Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[F:18][C:19]([F:29])([F:28])[C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[C:20]([C:19]([F:18])([F:28])[F:29])[CH:21]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1cccc(C(F)(F)F)c1
Solvent: COCCOC
Product: N#Cc1c(NCc2cccc(C(F)(F)F)c2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 3-(trifluoromethyl)benzylamine in DME. ES-MS m/e (%): 360 (M+H+, 100).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1C.BrC1C=CC(C(Cl)=O)=CC=1>>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([C:14](=[O:15])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:17][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Agent: O=C(Cl)c1ccc(Br)cc1
Product: O=C(Cc1ccccc1)c1ccc(Br)cc1

Procedure:
The title compound was prepared according to the procedure of step 1 in the Example 169 using benzyl bromide and 4-bromo-3-methylbenzoyl chloride, instead of 4-bromobenzoyl chloride.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:25][C:26]1[CH:31]=[CH:30][C:29](CO)=[C:28]([CH3:34])[CH:27]=1>CCCCCC>[Br:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:1][Br:5])=[C:28]([CH3:34])[CH:27]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(Br)ccc1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: Cc1cc(Br)ccc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After carbon tetrabromide (6.7 g, 20 mmol) and triphenylphosphine (5.2 g, 20 mmol) were added to a solution of (4-bromo-2-methylphenyl)methanol (3.7 g, 18.4 mmol) which was synthesized according to the method described in literature (Dawson, M. I., et al., J. Med. Chem., 1984, vol. 27, pp. 1516-1531) under ice-cooling, the mixture was stirred at room temperature for 1 hour. Hexane was added to the reaction mixture and the insolubles were removed by filtration. After the obtained filtrate was poured into water and the mixture was extracted with ethyl acetate, the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=10/0-10/1) to give a crudely purified 4-bromo-1-(bromomethyl)-2-methylbenzene. Potassium cyanide (1.3 g, 20 mmol) was added to a solution of crude 4-bromo-1-(bromomethyl)-2-methylbenzene obtained in the above in a mixture of ethanol-water (3:1, 40 ml), and the mixture was stirred at 60° C. for 1.5 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=6/1-3/1) to give (4-bromo-2-methylphenyl)acetonitrile as a pale orange solid (2.4 g, two-step total yield: 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:20])[CH2:19][CH2:18][C:13]2(OCC[O:14]2)[CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:21]([NH2:24])(=[O:23])=[O:22])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:20])[CH2:19][CH2:18][C:13](=[O:14])[CH2:12][CH2:11]1
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCC3(CC2)OCCO3)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: O
Product: NS(=O)(=O)c1cnc(OCC2(F)CCC(=O)CC2)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of EXAMPLE 443C (1.6 g) and pyridinium p-toluenesulfonate (1.2 g) in acetone (10 mL) was added water (2 mL) and the mixture was stirred in a Biotage Initiator microwave reactor at 100° C. for 10 minutes. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4, and filtered. Concentration of the filtrate gave the crude product.
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]23[CH2:23][CH:18]4[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]4)[CH2:15]2)[CH2:21]3)=[N:11][CH:12]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][C:33]=1[C:34](Cl)=[O:35]>O>[C:14]12([O:13][C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:34](=[O:35])[C:33]4[CH:37]=[C:38]([N+:41]([O-:43])=[O:42])[CH:39]=[CH:40][C:32]=4[Cl:31])=[CH:12][N:11]=3)[CH2:15][CH:16]3[CH2:22][CH:20]([CH2:19][CH:18]([CH2:17]3)[CH2:23]1)[CH2:21]2
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)nc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(OC23CC4CC(CC(C4)C2)C3)nc1)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
To 5 mL of a tetrahydrofuran solution comprising 290 mg of 5-amino-2-(1-adamantyloxy)pyridine) and 150 mg of triethylamine, 5 mL of a tetrahydrofuran solution comprising 260 mg of 2-chloro-5-nitrobenzoylchloride was dropwise added, followed by stirring for about 30 minutes, and then water was added, and the precipitated crystals were collected by filtration. The collected crystals were washed with water and then dried to obtain 330 mg of N-(2-(1-adamantyloxy)-5-pyridyl)-2-chloro-5-nitrobenzamide (Compound No. 123) having a melting point of from 98 to 105° C.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([CH:9]=CN)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]1(=[O:25])[O:20][C:18](=[O:19])[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]2[CH2:15]1.[C:26](#[N:28])C>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH:9]2[CH:15]([C:14]([OH:20])=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18](=[O:19])[N:28]2[CH3:26])=[CH:12][CH:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CC(C)(C)c1ccc(C=CN)cc1
Reactant: CC#N
Product: CN1C(=O)c2ccccc2C(C(=O)O)C1c1ccc(C(C)(C)C)cc1

Procedure:
To 170 ml of a solution containing 18.67 g of N-(4-t-butylbenzylidene)methylamine in acetonitrile, 18.00 g of homophthalic anhydride was added and the mixture was allowed to react at room temperature for 14 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography [chloroform/ethyl acetate (6/1)] to obtain 33.73 g of 3-(4-t-butylphenyl)-4-hydroxycarbonyl-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline (mixture of diastereomers). The thus obtained mixture of diastereomers was again subjected to silica gel column chromatography [chloroform/ethyl acetate (6/1)] to obtain 15.2 g of cis compound and 8.03 g of trans compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:39]([CH3:40])[CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:41])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][OH:49])[CH:46]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:59][S:60](Cl)(=[O:62])=[O:61]>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[C@H:35]([CH3:41])[CH2:36][CH2:37][CH2:38][C@@H:39]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:42]2[CH:43]=[N:44][N:45]([CH2:47][CH2:48][O:49][S:60]([CH3:59])(=[O:62])=[O:61])[CH:46]=2)[N:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCO)c4)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1CCC[C@H](C)N1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOS(C)(=O)=O)c4)c4ccccc43)cn12
Reaction time: 1 h

Procedure:
To an ice-bath cooled solution of Intermediate 124b (174 mg, 0.26 mmol) in DCM (3 mL) was added DIPEA (182 μL, 1.0 mmol) followed by methanesulfonyl chloride (41 μL, 0.52 mmol). The reaction mixture was stirred for 1 h and then quenched with water. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo to afford the title compound (Quantitative). Product used in the following step without further purification. LCMS (Method 4): Rt 3.47 min, m/z 746 [MH+].
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:41])=[C:11]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]3([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[NH:17][CH:16]2[C:38](O)=[O:39])[CH:12]=[CH:13][CH:14]=1.[NH2:42][C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:50][O:49][C:47](=[O:48])[C:46]1[CH:51]=[CH:52][C:43]([NH:42][C:38]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:41])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]3([CH3:37])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[NH:17]2)=[O:39])=[CH:44][CH:45]=1
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC1(CC2NC(C(=O)O)C(c3cccc(Cl)c3F)C2(C#N)c2ccc(Cl)cc2F)CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC3(C)CCCCC3)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Yield: 40.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 102c (0.41 g, 0.66 mmol) was reacted with methyl 4-aminobenzoate (0.2 g, 1.3 mmol), HATU (0.45 g, 1.2 mmol) and iPr2NEt (0.29 mL, 1.7 mmol) in CH2Cl2 at room temperature to give rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester as a white solid (0.17 g, 41%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[CH:24]=[CH:25][C:18]=23)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:8][C:4]1[N:3]=[C:2]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]3[N:23]([S:26]([C:29]4[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=4)(=[O:27])=[O:28])[CH:24]=[CH:25][C:18]=23)[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(B4OC(C)(C)C(C)(C)O4)ccnc32)cc1
Reactant: Fc1cccc(Br)n1
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: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(F)n4)ccnc32)cc1

Procedure:
In a 20 mL microwave tube, 2-Bromo-6-fluoropyridine (L) (682 mg, 3.3 mmol, 1.2 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (B)(1.1 g, 2.8 mmol, 1 equiv.) and Pd(PPh3)4 (323 mg, 0.28 mmol), 0.1 equiv.) were suspended in a mixture of DME (10 mL) and aqueous Na2CO3 2M (3 mL). The container was sealed and the reaction mixture was exposed to microwave irradiation for 30 min at 160° C. The resulting mixture was diluted in ethyl acetate, washed with water and dried over anhydrous Na2SO4. The crude material was purified by flash chromatography on silica gel, eluting with hexanes/ethyl acetate mixtures (90:10 to 60:40). The title compound J was isolated as a pale yellow solid (2.1 g, 50%).
Reaction SMILES: Br[CH:2](Br)[C:3]1[C:4]([Cl:21])=[CH:5][C:6]([Cl:20])=[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([O:15][CH:16]([F:18])[F:17])[N:11]([CH3:19])[N:10]=2)[CH:8]=1.S(=O)(=O)(O)[OH:24]>>[Cl:14][C:13]1[C:9]([C:7]2[C:6]([Cl:20])=[CH:5][C:4]([Cl:21])=[C:3]([CH:8]=2)[CH:2]=[O:24])=[N:10][N:11]([CH3:19])[C:12]=1[O:15][CH:16]([F:18])[F:17]
Reactant: Cn1nc(-c2cc(C(Br)Br)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: O=S(=O)(O)O
Product: Cn1nc(-c2cc(C=O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Temperature: 103 °C
Reaction time: 0.08 h

Procedure:
45.5 g (91 mmol) of 3-(5-dibromomethyl-2,4-dichlorophenyl)-4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazole were added, a little at a time, to 65 ml of concentrated sulfuric acid at 85° C., during which process the mixture was heated slowly to 95° C. The reaction mixture was subsequently stirred at 103° C. for a further 5 minutes, whereupon it was stirred into 600 ml of ice-water. The product was extracted using dichloromethane. The organic phase was washed using saturated sodium chloride solution, dried over magnesium sulfate, filtered and finally concentrated. The crude product was purified by dissolving in hexane/ethyl acetate (1:1) and filtering the solution through a silica gel bed. Yield after concentration: 20 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4](=[O:12])[CH2:3]1.[CH3:14][CH:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:14]([CH:3]1[C:2]([CH3:13])([CH3:1])[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[C:4]1=[O:12])[CH:15]=[CH:16][CH3:17]
Reactant: C=CC(C)O
Reactant: Cc1ccc2c(c1)C(=O)CC2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(C)(C)OC
Product: CC=CCC1C(=O)c2cc(C)ccc2C1(C)C
Yield: 51 %

Procedure:
A solution of 18.9 g of 3,3,6-trimethyl-1-indanone, 22.4 ml of 3-buten-2-ol and 300 mg of p-toluenesulfonic acid in 200 ml of 2,2-dimethoxy-propane was boiled under reflux for 64 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate 6:1). In addition to 4.5 g of educt, there were obtained 12.7 g (51%) of (RS)-2-(2-buten-1-yl)-3,3,6-trimethyl-1-indanone as a yellow oil
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH:9][C:10]3[CH:15]=[C:14]([Cl:16])[N:13]=[C:12](Cl)[N:11]=3)[NH:7][N:8]=2)[CH2:3][CH2:2]1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[SH:28].C(N(CC)CC)C>C(O)(C)(C)C>[Cl:16][C:14]1[N:13]=[C:12]([S:28][C:19]2[CH:20]=[CH:21][C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:18]=2)[N:11]=[C:10]([NH:9][C:6]2[NH:7][N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=2)[CH:15]=1
Reactant: Clc1cc(Nc2cc(C3CC3)n[nH]2)nc(Cl)n1
Reactant: Sc1ccc2ccccc2c1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Clc1cc(Nc2cc(C3CC3)n[nH]2)nc(Sc2ccc3ccccc3c2)n1
Temperature: 25 °C

Procedure:
To a solution of (5-cyclopropyl-2H-pyrazol-3-yl)-(2,6-dichloropyrimidin-4-yl)-amine (211 mg, 0.781 mmol) and 2-naphthalenethiol (125-mg, 0.781 mmol) in tert-butanol (5 mL) was added triethylamine (174 μL, 1.25 mmol) and the resulting mixture was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO3. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, Hexane/AcOEt gradient) to afford (6-chloro-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5](N(CC)CC)C.[CH3:12][OH:13].[C:14]([C:17]12[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][C:19]([C:27](O)=[O:28])([CH2:20]3)[CH2:18]1)[CH2:24]2)([OH:16])=[O:15]>CN(C=O)C>[CH3:12][O:13][C:27]([C:19]12[CH2:20][CH:21]3[CH2:22][CH:23]([CH2:24][C:17]([C:14]([O:16][CH3:5])=[O:15])([CH2:26]3)[CH2:18]1)[CH2:25]2)=[O:28]
Reactant: O=C(O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Reactant: CO
Reactant: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C12CC3CC(C1)CC(C(=O)OC)(C3)C2
Reaction time: 2 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1,3-dicarboxyadamantane obtained by the method of Example 64 was dissolved in 10 ml of DMF. To the mixture, 30 mmole of thionyl chloride was added dropwise over 30 minutes and the mixture was heated to begin to reflux around the conclusion of addition. After refluxing for 2 hours, the mixture was cooled. To the mixture, 40 mmole of triethylamine was added followed by 22 mmole of methanol over 30 minutes while retaining the temperature of the mixture at 10° C. or less, and then stirred for more 2 hours. As a result, the conversion of 1, 3-dicarboxyadamantane was 99%, and 1,3-bis(methoxycarbonyl)adamantane (yield 95%) was formed.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:19][C:18]([C@@H:20]4[CH2:24][CH2:23][CH2:22][N:21]4[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:17][CH:16]=3)=[CH:11][CH:10]=2)O1.Cl[C:34]1[N:39]=[CH:38][C:37]([C:40]2[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:43]([C@@H:53]3[CH2:57][CH2:56][CH2:55][N:54]3[C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[N:42][CH:41]=2)=[CH:36][N:35]=1.C([O-])(O)=O.[Na+].COCCOC>C(OCC)(=O)C.O>[C:61]([O:60][C:58]([N:54]1[CH2:55][CH2:56][CH2:57][C@H:53]1[C:43]1[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:40]([C:37]2[CH:36]=[N:35][C:34]([C:9]3[CH:10]=[CH:11][C:12]([C:15]4[NH:19][C:18]([C@@H:20]5[CH2:24][CH2:23][CH2:22][N:21]5[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[N:17][CH:16]=4)=[CH:13][CH:14]=3)=[N:39][CH:38]=2)=[CH:41][N:42]=1)=[O:59])([CH3:64])([CH3:63])[CH3:62]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2cnc(Cl)nc2)n1COCC[Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ncc(-c4cnc([C@@H]5CCCN5C(=O)OC(C)(C)C)n4COCC[Si](C)(C)C)cn3)cc2)[nH]1
Temperature: 80 °C
Yield: 98.3 %

Procedure:
Pd(Ph3)4 (0.12 g, 0.103 mmol) was added in one portion to a stirred suspension of (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1c, 1.00 g, 2.27 mmol), (S)-tert-butyl 2-(5-(2-chloropyrimidin-5-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (152c-1, 0.99 g, 2.06 mmol) and NaHCO3 (0.87 g, 10.3 mmol) in a solution of DME (20 mL) and H2O (6 mL) at room temperature under N2. The vessel was sealed and the mixture was placed into a preheated (80° C.) oil bath and stirred at 80° C. for 16 h before additional catalyst (0.12 g) was added. After heating the mixture for an additional 12 h at 80° C., the mixture was cooled to ambient temperature, diluted with ethyl acetate and washed with sat'd NaHCO3 soln and brine prior to drying over anhydrous sodium sulfate and solvent concentration. Purification of the residue by Biotage™ flash chromatography on silica gel using a 40M column (preequilibrated with 40% B followed by step gradient elution with 40% B to 40% B for 150 mL, 40% B to 100% B for 1500 mL, 100% B to 100% B for 1000 mL where B=ethyl acetate and A=hexanes) furnished the title compound as a yellow foam (1.533 g, 98%). A small amount of the yellow foam was further purified for characterization purposes by pHPLC (Phenomenex GEMINI, 30×100 mm, S10, 10 to 100% B over 13 minutes, 3 minute hold time, 40 mL/min, A=95% water, 5% acetonitrile, 10 mM NH4OAc, B=10% water, 90% acetonitrile, 10 mM NH4OAc) to yield 95% pure title compound as a white solid.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]([NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH2:19])[CH:16]=2)[CH2:11]1)(=[O:8])[CH3:7]>OS(O)(=O)=O>[C:6]([NH:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][C:14]([N+:1]([O-:4])=[O:2])=[C:15]([NH2:19])[CH:16]=2)[CH2:11]1)(=[O:8])[CH3:7]
Reactant: CC(=O)NC1Cc2ccc(N)cc2C1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)NC1Cc2cc(N)c([N+](=O)[O-])cc2C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
1.62 g of KNO3 is introduced in portions into 2.85 g (15 mmol) of 2-acetylamino-5-aminoindan in 7.5 ml of concentrated H2SO4 that has been cooled to 0° C. The whole is stirred for 3 hours at 0° C. and then poured into ice-cold 6N sodium hydroxide solution, stirred, extracted with methylene chloride and then washed, dried and evaporated. 2.8 g of a black solid are isolated, which is purified on silica (eluant:methylene chloride/methanol: 97/3). In that manner, 1.46 g of the expected product are isolated. Yield: 42%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH2:7].[N+:11]([C:14]1[CH:32]=[CH:31][C:17]([CH2:18][O:19][C:20](SC2N=C(C)C=C(C)N=2)=[O:21])=[CH:16][CH:15]=1)([O-:13])=[O:12]>O1CCCC1>[N+:11]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][O:19][C:20]([NH:7][CH2:6][C:5]2[CH:4]=[C:3]([CH:10]=[CH:9][CH:8]=2)[CH2:2][OH:1])=[O:21])=[CH:31][CH:32]=1)([O-:13])=[O:12]
Reactant: Cc1cc(C)nc(SC(=O)OCc2ccc([N+](=O)[O-])cc2)n1
Reactant: NCc1cccc(CO)c1
Solvent: C1CCOC1
Product: O=C(NCc1cccc(CO)c1)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h

Procedure:
To 3-hydroxymethylbenzylamine (1.37 g) in tetrahydrofuran (30 ml), a solution of S-p-nitrobenzyloxycarbonyl-4,6-dimethyl-2-mercaptopyrimidine (6.2 g) in tetrahydrofuran (20 ml) was added at room temperature, followed by stirring for 1 hours. The resulting precipitates were removed by filtration and the filtrate was diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to give an oily residue which was then crystallized from diethyl etherdichloromethane to give 3-(p-nitrobenzyloxycarbonyl)aminomethylbenzyl alcohol.