]([OH:8])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1cccc([N+](=O)[O-])c1C
Agent: [K]
Solvent: CCOCC
Product: Cc1cccc([N+](=O)[O-])c1CC(=O)O
Yield: 45 %

Procedure:
Diethyl oxalate (30 mL) in 20 mL dry ether was added with stirring to 19 g potassium eethoxide suspended in 50 mL of dry ether. The mixture was cooled in an ice bath and 20 mL of 3-nitro-o-xylene in 20 mL of dry ether was slowly added. The thick dark red mixture was heated to reflux for 0.5 hr, concentrated to a dark red solid, and treated with 10% sodium hydroxide until almost all of the solid dissolved. The dark red mixture was treated with 30% hydrogen peroxide until the red color changed to yellow. The mixture was treated alternatively with 10% sodium hydroxide and 30% hydrogen peroxide until the dark red color was no longer present. The solid was filtered and the filtrate acidified with 6 N hydrochloric acid. The resulting precipitate was collected by vacuum filtration, washed with water, and dried under vacuum to give 9.8 g (45% yield) of 2-methyl-6-nitrophenylacetic acid as an off-white solid. The solid was hydrogenated in methanol over 10% palladium on carbon to give 9.04 g of 4-methyl-2-oxindole as a white solid.
Reaction SMILES: [CH3:1][Mg]Cl.[CH2:4]([NH:6][C:7](=[O:39])[NH:8][C:9]1[CH:31]=[C:30]([NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:12]([C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=2)=[O:14])=[CH:11][N:10]=1)[CH3:5]>C1COCC1>[CH2:4]([NH:6][C:7](=[O:39])[NH:8][C:9]1[CH:31]=[C:30]([NH:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:12]([C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][C:24](=[O:25])[CH3:1])=[CH:20][CH:21]=2)=[O:14])=[CH:11][N:10]=1)[CH3:5]
Reactant: C[Mg]Cl
Reactant: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccc(CCC(=O)N(C)OC)cc2)cn1
Solvent: C1CCOC1
Product: CCNC(=O)Nc1cc(Nc2ccccc2)c(C(=O)Nc2ccc(CCC(C)=O)cc2)cn1
Temperature: 0 °C
Yield: 56.1 %

Procedure:
Methylmagnesium chloride (100 μmol, 0.3 mmol) was added to THF (1 mL) and cooled to 0° C. Compound 123 (8 mg, 0.016 mmol) was dissolved in THF (1 mL) and this solution added dropwise to the Grignard at 0° C. The mixture was allowed to warm slowly to RT over 1 h then quenched with NH4Cl and diluted with water and EtOAc. The mixture was extracted into EtOAc and the organics combined and dried with brine then Na2SO4 then evaporated to dryness. The residue was applied to a silica column in DCM (1 mL) and MeOH (2 drops) and eluted with MeOH in DCM to afford Compound 122 (4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10](Cl)=[O:11])=[C:4]([CH3:13])[CH:3]=1.C(=O)([O-])O.[Na+].[CH3:19][O:20][C:21]([C:23]1([NH:31][OH:32])[CH2:28][CH2:27][N:26]([O:29][CH3:30])[CH2:25][CH2:24]1)=[O:22]>C1COCC1>[CH3:19][O:20][C:21]([C:23]1([N:31]([C:10](=[O:11])[CH2:9][C:5]2[C:6]([CH3:8])=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[CH3:13])[OH:32])[CH2:28][CH2:27][N:26]([O:29][CH3:30])[CH2:25][CH2:24]1)=[O:22]
Reactant: Cc1cc(Cl)cc(C)c1CC(=O)Cl
Reactant: COC(=O)C1(NO)CCN(OC)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(N(O)C(=O)Cc2c(C)cc(Cl)cc2C)CCN(OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of (4-chloro-2,6-dimethyl-phenyl)-acetyl chloride (2.90 g, 13.4 mmol) in THF (25 ml) was added sodium hydrogen carbonate (1.90 g, 22.7 mmol) at 0° C., followed by 4-hydroxyamino-1-methoxy-piperidine-4-carboxylic acid methyl ester (preparation example 11, step 3; compound P4ii.2) (2.73 g, 13.4 mmol) dissolved in THF (25 ml) dropwise. The reaction mixture was stirred at 0° C. for 30 minutes, then further 30 minutes at room temperature. After completion of the reaction indicated by TLC and LC/MS, the reaction mixture was filtered and the residue (NaCl) washed with THF. The filtrate was concentrated to dryness and stirred several times with little amounts of an ether/hexane mixture (1:1) to remove side products. Finally, the compound was washed with ether to yield pure 4-{[2-(4-chloro-2,6-dimethyl-phenyl)-acetyl]-hydroxy-amino}-1-methoxy-piperidine-4-carboxylic acid methyl ester (compound P3ii.34) as white solid. Yield: 3.7 g, mp 228-231° C.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:29]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH2:17][CH2:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[S:29])[NH:10][C:4]=2[CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C1Nc2cc(Br)ccc2N2CCc3cccc1c32
Yield: 63.4 %

Procedure:
To 9-bromo-1,2-dihydrobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6-one (9 g) in toluene (175 ml), under nitrogen, was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide (12.6 g). The mixture was refluxed for 1 hr and concentrated under reduced pressure. Recrystallization of the residue from chloroform: hexane afforded 6 g (63%) of product, mp 196°-197° C.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH:23]=O)([CH3:18])([CH3:17])[CH3:16].[Cl:28][C:29]1[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=1[NH2:31].C(O)(=O)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:15]([O:19][C:20](=[O:27])[NH:21][C:22]([CH3:26])([CH3:25])[CH2:23][NH:31][C:30]1[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=1[Cl:28])([CH3:18])([CH3:17])[CH3:16]
Reactant: Nc1ccccc1Cl
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(CNc1ccccc1Cl)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
4.07 g of sodium triacetoxyborohydride (19.3 mmol) was added to a solution of 3.00 g of (1,1-dimethyl-2-oxoethyl)carbamic acid t-butyl ester obtained in Reference Example 3 (16.0 mmol), 2.04 g of 2-chloroaniline (16.0 mmol) and 0.92 ml of acetic acid (16.0 mmol) in methylene chloride (160 ml) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. A saturated sodium bicarbonate aqueous solution was added to the reaction mixture, followed by extraction with methylene chloride. Then, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:hexane/ethyl acetate=5/1) to obtain 3.49 g of the title compound (yield: 73%).
Reaction SMILES: [CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[C:10](/[CH:20]=[CH:21]/[C@@H:22]([OH:30])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([OH:28])=[O:27])=[C:9]([CH:31]([CH3:33])[CH3:32])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4].[CH3:34]O[N-]C.[CH2:38](O)[CH3:39].[OH-].[Na+]>O>[CH:9]([NH:8][CH:38]([CH3:39])[CH3:34])([CH3:31])[CH3:10].[CH3:1][N:2]([C:7]1[N:12]=[C:11]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)[C:10](/[CH:20]=[CH:21]/[C@@H:22]([OH:30])[CH2:23][C@@H:24]([OH:29])[CH2:25][C:26]([OH:28])=[O:27])=[C:9]([CH:31]([CH3:33])[CH3:32])[N:8]=1)[S:3]([CH3:6])(=[O:5])=[O:4]
Reactant: CCO
Reactant: C[N-]OC
Agent: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)NC(C)C
Reaction time: 16 h

Procedure:
E-(7-{2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl}-[(3R,5S)-3,5-dihydroxy-hept-6-enoic acid])-N-methoxy-N-methyl-amide (38.3 g), ethyl alcohol (300.0 mL), and a solution of sodium hydroxide (5.1 g) in water (60.0 mL) were added to a reactor. The reaction mixture was stirred for 16 hours while maintaining the temperature of 20˜25° C., and then concentrated under reduced pressure. Ethyl acetate (240.0 mL) and water (360.0 mL) were added to the resulting residue under stirring. Ethyl acetate (240.0 mL) was added to the separated water layer, which was then adjusted to pH 3.0˜4.0 using 1N hydrochloric acid solution. The separated organic layer was concentrated under reduced pressure. Tetrahydrofuran (900.0 mL) and diisopropylamine (12.0 mL) were added to the resulting residue. The reaction mixture was stirred at 20˜25° C. for over 12 hours and then filtered under reduced pressure. The resulting white solid was dried under vacuum to obtain E-7-[2-(N-methyl-N-methanesulfonylamino)-4-(4-fluorophenyl)-6-isopropyl-pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid diisopropylamine salt (38.0 g, yield 90%, HPLC purity 99.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[CH:13][N:12]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:5][CH:4]=1
Reactant: Clc1ncnc2ccccc12
Reactant: COc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ncnc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.3 %

Procedure:
To a stirred solution of 4-methoxyphenol (75 mg, 0.60 mmol) and 4-chloro-quinazoline (125 mg, 76 mmol) in 3 mL of DMF was added sodium hydride (60% oil suspension, 30 mg, 0.75 mmol) at 0° C., then the reaction mixture was allowed to warm to room temperature and stirred for 5 h. The reaction was quenched by adding 50 uL of water and diluted with 25 mL of ethyl acetate. It was washed with water (25 mL×3), saturated NaCl, dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by chromatography (25% ethyl acetate/hexanes) to give the title compound (134 mg, 0.53 mmol, 89%). 1H NMR (CDCl3): 8.78 (s, 1H), 8.38 (m, 1H), 7.89-8.02 (m, 2H), 7.67 (m, 1H), 7.19 (m, 1H), 7.00 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: [Cl:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[Cl:1][CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:21][CH:22]=2)=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)Cc1ccc(CCOc2ccc(O)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(Cl)Cc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: -20 °C
Yield: 95.4 %

Procedure:
Methyl 2-chloro-3-{4-[2-(4-hydroxyphenoxy)ethyl]phenyl}propanoate (334 mg, 1.0 mmol) and triethylamine (303 mg, 3.0 mmol) was dissolved in 20 ml dichlormethane and cooled to −20° C. under nitrogen atmosphere. Methanesulfonyl chloride (114 mg, 1.0 mmol) was added dropwise. The mixture was allowed to reach room temperature. After 2 hours dichlormethane was added, the mixture was washed (water, brine), dried (Na2SO4) and evaporated under reduced pressure to yield 394 mg pure product (yield 96%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]=[S:8])=[O:5])[CH3:2].[CH:9]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>O1CCCC1>[C:4]([NH:6][C:7](=[S:8])[O:15][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: OC1CCCCC1
Reactant: CCOC(=O)N=C=S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(=S)OC1CCCCC1
Yield: 70.9 %

Procedure:
65.6 g of ethoxycarbonyl isothiocyanate were added to a mixture of 50.1 g of cyclohexanol, 100 ml of tetrahydrofuran and 10 ml of triethylamine and the mixture was refluxed for 20 hours after which the tetrahydrofuran was distilled under reduced pressure. Ether was added to the residue and the ether phase was extracted with aqueous potassium hydroxide solutions. The aqueous phase was recovered by decanting and was acidified with N hydrochloric acid. The aqueous phase was extracted with ether and the ether phase was dried and concentrated to dryness under reduced pressure to obtain 82 g of cyclohexyl N-carbethoxy-thiocarbamate. The product was purified by chromatography over silica gel with elution with an 8-2 cyclohexane-ethyl acetate mixture.
Reaction SMILES: [C:1]([C:5]1[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]([CH3:12])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.CN(C=O)C.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(=O)(O)[O-].[Na+]>[C:29]([Si:26]([O:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:6]([S:13][C:14]#[N:15])=[CH:7][C:8]=1[CH3:12])([CH3:28])[CH3:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(SC#N)c(C(C)(C)C)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(SC#N)c(C(C)(C)C)cc1O[Si](C)(C)C(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 2.0 g (9.0 mmol) of 5-tert-butyl-2-methyl-4-thiocyanato-phenol (prepared in Example GGG), imidazole (0.800 g, 11.8 mmol) and DMF (10 mL) was treated with t-butyldimethylsilylchloride (1.64 g, 10.9 mmol) and stirred overnight. The mixture was diluted with saturated sodium bicarbonate and the mixture extracted with hexanes. The hexane layers were combined, dried (Na2 SO4), and the solvent removed in vacuo to yield the title compound. 1H NMR (CDCl3) δ 0.23 (s, 6 H), 1.01 (s, 9 H), 1.45 (s, 9 H), 2.16 (s, 3 H), 6.87 (s, 1 H), 7.49 (s, 1 H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[CH:16]([N:29]1[CH2:34][C@H:33]([CH3:35])[NH:32][C@H:31]([CH3:36])[CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(C(C)C)CC)(C)C>CN(C)C(=O)C>[CH:16]([N:29]1[CH2:30][C@@H:31]([CH3:36])[N:32]([CH2:2][CH2:3][CH2:4][N:5]2[C:9](=[O:10])[C:8]3[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:6]2=[O:15])[C@@H:33]([CH3:35])[CH2:34]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: C[C@@H]1CN(C(c2ccccc2)c2ccccc2)C[C@H](C)N1CCCN1C(=O)c2ccccc2C1=O

Procedure:
N-(3-Bromopropyl)phthalimide (2.50 g, 9.33 mmol) is added to a stirred solution of benzhydryl-3,5-cis-dimethylpiperazine (2.61 g, 9.33 mmol) and diisopropylethylamine (1.81 g, 14.0 mmol) in N,N-dimethylacetamide (25 mL). The resultant mixture is heated at 120° C. for 48 hours. After concentration and subsequent chromatography on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane: 0-1%, 2-[3-(4-benzhydryl-2,6-cis-dimethylpiperazin-1-yl)-propyl]-isoindole-1,3-dione is obtained as a brown oil (1.98 g, 45% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:22]=[CH:21][C:6]([NH:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[C:9]#N)=[CH:5][CH:4]=1.O=[CH:24][C:25](=C)[CH3:26]>>[CH3:26][C:25]1[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[N:7]([C:6]2[CH:21]=[CH:22][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH:24]=1
Reactant: CSc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1
Reactant: C=C(C)C=O
Product: CSc1ccc(-n2cc(C)cc2-c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(iii), but using α-(4-methylthioanilino)-α-(4-sulfamoylphenyl)acetonitrile [prepared as described in step (ii) above] and methacrolein as starting materials, the title compound was obtained as a slightly yellow powder (yield 33%), melting at 194-196° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[OH:52][CH2:53][C:54]1[CH:55]=[C:56](B(O)O)[CH:57]=[CH:58][C:59]=1[CH3:60].C([O-])([O-])=O.[Cs+].[Cs+]>C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14]([C:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C@H:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:56]3[CH:57]=[CH:58][C:59]([CH3:60])=[C:54]([CH2:53][OH:52])[CH:55]=3)=[CH:41][C:40]=2[N:46]2[CH:50]=[CH:49][C:48]([CH3:51])=[N:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1
Reactant: Cc1ccc(B(O)O)cc1CO
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(-c5ccc(C)c(CO)c5)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(4-bromo-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (Step 2, Example 1u) (300 mg, 0.4 mmol, Step 2) in ethanol (2 mL) and water (0.5 mL) was added (3-(hydroxymethyl)-4-methylphenyl)boronic acid (CAS#1451391-54-0; 120 mg, 0.7 mmol), PdCl2(PPh3)2 (41 mg, 0.058 mmol), and Cs2CO3 (390 mg, 1.2 mmol). The reaction was heated to 60° C. for 16 h, then cooled to RT, filtered through celite and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(3′-(hydroxymethyl)-4′-methyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate a white solid.