Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2].[NH2:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][C:25]([NH:27][CH:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][CH2:29]3)=[O:26])[CH:22]=2)[O:17][C:16]([CH3:39])([CH3:38])[CH:15]1[OH:40].C(N(CC)CC)C.CN(C)C=O>ClCCl.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([CH2:24][C:25]([NH:27][CH:28]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[CH2:31][CH2:30][CH2:29]4)=[O:26])[CH:22]=3)[O:17][C:16]([CH3:38])([CH3:39])[CH:15]2[OH:40])(=[O:11])=[O:10])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)Oc2ccc(CC(=O)NC3CCCc4ccccc43)cc2C(N)C1O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(S(=O)(=O)NC2c3cc(CC(=O)NC4CCCc5ccccc54)ccc3OC(C)(C)C2O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
1.67 g 4-ethyl benzenesulfonyl chloride was added dropwise to a solution of 3.75 g of the 2-(4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-N-1,2,3,4-tetrahydronaphth-1-yl acetamide obtained above and 8.4 ml triethylamine in 160 ml dichloromethane. In addition 5 ml of dimethyl formamide (=DMF) was added, and the resulting mixture was stirred for 18 hours at room temperature. Then 100 ml water was added, and the mixture was stirred for another 5 minutes. The organic phase was separated, and the solvent was evaporated at reduced pressure. The remaining residue was chromatographed on silica gel (mobile phase: ethyl acetate/cyclohexane/methanol 110:140:2 v/v/v), and the product phases were combined and reduced in volume. The residue was stirred with petroleum ether/diethyl ether 10:1 v/v. The resulting crystals were removed by suction and dried on a rotary evaporator at 40° C. and 25 bar. 2.3 g of the title compound was obtained as colorless crystals.
Reaction SMILES: C[O:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[N:25]2CC2C=CC(OC)=CC=2)[CH2:20][C@H:19]2[CH2:21][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH:11]=[CH:12][CH2:13][CH2:14][C:15]([CH3:23])=[CH:16][C:17](=[O:22])[O:18]2)[O:4]1.CO[C@]1([C@@H]2CSC(=O)N2CC2C=CC(OC)=CC=2)C[C@H]2C[C@@H](CCCC=CCCC(C)=CC(=O)O2)O1>>[OH:2][C@:3]1([C@@H:24]2[CH2:28][S:27][C:26](=[O:29])[NH:25]2)[CH2:20][C@H:19]2[CH2:21][C@@H:5]([CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH:11]=[CH:12][CH2:13][CH2:14][C:15]([CH3:23])=[CH:16][C:17](=[O:22])[O:18]2)[O:4]1
Reactant: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCCC=CC=CCCC(C)=CC(=O)O3)O2)cc1
Agent: C/C1=C/C(=O)O[C@@H]2C[C@@H](CCC/C=C\C=C\CC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Agent: COc1ccc(CN2C(=O)SC[C@H]2[C@@]2(OC)C[C@H]3C[C@@H](CCC/C=C\CC/C(C)=C\C(=O)O3)O2)cc1
Product: CC1=CC(=O)O[C@@H]2C[C@@H](CCCC=CC=CCC1)O[C@@](O)([C@@H]1CSC(=O)N1)C2

Procedure:
Application of the method shown in Example 46, with the modification that (R)-4-((1R,4Z,8E,10Z,15R,17R)-17-methoxy-5-methyl-3-oxo-2,16-dioxa-bicyclo[13.3.1]nonadeca-4,8,10-trien-17-yl)-3-(4-methoxybenzyl)thiazolidin-2-one is substituted for (R)-4-((1R,4Z,8Z,13R,15R)-15-methoxy-5-methyl-3-oxo-2,14-dioxa-bicyclo[11.3.1]heptadeca-4,8-dien-15-yl)-3-(4-methoxybenzyl)thiazolidin-2-one, affords the title compound.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:38])[CH2:14][N:15]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[C:24]([O:26]C(C)(C)C)=[O:25])=[O:18])=[O:7])(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[CH2:31]([N:15]([CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:38])[CH2:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[C:24]([OH:26])=[O:25])=[O:18])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)[C@H]1CCCN1C(=O)CN(CC(=O)N1CCC[C@@H]1C(=O)OC(C)(C)C)Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)[C@H]1CCCN1C(=O)CN(CC(=O)N1CCC[C@@H]1C(=O)O)Cc1ccccc1
Reaction time: 8 h
Yield: 94 %

Procedure:
A solution of 200 mg (0.38 mmol) (R)-1-[[Benzyl-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethyl]-amino]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 2 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 189 mg (94%) of the title compound as white crystals.
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([O:18]C)=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21].Cl.C(O)(=O)C>O>[F:1][C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([OH:18])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21]
Reactant: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2C
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CN1CCc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 75.8 %

Procedure:
29.1 g of methyl ester (6) obtained in Example 2 (1) was added to 80 ml of concentrated hydrochloric acid and 320 ml of acetic acid, and the solution was heated under reflux for 3.5 hours. After air-cooled, 500 ml of water was added to the solution, and the solid was filtered off and washed consecutively with water, ethanol and ether to obtain 23.2 g of crude solid. The obtained crude solid was recrystallized from ethanol and chloroform to obtain 21 g of subject compound (8) in a 80% yield. The result of the analysis of this compound was as follows.
Reaction SMILES: [N:1]1SC=C2C=CC=CC=12.N1SC(C(=O)C(O)=O)=C2N=CC=CC=12.[N:24]1[S:25][CH:26]=[C:27]2[CH:32]=[CH:31][CH:30]=[N:29][C:28]=12.NC1N=CC=CC=1C#N.N.S>>[NH2:24][C:28]1[N:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:26]([NH2:1])=[S:25]
Reactant: c1cnc2nscc2c1
Reactant: c1ccc2nscc2c1
Agent: N
Agent: N#Cc1cccnc1N
Agent: O=C(O)C(=O)c1snc2cccnc12
Product: NC(=S)c1cccnc1N

Procedure:
Scheme I-19 depicts the preparation of isothiazolobenzene or isothiazolopyridine glyoxylic acid derivatives which may be employed to prepare compounds of formula I. 3-methyl isothiazolopyridines can be prepared as depicted in step a by using methodology as described in Taurins, A.; Khouw, V. T. Can. J. Chem. 1973, 51(11), 1741-1748. For example Isothiazolo[3,4-b]pyridine was synthesized from 2-aminonicotinonitrile in three steps: by the reaction with NH3 and H2S to produce 2-aminothionicotinamide; oxidative cyclization with H2O2 to give 3-amino-isothiazolo[3,4-b]pyridine, followed by diazotization and reduction with hypophosphorous acid. 3-Aminoisothiazolo[4,3-b]pyridine was prepared in a similar way from 3-aminopicolinonitrile via 3-aminothiopicolinamide. Isothiazolo[5,4-b]pyridine was synthesized from 2-chloronicotinonitrile in three steps: reduction with HCO2H in the presence of Raney Nickel to obtain 2-chloronicotinaldehyde; transformation of the latter into 2-thiocyanonicotinaldehyde; and cyclization with NH3 to obtain isothiazolo[5,4-b]pyridine. 3-Methylizothiazolo[5,4-c]pyridine was prepared by cyclization of 4-acetyl-3-thiocyanopyridine with NH3. Alternatively, the 3-methylisothiazolopyridines may be prepared as described in Chimichi, S.; Giomi, D.; Tedeschi, P. Synth. Commun. 1993, 23(1), 73-78 in a single step procedure by treating a cyanomercaptopyridine with methyllithium in an appropriate solvent such as tetrahydrofuran to provide the 3-methylisothiazolopyridine derivative. As described previously for Scheme I-18 the methyl group may be converted to the bromide with N-bromosuccinimide as shown in step b. Bromide displacement with cyanide, as shown in step c, followed by hydrolysis and esterification, as shown in step d, provides the methyl ester. Oxidation of the methyl ester to the oxalate can then be carried out as depicted in step e. The oxidation can be carried out in one step with selenium dioxide to provide the oxalate. Alternatively, the methyl ester can be treated with a strong base such as lithium bistrimethylsilyl amide in tetrahydrofuran at reduced temperature followed by camphorsulfonyl oxaziridine to provide the corresponding α-hydroxy ester which may be oxidized with the Dess-Martin reagent in order to obtain the oxalate. The oxalate may then be hydrolyzed under standard conditions as depicted by step f to provide the oxalic acid derivative. The oxalic acid derivative may then be coupled to an appropriate piperazine derivative to provide a compound of Formula I.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([CH2:17][CH2:18][CH3:19])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C([Li])CCC.C(Cl)(Cl)(Cl)[Cl:26]>O1CCCC1>[Cl:26][C:16]1[N:11]2[N:10]=[C:9]([CH2:17][CH2:18][CH3:19])[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=3)=[C:12]2[CH:13]=[CH:14][CH:15]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCCc1nn2ccccc2c1-c1ccnc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCc1nn2c(Cl)cccc2c1-c1ccnc(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A solution of 3-(2-fluoropyridin-4-yl)-2-propylpyrazolo[1,5-a]pyridine (109 mg, 0.42 mmol) in tetrahydrofuran (5 mL) was cooled to −78° C. Butyllithium (0.4 mL, 1.6 M in hexane, 0.64 mmol) was added dropwise and the resultant solution was stirred at −78° C. for 45 minutes. Carbon tetrachloride (0.3 mL) was added and the mixture was stirred at −78° C. for 30 minutes and then quenched byt the addition of methanol while cold. Upon warming to room temperature water and ether were added and the layers separated. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed flash chromatography on silica gel (4:1 to 2:1 hexane-ethyl acetate) provided 7-chloro-3-(2-fluoropyridin-4-yl)-2-propylpyrazolo[1,5-a]pyridine (77 mg, 63%) as an orange solid. 1H NMR (CDCl3) δ 8.33 (d, 1H), 7.58 (d, 1H), 7.30 (m, 1H), 7.22 (t, 1H), 7.02–6.98 (m, 2H), 2.99 (t (m, 2H), 1.01 (t, 3H); 19F NMR (CDCl3) δ −68.11; MS m/z 290 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([S:6](Cl)(=[O:8])=[O:7])=[CH:2]1.[NH2:10][C:11]1[O:15][N:14]=[C:13]([CH3:16])[C:12]=1[Br:17]>>[Br:17][C:12]1[C:13]([CH3:16])=[N:14][O:15][C:11]=1[NH:10][S:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2ccsc2)c1Br
Yield: 22 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)thiophene-3-sulfonamide was prepared in the same manner as described in Example 2 from thiophene-3-sulfonyl chloride with 5-amino-4-bromo-3-methylisoxazole in 22% yield. Purification by column chromatography using 10% MeOH/CHCl3 as eluent gave a pale brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].[CH3:15][O:16][CH2:17][CH2:18][NH2:19]>O>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:19][CH2:18][CH2:17][O:16][CH3:15])([O-:3])=[O:2]
Reactant: COCCN
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: O
Product: COCCNc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]

Procedure:
0.05 mol (10.8 g) of 2,6-dinitro-4-methylchlorobenzene is added gradually, in the course of 10 minutes, whilst stirring, to 25 ml of methoxyethylamine, the reaction medium being cooled as necessary so as not to exceed 50° C. When the addition has ended, the stirring is maintained for 5 minutes and the reaction medium is then poured into 100 ml of iced water. The expected product precipitates. It is filtered off, washed with water and recrystallised from ethanol. After drying in vacuo, it melts at 75° C.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:26]Br>>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:26][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(C(=O)c2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)cc(F)c2)c1
Yield: 53.3 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (220 mg, yield: 53.3%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([CH2:15][CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:7](=[O:21])[C:6](=[O:22])[NH:5]2.C([O-])=O.[NH4+]>C(O)(C)C.O.[Pd]>[NH2:12][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:22])[C:7](=[O:21])[N:8]2[CH2:15][CH:16]([CH2:17][CH3:18])[CH2:19][CH3:20])=[CH:3][CH:2]=1
Reactant: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2ccc(N)cc21

Procedure:
36.0 g (0.112 mol) of 6-chloro-1-(2-ethylbutyl)-7-nitro-2,3(1H,4H)-quinoxalinedione were dissolved in 500 ml of isopropanol under nitrogen, and a solution of 70.6 g (1.12 mol) of ammonium formate in 100 ml of water was added. 3.5 g of palladium/carbon (10%) were added and the mixture was refluxed for 1 h. It was subsequently filtered, and the filtrate was concentrated under reduced pressure. The residue was partitioned between aqueous sodium bicarbonate solution and ether. The ether phase was separated off, dried and concentrated under reduced pressure.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]1>>[CH:1]1([C:4]2[CH:5]=[C:6]([NH:10][C:11]3[O:12][CH2:13][C:14]4[CH:20]=[C:19]([NH:21][C:30](=[O:31])[CH2:29][N:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2c(c1)COC(Nc1cccc(C3CC3)c1)=N2
Reactant: CN1CCN(CC(=O)O)CC1
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)COC(Nc2cccc(C4CC4)c2)=N3)CC1
Yield: 25.1 %

Procedure:
Prepared from N2-(3-cyclopropyl-phenyl)-4H-benzo[d][1,3]oxazine-2,6-diamine (160 mg, 0.57 mmol) and and 4-methylpiperazin-1-acetic acid (109 mg, 0.69 mmol) according to the procedure described for example 93. Obtained the title compound as an off-white solid (60 mg, 25%), MS (ISP) m/e=420.3 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:12])[C:4]=1[CH3:13].[CH:14]([Li])(CC)C.CI.O>O1CCCC1>[CH2:12]([C:5]1[C:4]([CH3:13])=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[CH3:14]
Reactant: COc1ccc(C(=O)O)c(C)c1C
Reactant: [Li]C(C)CC
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CCc1c(C(=O)O)ccc(OC)c1C
Temperature: -78 °C

Procedure:
20.0 g of 4-methoxy-2,3-dimethylbenzoic acid (C1) are dissolved in one litre of tetrahydrofuran in a dry nitrogen atmosphere and subsequently cooled to −78° C. 300 ml of sec-butyllithium (1.4 M in cyclohexane) are then added dropwise to give a red solution. The red solution is stirred at −78° C. for a further hour. 34.5 ml of methyl iodide are then added, and the resultant suspension is stirred for one hour without cooling. 300 ml of water are subsequently added, and the solution is extracted, using ethyl acetate, twice with 300 ml of ethyl acetate each time. The aqueous phase is subsequently filtered, the filtrate is cooled in an ice bath, adjusted to pH 1 by addition of hydrochloric acid (3.0 M) and stirred for a further 30 minutes. The suspension is then filtered and washed with water. The filter cake is dried at 110° C. in vacuo, giving 20.9 g of the title compound as colourless solid having a melting point of 180° C. (MS: 195.2 (MH+)).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=3)[C:10]2=[S:29])=[CH:5][C:4]=1[F:30].[CH3:31][NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>C1(C)C=CC=CC=1>[CH:33]1([N:32]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([N:9]3[C:13]([CH3:15])([CH3:14])[C:12](=[O:16])[N:11]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=4)[C:10]3=[S:29])=[CH:5][C:4]=2[F:30])[CH3:31])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(CCl)c(F)c1
Reactant: CNC1CCCCC1
Solvent: Cc1ccccc1
Product: CN(Cc1ccc(N2C(=S)N(c3ccc(C#N)c(C(F)(F)F)c3)C(=O)C2(C)C)cc1F)C1CCCCC1
Yield: 16.4 %

Procedure:
Compound 4 was prepared according to General Method 2. A solution of 4-(3-(4-(chloromethyl)-3-fluorophenyl)-4,4-dimethyl-5-oxo-2-thioxoimidazolidin-1-yl)-2-(trifluoromethyl)benzonitrile (40 mg, 0.08 mmol) and N-methylcyclohexanamine (30 mg, 0.24 mmol) in toluene 5 mL was refluxed for 12 h. The solvent was removed and residue was purified by silica gel chromatography (eluant: 60% ethyl acetate in hexane) to obtain 7 mg of desired product as brown viscous oil, HPLC, Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min. 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 9.663 min, M+1, 533
Reaction SMILES: Cl.[CH3:2][C@H:3]1[CH2:8][N:7]([S:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)(=[O:11])=[O:10])[CH2:6][CH2:5][NH:4]1.Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[F:28][C:25]([F:26])([F:27])[C:24]([C:21]1[CH:22]=[N:23][C:18]([N:4]2[CH2:5][CH2:6][N:7]([S:9]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)(=[O:11])=[O:10])[CH2:8][C@@H:3]2[CH3:2])=[N:19][CH:20]=1)([OH:33])[C:29]([F:32])([F:31])[F:30]
Reactant: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Reactant: OC(c1cnc(Cl)nc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 85 °C

Procedure:
A 20-mL vial was charged with (S)-2-methyl-4-(2-thiophenylsulfonyl)piperazine hydrochloride (0.75 g, 2.6 mmol, Example 27), (2-chloro-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.92 g, 3.3 mmol, Intermediate D), 15 mL of dioxane, and Hünig's base (1.2 mL, 6.6 mmol). The mixture was heated at 85° C. for 12 h and then concentrated and purified via column chromatography on silica gel (0 to 50% EtOAc in hexanes) delivered 1,1,1,3,3,3-hexafluoro-2-(2-((2S)-2-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)-5-pyrimidinyl)-2-propanol (0.360 g). 1H NMR (400 MHz, CD3OD) δ=8.58 (s, 2H), 7.87 (d, J=5.1 Hz, 1H), 7.66-7.63 (m, 1H), 7.28-7.23 (m, 1H), 5.14 (br. s., 1H), 4.76 (d, J=13.9 Hz, 1H), 3.83 (d, J=11.3 Hz, 1H), 3.67 (d, J=11.5 Hz, 1H), 3.40 (s, 1H), 2.69-2.58 (m, 1H), 2.47 (dt, J=3.6, 12.0 Hz, 1H), 1.36 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 491.0 (M+H)+. GK-GKRP IC50 (Binding)=0.362 μM; GK-GKRP EC50 (LC MS/MS-2)=0.470 μM.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][NH:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C@@H:12]([C:22]([O:24][CH3:25])=[O:23])[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].C1COCC1.[CH:36]1[CH:41]=[CH:40][C:39]([CH2:42][O:43][C:44](Cl)=[O:45])=[CH:38][CH:37]=1>O>[CH2:42]([O:43][C:44]([N:14]1[CH2:15][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:11][C@H:12]([C:22]([O:24][CH3:25])=[O:23])[C@@H:13]1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:45])[C:39]1[CH:40]=[CH:41][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN[C@H]1c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1C[C@@H](CO[Si](C)(C)C(C)(C)C)CN(C(=O)OCc2ccccc2)[C@H]1c1ccccc1
Yield: 102.3 %

Procedure:
To a stirred and ice-cooled mixture of (2R*,3S*,5R*)-5-(tert-butyldimethylsilyloxy)methyl-3-methoxycarbonyl-2-phenylpiperidine (4.86 g, 13.4 mmol), NaHCO3 (1.68 g, 20.1 mmol), THF (5.0 ml), and H2O (30.0 ml) was added Cbz-Cl (2.51 g, 14.7 mmol), and the mixture was stirred with ice-cooling for 30 minutes. The mixture was extracted with AcOEt (40.0 ml×3). The combined AcOEt extracts were washed with sat. NaCl aq. solution (×1), dried (MgSO4), and concentrated in vacuo to give a viscous pale yellow oil (6.82 g). This was flash chromatographed over SiO2 (Merck Kieselgel 60, 80.0 g). Elution with n-hexane-AcOEt (30:1/20: 1) gave title compound (6.51 g, 97.9%) as a viscous colorless oil. IRmax (film): 1735(s), 1700(s), 1605(w), 1585(w), 1495(m), 1250(s), 1115(s), 775(s), 740(m), 700(s) cm-1 ; 1H-NMR δ: 7.45-7.31(m, 4H), 7.31-7.15(m, 6H), 6.05(d, J=5.5 Hz, 0.6H), 5.87(d, J=5.5 Hz, 0.4H), 5.32-5.10(5.30, 5.25, 5.21, 5.18, and 5.13; m, 2H), 4.20-4.05(m, 1H), 3.65-3.45(m, 2.4H), 3.60(br.s, 3H), 3.40(dd, J=9.9, 6.6 Hz, 0.6H), 3.08-2.91(m, 1H), 2.63(dd, J=11.7, 11.7 Hz, 0.4H), 2.52(dd, J=13.6, 11.7 Hz, 0.6H), 2.11-1.98(m, 1H), 1.98-1.70(m, 2H), 0.86(s, 3.6H), 0.83(s, 5.4H), 0.026, 0.018, and 0.008(each s, total 6H) ppm.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Br:11])[CH:5]=1)=[O:3].[Se](=O)=[O:13]>O1CCOCC1.O>[Br:11][C:6]1[CH:5]=[C:4]([C:2](=[O:3])[CH:1]=[O:13])[CH:9]=[CH:8][C:7]=1[F:10]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: O=CC(=O)c1ccc(F)c(Br)c1
Temperature: 25 °C

Procedure:
To 3-bromo-4-fluoroacetophenone (11.0 g) in 1,4-dioxane (160 ml) and water (15 ml) was added selenium dioxide (8.8 g). The mixture was heated at reflux for 10 h, cooled to room temperature, and the solvent then removed at reduced pressure. The residue was suspended in 50% diethyl ether in isohexane, and residual solid removed by filtration. The filtrate was dried over Na2SO4, and solvent then evaporated to give (3-bromo-4-fluorophenyl)oxoacetaldehyde as a yellow oil, which was used without further purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[CH3:25][S:26][CH2:27][CH2:28][C:29](=[O:33])[C:30]([O-])=[O:31].[Na+].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:8]1[N:7]=[C:6]([N:19]2[CH2:24][CH2:23][N:22]([C:30](=[O:31])[C:29](=[O:33])[CH2:28][CH2:27][S:26][CH3:25])[CH2:21][CH2:20]2)[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CSCCC(=O)C(=O)[O-]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCCC(=O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (200 mg, 0.63 mmol), sodium 4-methylsulfanyl-2-oxo-butyrate (160 mg, 0.94 mmol), BOP (414 mg, 0.94 mmol), and triethylamine (348 μL, 2.5 mmol) in 2.1 mL of CH2Cl2 was stirred at room temperature for 1 h. After adding saturated NaHCO3 solution, the mixture was extracted with CH2Cl2. The organic extracts were dried over Na2SO4 and concentrated to give 1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-4-(methylthio)butane-1,2-dione. LC/MS: m/z 451.2 (M+H)+ at 3.10 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).