Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH2:2]([OH:7])[C:3]([F:6])([F:5])[F:4].[CH3:8][C:9]([CH3:31])([CH3:30])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=1)=[O:11]>O1CCCC1>[CH3:8][C:9]([CH3:31])([CH3:30])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([O:7][CH2:2][C:3]([F:6])([F:5])[F:4])[N:21]=1)=[O:11]
Reactant: Cc1ccc(NC(=O)C(C)(C)C)c(-c2ccnc(S(C)(=O)=O)n2)c1
Reactant: OCC(F)(F)F
Agent: [Na]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)C(C)(C)C)c(-c2ccnc(OCC(F)(F)F)n2)c1
Reaction time: 1.5 h
Yield: 89.8 %

Procedure:
0.10 g sodium metal was covered under nitrogen with 15 mL anhydrous tetrahydrofuran and 1 g trifluoroethanol was added dropwise with stirring. Stirring was continued for 1.5 h at which time the sodium was completely reacted. A solution of 0.4 g 2,2-dimethyl-N-[4-methyl-2-[2-(methylsulfonyl)-4-pyrimidinyl]phenyl]propanamide was added via syringe and stirring continued overnight under nitrogen. The reaction mixture was quenched with water and extracted with ether. The organic extracts were washed with water and brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The crude product was purified by chromatography on silica gel using 40:1 chlorobutane/ethyl acetate mixture as eluent to yield 0.38 g of the title compound as white crystals melting at 126°-128° C. 1H NMR (CDCl3): δ 1.28 (s,9H), 2.40 (s,3H), 4.85 (q,2H), 7.30-8.6 (5H), 11.9(s,1H,NH).
Reaction SMILES: [C:1]([N:5]=[C:6]([NH:12][C:13](=[O:15])[O-])[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)(C)(C)[CH3:2].C(OCC)(=O)C#C.C([O-])([O-])=O.[K+].[K+]>CCO>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:6]1[N:12]=[C:13]([OH:15])[CH:2]=[CH:1][N:5]=1
Reactant: CC(C)(C)N=C(NC(=O)[O-])c1cccs1
Agent: C#CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Oc1ccnc(-c2cccs2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
A mixture of tert-butylimino(thiophen-2-yl)methylcarbamate (2 g, 12 mmol, 1.0 eq), ethyl propiolate (1.4 g, 13 mmol, 1.1 eq.) and K2CO3 (1.7 g, 12 mmol, 1.0 eq) in EtOH (60 mL) was stirred at 80° C. overnight. The solid was collected and washed with ether to provide 2-(thiophen-2-yl)pyrimidin-4-ol (1.1 g, 53%) for the next step. LC-MS (m/z)=179 [M+H]+
Reaction SMILES: Br.C([O:6][C:7](=[O:35])[CH:8]([NH:27]C(OC(C)(C)C)=O)[CH2:9][S:10](=[O:26])(=[O:25])[CH2:11][CH2:12][NH:13][C:14](=[NH:24])[CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(C)(C)C>Cl.O1CCOCC1>[NH2:27][CH:8]([CH2:9][S:10](=[O:26])(=[O:25])[CH2:11][CH2:12][NH:13][C:14](=[NH:24])[CH2:15][O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:7]([OH:35])=[O:6]
Reactant: CC(C)(C)OC(=O)NC(CS(=O)(=O)CCNC(=N)COCc1ccccc1)C(=O)OC(C)(C)C
Agent: Br
Agent: Cl
Solvent: C1COCCO1
Product: N=C(COCc1ccccc1)NCCS(=O)(=O)CC(N)C(=O)O
Temperature: 65 °C

Procedure:
t-Butyl-6-(2-benzyloxy-1-iminoethylamino)2-t-butoxycarbonylamino-4,4-dioxo-4-thiahexanoate hydrobromide (0.97 g) (prepared by a method analagous to that described in Example 1A from Intermediates A and 3B) was stirred in 4M HCl/dioxane (12 ml) at room temperature for 6 hours. The solvent was evaporated and the residual gum triturated with dry ether (20 ml). A white solid slowly formed on standing. The ether was decanted off and the very hygroscopic solid washed with fresh ether and dried in vacuo with warming to 65° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9](C)([CH3:41])[CH2:10][NH:11][CH2:12][C:13]1[O:17][CH:16]=[C:15]([C:18]2[CH:19]=[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=2)[NH:23][CH:22]=[C:21]3[CH:30]2[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]2)[CH:14]=1.[CH3:43][C:44](C)(C)CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:9]1([CH2:10][NH:11][CH2:12][C:13]2[O:17][CH:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=3)[NH:23][CH:22]=[C:21]4[CH:30]3[CH2:31][CH2:32][N:33]([S:36]([CH2:39][CH3:40])(=[O:37])=[O:38])[CH2:34][CH2:35]3)[CH:14]=2)[CH2:8][CH2:44][CH2:43][CH2:41]1
Reactant: CC(C)(C)CN
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(CNCC(C)(C)C)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4coc(CNCC5CCCC5)c4)cc23)CC1
Yield: 25.1 %

Procedure:
The title compound was prepared according to the general procedure of 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide trifluoroacetate, substituting 1-cyclopentylmethanamine (137 mg, 1.4 mmol) for 2,2-dimethyl-1-propanamine to afford 22 mg of the title compound (25.1%).
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1>>[N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:20]=[CH:19][C:16]([CH2:17][N:21]4[CH2:26][CH2:25][S:24][CH2:23][CH2:22]4)=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)cc1
Product: c1cc(N2CCC(CN3CCCC3)CC2)ccc1CN1CCSCC1

Procedure:
Prepared from the product of Example 9 and thiomorpholine.
Reaction SMILES: [C:1]([NH:4][CH:5]1[C:30](=[O:31])[N:7]2[C:8]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:9]([CH2:12][OH:13])[CH2:10][S:11][C@H:6]12)(=[O:3])[CH3:2].C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:43])C=1>C(O)(C)C>[C:1]([NH:4][CH:5]1[C:30](=[O:31])[N:7]2[C:8]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])=[C:9]([CH2:12][OH:13])[CH2:10][S:11](=[O:43])[C@H:6]12)(=[O:3])[CH3:2]
Reactant: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS(=O)[C@H]12

Procedure:
To a stirred, cooled (0°-5° C.) solution of 876 mg. of benzhydryl 7-acetamido-3-hydroxymethyl-3-cephem-4-carboxylate in a mixture of 40 ml. of methylene chloride and 20 ml. of isopropanol there was added dropwise 407 mg. (equivalent, about 85% pure) of m-chloroperbenzoic acid in 20 ml. of isopropanol, During the addition a precipitate was formed which was collected and washed with ethyl acetate yielding 800 mg. of the titled compound, m.p. 178°-179° C. The NMR, IR, and UV spectra were consistent with the assigned structure.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[C:38]([CH3:44])=[N:39][N:40]([CH3:43])[C:41]=1[CH3:42]>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[C:38]([CH3:44])=[N:39][N:40]([CH3:43])[C:41]=3[CH3:42])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: Cc1nn(C)c(C)c1Br
Product: Cc1nn(C)c(C)c1-c1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-1,3,5-trimethyl-1H-pyrazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=462 [M+H]+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]([OH:31])=[C:27]3[C:22]=2[CH2:23][CH2:24][CH2:25][NH:26]3)[CH2:15][CH2:14]1.C(N(CC)CC)C>O1CCCC1>[C:1]([N:26]1[C:27]2[C:22](=[C:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=4[O:6][CH3:5])[CH2:14][CH2:15]3)[CH:30]=[CH:29][C:28]=2[OH:31])[CH2:23][CH2:24][CH2:25]1)(=[O:3])[CH3:2]
Reactant: COc1ccccc1N1CCN(CCc2ccc(O)c3c2CCCN3)CC1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CCc2ccc(O)c3c2CCCN3C(C)=O)CC1
Temperature: 5 °C
Reaction time: 2 h

Procedure:
A solution of 1.45 ml of acetyl chloride is 20 ml of tetrahydrofuran is added at 5° C. to a solution of 7.34 g of 5-{2-[4-(2-methoxyphenyl)piperazinyl]ethyl}-8-hydroxy-1,2,3,4-tetrahydro quinoline in 140 ml of anhydrous tetrahydrofuran containing 2.8 ml of triethylamine. This is stirred for 2 hours at 5° C. and then for 1 hour at room temperature. Then, the insoluble substance is filtered off and concentrated to dryness under reduced pressure. The residue is purified by chromatoflash on 750 g of silica (70-230 mesh) by eluating with the mixture CH2Cl3 /CH3OH (95/5).
Reaction SMILES: C([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[C:7]([Cl:15])[C:8]([SH:14])=[CH:9][CH:10]=2)[CH2:5]1)(=O)C.ClC1C(O)=CC=C2C=1C=NC=C2.CN(C)C(Cl)=S.ClC1C(SC(=O)N(C)C)=CC=C2C=1C=NC=C2>>[Cl:15][C:7]1[C:8]([SH:14])=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[N:4][CH:13]=[CH:12]2
Reactant: CC(=O)N1CCc2ccc(S)c(Cl)c2C1
Agent: CN(C)C(=O)Sc1ccc2ccncc2c1Cl
Agent: CN(C)C(=S)Cl
Agent: Oc1ccc2ccncc2c1Cl
Product: Sc1ccc2ccncc2c1Cl

Procedure:
Alternatively, N-acetyl-8-chloro-7-mercapto-1,2,3,4-tetrahydroisoquinoline can be prepared by reacting 8-chloro-7-hydroxyisoquinoline with dimethylthiocarbamyl chloride and rearranging the resulting compound to 8-chloro-7-dimethylcarbamoylthioisoquinoline. This compound is hydrolyzed to give 8-chloro-7-mercaptoisoquinoline which is then reduced and acylated.
Reaction SMILES: [NH2:1][C:2]1([CH2:8][C:9]([O:11]CC)=O)[CH2:5][S:4](=[O:7])(=[O:6])[CH2:3]1.CO.[NH3:16]>>[NH2:1][C:2]1([CH2:8][C:9]([NH2:16])=[O:11])[CH2:5][S:4](=[O:7])(=[O:6])[CH2:3]1
Reactant: CCOC(=O)CC1(N)CS(=O)(=O)C1
Reactant: N
Solvent: CO
Product: NC(=O)CC1(N)CS(=O)(=O)C1
Temperature: 45 °C
Reaction time: 48 h

Procedure:
Ethyl 2-(3-amino-1,1-dioxo-thietan-3-yl)acetate (example 160c, 550 mg, 2.65 mmol) was dissolved in ammonia 7.0M in methanol (9 ml, 63.0 mmol) and the reaction flask was sealed (size of the flask was chosen to minimize the volume for gas expansion in order to minimize ammonia evaporation). The reaction was stirred at 45° C. for 2 days. Volatiles were removed in vacuo to yield a crude material (523 mg) containing a 4:1 ratio of amide:methyl ester. The crude material was used without any further purification; MS (ESI, m/z): 179.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][CH:24]([C:26]1[O:30][N:29]=[C:28]([CH2:31][NH2:32])[CH:27]=1)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[CH:12][N:11]=[C:10]([C:20]([NH:32][CH2:31][C:28]3[CH:27]=[C:26]([CH:24]([CH3:25])[CH3:23])[O:30][N:29]=3)=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)cn1
Reactant: CC(C)c1cc(CN)no1
Product: CC(C)c1cc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example D) and 5-(1-methylethyl)-3-isoxazolemethanamine (CAS Registry No. 154016-49-6) as starting materials; LC-MS (UV peak area/ESI) 98.5%, 454.1122 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Cl:15])(=O)C>>[CH3:1][O:2][CH:3]([Cl:15])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)Cl
Reactant: COC(OC)c1ccccc1
Product: COC(Cl)c1ccccc1
Temperature: 45 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
To a 300 mL-volume Kjeldahl flask, 50 g of benzaldehyde dimethyl acetal and 27.08 g of acetyl chloride were added, and the mixture was stirred at 45° C. for 3 hours. After the reaction, the low boiling point residue was removed under reduced pressure to obtain 49.8 g of α-chlorobenzyl methyl ether.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[O:12]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[O:12]([C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)=[O:23])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc2ncccc2c1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2ncccc2c1)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 92.7 %

Procedure:
To a solution of 6-aminoquinoline (250 mg, 1.04 mmol) in N,N-dimethylformamide (15 mL) were added 3-phenoxybenzoic acid (371 mg, 1.73 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (722 mg, 1.90 mmol) and triethylamine (603 μl, 4.33 mmol), and the solution was stirred for 2 days at room temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate, the organic layer was washed with water, an aqueous solution of saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then, concentrated in vacuo. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the title compound (328 mg, 0.964 mmol, 93%) was obtained.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[C:7]([NH:10][C:11]1[S:12][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:14][N:15]=1)(=[O:9])[CH3:8].C(N(CC)CC)C>O1CCOCC1>[OH:4][CH2:3][C:2]([NH:1][S:16]([C:13]1[S:12][C:11]([NH:10][C:7](=[O:9])[CH3:8])=[N:15][CH:14]=1)(=[O:17])=[O:18])([CH3:6])[CH3:5]
Reactant: CC(=O)Nc1ncc(S(=O)(=O)Cl)s1
Reactant: CC(C)(N)CO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ncc(S(=O)(=O)NC(C)(C)CO)s1
Temperature: 25 °C
Reaction time: 17 h
Yield: 59 %

Procedure:
To a stirred solution of 2-amino-2-methyl-1-propanol (1.11 g, 12.5 mmol) in dioxane (20 ml) was added at 0° C. (ice water bath) 2-acetamido-thiazole-5-sulfonyl chloride [CAS No. 69812-30-2; commercially available] (1.0 g, 4.15 mmol) and triethylamine (0.64 ml, 4.57 mmol). The light yellow suspension was stirred at room temperature for 17 h, and evaporated. The crude product was further purified by column chromatography on silica gel (ethyl acetate) to yield 2-acetamido-thiazole-5-sulfonic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.72 g, 59%) as a white solid. MS (ISP) 292.1 [(M−H)−]; mp 206° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH2:17])[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([NH:17][C:10]([C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: CCOC(C)=O
Product: CCCCNC(=O)[C@@H]1C[C@H]1c1ccccc1

Procedure:
Following the procedure of Example 1 above and using trans-2-phenyl-1-cyclopropanecarbonyl chloride and n-butylamine (and ethyl acetate in place of benzene), the title compound was prepared as a waxy white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[NH2:16].[Cl:21][CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27].O>CC1C=C(C)N=C(C)C=1>[Cl:21][CH2:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:16][C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([O:6][CH2:5][C:4]3[CH:17]=[C:18]([F:20])[CH:19]=[C:2]([F:1])[CH:3]=3)[CH:8]=2)[NH:12][N:11]=1)=[O:27]
Reactant: O=C(Cl)c1cccc(CCl)c1
Reactant: Nc1n[nH]c2ccc(OCc3cc(F)cc(F)c3)cc12
Solvent: Cc1cc(C)nc(C)c1
Solvent: O
Product: O=C(Nc1n[nH]c2ccc(OCc3cc(F)cc(F)c3)cc12)c1cccc(CCl)c1
Temperature: 4 °C
Yield: 56 %

Procedure:
5-(3,5-Difluoro-benzyloxy)-1H-indazol-3-ylamine (550 mg, 2 mmol) was dissolved in sym-collidine, cooled to 4° C. and treated with neat 3-chloromethyl-benzoyl chloride (0.34 mL, 2.4 mmol). After 1 hour the reaction mixture was added drop wise into iced water, with stirring and separation of a yellow oil occurred. Then, EtOAc (50 mL) and 2N HCl (25 mL) were added. The organic phase was separated, washed with aqueous NaHCO3 (50 mL), brine, dried over sodium sulfate and evaporated to dryness. After purification over silica gel (eluent: DCM:MeOH 95:5) 378 mg of title compound were obtained as a whitish solid in 56% yield.
Reaction SMILES: [F:1][C:2]1([F:54])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][C@H:35]5[CH2:39][O:38]C(C)(C)[O:36]5)=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:42]([F:53])[C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:52])([F:51])[F:50])=[CH:45][CH:44]=2)[CH2:4][CH2:3]1.Cl.[OH-].[Na+].[Cl-].[Na+]>CO>[F:54][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][C@H:35]([OH:36])[CH2:39][OH:38])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:42]([F:53])[C:43]2[CH:48]=[CH:47][C:46]([C:49]([F:50])([F:52])[F:51])=[CH:45][CH:44]=2)[CH2:6][CH2:7]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@H]5COC(C)(C)O5)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OC[C@H](O)CO)cn4)CC3)c([C@@H](F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2[C@@H](O)C1
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
To a solution of 108.4 mg (0.142 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-2-[1-(5-{[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}pyrimidin-2-yl)piperidin-4-yl]-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 26, in 2 ml of methanol, 0.5 ml of 2 N hydrochloric acid was added, and the mixture was stirred at 50° C. for 3 hours. After completion of the reaction, 0.5 ml of 2 N sodium hydroxide aqueous solution was added to the reaction solution, then saturated sodium chloride aqueous solution was added, and the reaction solution was extracted with ethyl acetate. The obtained organic phases were combined, washed with saturated sodium chloride aqueous solution, dried with magnesium sulfate and then filtered, and the solvent was distilled off under reduced pressure to provide 101.2 mg of the title compound as a white solid (yield: 99%).
Reaction SMILES: Br[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.[NH2:11][CH:12]([C:14]1[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([N:27]([C:32]([O:34][CH3:35])=[O:33])[C:28]([O:30][CH3:31])=[O:29])[C:17]([CH3:36])=[C:16]([Cl:37])[CH:15]=1)[CH3:13].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:37][C:16]1[CH:15]=[C:14]([CH:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH3:13])[C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=2)=[C:18]([N:27]([C:32]([O:34][CH3:35])=[O:33])[C:28]([O:30][CH3:31])=[O:29])[C:17]=1[CH3:36]
Reactant: COC(=O)N(C(=O)OC)c1c(C)c(Cl)cc(C(C)N)c1-c1cccc(F)c1
Reactant: Brc1ncnc2[nH]cnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COC(=O)N(C(=O)OC)c1c(C)c(Cl)cc(C(C)Nc2ncnc3[nH]cnc23)c1-c1cccc(F)c1
Temperature: 90 °C

Procedure:
A mixture of 6-bromo-9H-purine (36 mg, 0.18 mmol), dimethyl [6-(1-aminoethyl)-4-chloro-3′-fluoro-3-methylbiphenyl-2-yl]imidodicarbonate (66 mg, 0.17 mmol), and N,N-diisopropylethylamine (0.058 mL, 0.33 mmol) in isopropyl alcohol (0.6 mL) was heated at 90° C. under nitrogen overnight. The mixture was evaporated and the resulting mixture was purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired. LCMS calculated for C24H23ClFN6O4 (M+H)+: m/z=513.1. found: 513.2.
Reaction SMILES: O[N:2]1[C:23](=[O:24])[NH:22][C@H:21]2[C@@H:3]1[CH2:4][S:5][C@H:6]2[CH2:7][CH2:8][CH2:9][CH:10](N1C(=O)CCC1=O)[C:11](=[O:13])[OH:12]>CS(C)=O>[OH:13][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[C@@H:21]2[C@@H:3]([NH:2][C:23]([NH:22]2)=[O:24])[CH2:4][S:5]1)=[O:12]
Reactant: O=C(O)C(CCC[C@@H]1SC[C@H]2[C@@H]1NC(=O)N2O)N1C(=O)CCC1=O
Solvent: CS(C)=O
Product: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reaction time: 1 h

Procedure:
Dissolve 1 mg of N-hydroxysuccinimidobiotin (bio-NHS) in 1 ml dimethylsulfoxide. Add 7 ul of bio-NHS solution to protein (a 3 fold molar excess). Let sit 1 hr at room temperature. Dialyze vs PBS.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH3:13])=[C:9]([CH3:12])[C:10]=1[OH:11])([O:3][CH2:4][CH3:5])=[O:2].[CH2:14]([CH:16]1[O:18][CH2:17]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:6]1[NH:7][C:8]([CH3:13])=[C:9]([CH3:12])[C:10]=1[O:11][CH2:14][CH:16]1[O:18][CH2:17]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1O
Reactant: BrCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1[nH]c(C)c(C)c1OCC1CO1
Temperature: 0 °C
Yield: 93.4 %

Procedure:
100 g of 2-carboethoxy-3-hydroxy-4,5-dimethylpyrrole, 150 g of epibromohydrin and 152 g of dry potassium carbonate in 500 ml of acetone are refluxed for 16 hours. When it has cooled, the entire reaction mixture is poured into 3 liters of ice water, the batch is extracted with ether and the combined extracts are washed with 2 N sodium hydroxide solution and water and dried over sodium sulfate. The evaporation residue which remains after distilling off the ether and the excess epibromohydrin is extracted with heptane. 122 g of 1-(2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy)-2,3-epoxypropane, of melting point 70°-71° C., are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)[CH:21]=2)[S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:33][C:34]1[CH:35]=[C:36]([CH2:40][CH2:41][NH2:42])[CH:37]=[CH:38][CH:39]=1>>[F:33][C:34]1[CH:35]=[C:36]([CH2:40][CH2:41][NH:42][C:28]2[N:27]=[C:26]([C:22]3[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=3)[CH2:19][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[S:15]([CH3:18])(=[O:17])=[O:16])[CH:31]=[CH:30][N:29]=2)[CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cccc(-c3ccnc(Cl)n3)c2)S(C)(=O)=O)CC1
Reactant: NCCc1cccc(F)c1
Product: CS(=O)(=O)N(Cc1cccc(-c2ccnc(NCCc3cccc(F)c3)n2)c1)C1CCNCC1

Procedure:
Intermediate 30 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 484. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.4 (s, 1H), 8.3 (d, 1H) 8.1 (d, 1H) 7.7 (d, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.1 (m, 2H), 6.9 (t, 1H), 4.6 (s, 2H), δ 3.4 (t, 2H), 3.09 (s, 3H), δ 3.05 (m, 5H), 3.04 (t, 2H), 2.08 (m, 4H).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[C:13](O)=[C:12]([Cl:19])[CH:11]=1>CN(C=O)C>[Br:9][C:10]1[CH:15]=[C:14]([CH2:16][CH3:17])[C:13]([O:4][CH3:1])=[C:12]([Cl:19])[CH:11]=1
Reactant: O=C([O-])[O-]
Reactant: CCc1cc(Br)cc(Cl)c1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCc1cc(Br)cc(Cl)c1OC
Reaction time: 20 h
Yield: 904.9 %

Procedure:
Potassium carbonate (3.9 g, 28 mmol) followed by methyl iodide (0.58 mL, 9.3 mmol) were added to a solution of 4-bromo-2-chloro-6-ethyl-phenol (2.2 g, 9.3 mmol) in DMF (10 mL). The mixture was stirred for 20 hours and then partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The crude yellow oil was purified by flash column chromatography (0% to 3% EtOAc in hexanes) to give the desired product (21 g, 91%) 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.6 Hz, 3 H), 2.66 (q, J=7.6 Hz, 2 H), 3.82 (s, 3 H), 7.22 (s, 1 H), 7.37 (s, 1 H).