Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[C:5]([C:16]([O:18]CC)=[O:17])=[CH:4][N:3]=1.[Li+].[OH-]>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)nc1NCc1cnn(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1cc(CNc2nc(Cl)ncc2C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of give ethyl 2-chloro-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxylate (crude from step 1) in THF (9 mL), aq. 1N LiOH (6.6 mL, 6.6 mmol) was added. The mixture was stirred at room temperature overnight. THF was removed under vacuum, and the residue was acidified of with 1N HCl, the precipitated white solids were collected, and dried on vacuum to give 2-chloro-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxylic acid (1 g). MS 268.2, 270.2 (M+H, Cl pattern).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:13]2[CH:14]=[C:15]([NH2:16])[CH:17]=[CH:18][CH:19]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(B(O)O)cn1
Reactant: Nc1cccc(Br)c1
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
Product: COc1ncc(-c2cccc(N)c2)cn1
Temperature: 25 °C
Yield: 83 %

Procedure:
2-methoxypyrimidine-5-boronic acid (0.134 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.097 g in 83% yield.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[CH:13]=[C:12]([C:15](O)=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C1(C)C=CC=CC=1.S(Cl)(Cl)=O.Cl.Cl.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[CH2:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>O.CN(C)C=O.C(N(CC)CC)C>[O:1]=[C:2]1[C:14]2[CH:13]=[C:12]([C:15]([N:40]3[CH2:41][CH2:42][N:37]([CH2:36][C:35]4[CH:34]=[C:33]([O:32][CH3:31])[C:45]([O:46][CH3:47])=[C:44]([O:48][CH3:49])[CH:43]=4)[CH2:38][CH2:39]3)=[O:16])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: O=C(O)c1ccc2c(c1)C(=O)c1ccccc1-2
Reactant: COc1cc(CN2CCNCC2)cc(OC)c1OC
Agent: Cl
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(CN2CCN(C(=O)c3ccc4c(c3)C(=O)c3ccccc3-4)CC2)cc(OC)c1OC
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
A mixture of 9-oxo-2-fluorene carboxylic acid (1 g), toluene (10 ml), and thionyl chloride (3 ml) is heated for one hour under reflux. The mixture is evaporated to dryness. To the residue is added toluene (10 ml), and the mixture is again evaporated to dryness. Thus-obtained yellow powder is mixed with toluene (50 ml), and the mixture is added to a mixture of 1-(3,4,5-trimethoxybenzyl)piperazine dihydrochloride (1.8 g), triethylamine (4.3 g) and N,N-dimethylformamide (20 ml). The resulting mixture is left standing at room temperature for 30 minutes and treated with water (300 ml). The whole mixture is extracted with ethyl acetate (500 ml). The organic layer is washed with water, dried and concentrated to afford 1-(9-oxo-2-fluorenylcarbonyl)-4-(3,4,5-trimethoxybenzyl)piperazine (1.1 g) as pale yellow crystals, m.p. 166°-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:20]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:20])[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(NCc1ccc(Br)cc1)N1CCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(Br)cc1)C(=O)N1CCCC1
Reaction time: 0.25 h
Yield: 103.9 %

Procedure:
N-[(4-bromophenyl)methyl]-1-pyrrolidinecarboxamide (230 mg, 0.81 mmol), was dissolved in dimethylformamide (2 ml) and treated at room temperature with a 60% sodium hydride suspension in mineral oil (33 mg, 0.83 mmol). This mix was stirred for 15 minutes before being treated with iodomethane (116 mg, 0.82 mmol). The resulting mix was stirred at 20° C. for a total of 16.5 hours. The reaction was quenched with water (4 ml) and extracted into ethyl acetate (4 ml). The organic layer was dried over sodium sulphate and the solvent removed under reduced pressure to give the title compound as a colourless oil (250 mg, crude). LC/Mass Spec (ES): Found 297 (ES+), retention time 2.90 mins. C13H1779BrN2O requires 296.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:9]([O:11][C:12]1[C:13](=O)[C:14](=[O:19])[C:15]=1[O:16]CC)[CH3:10]>C(O)C>[CH2:9]([O:11][C:12]1[C:15](=[O:16])[C:14](=[O:19])[C:13]=1[NH:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1)[CH3:10]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: Nc1cccnc1O
Solvent: CCO
Product: CCOc1c(Nc2cccnc2O)c(=O)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
A mixture of 1.82 g (16.5 mmol, 1 eq) of 3-aminopyridin-2-ol and 3.6 ml (24.8 mmol, 1.5 eq) of 3,4-diethoxycyclobut-3-ene-1,2-dione (3.6 ml, 24.8 mmol) in solution in 87 ml of ethanol was stirred at ambient temperature for 16 hours and then heated at 50° C. for 3 days with formation of a precipitate. Ethanol was added in order to promote the fall of the precipitate, which was filtered off, washed with diethyl ether and dried under vacuum at 45° C. 3.47 g of 3-ethoxy-4-(2-hydroxypyridin-3-ylamino)cyclobut-3-ene-1,2-dione were obtained in the form of a brown solid. Yield=90%.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:42]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C1(P([Pd-4](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)C=CC=CC=1>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]4)[CH:42]=3)[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5cnn(C6CCN(C(=O)OC(C)(C)C)CC6)c5)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (0.20 g, 0.40 mmol) in N,N-dimethylformamide (8 mL) and water (2 mL) was added tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.15 g, 0.40 mmol), potassium carbonate (0.22 g, 1.59 mmol), and tetrakis(triphenylphosphino)palladium(0) (0.021 g, 0.018 mmol). The mixture was heated to 100° C. After 1 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated, and the residue purified via silica gel chromatography (5% methanol/dichloromethane elute) to provide 0.15 g (60%) of tert-butyl 4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH2:1](C1C(S(=O)(=O)N)=CC(C(O)=O)=CC=1SCCCC)C1C=CC=CC=1.[CH2:26]([C:33]1[C:41]([S:42](=[O:45])(=[O:44])[NH2:43])=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][C:34]=1[S:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([C:33]1[C:41]([S:42](=[O:45])(=[O:44])[NH2:43])=[CH:40][C:36]([C:37]([O:39][CH3:1])=[O:38])=[CH:35][C:34]=1[S:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc(SCc2ccccc2)c1Cc1ccccc1
Reactant: CCCCSc1cc(C(=O)O)cc(S(N)(=O)=O)c1Cc1ccccc1
Product: COC(=O)c1cc(SCc2ccccc2)c(Cc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
By replacing in Example 124, 4-benzyl-3-n-butylthio-5-sulfamylbenzoic acid with 4-benzyl-3-benzylthio-5-sulfamylbenzoic acid and following the procedure described, methyl 4-benzyl-3-benzylthio-5-sulfamylbenzoate is obtained with a melting point of 139°-140° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8](Cl)=[N:7][CH:6]=1)[CH3:2].[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.[Cu]>[Cl:11][C:9]1[CH:10]=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:13])[CH:6]=[N:7][C:8]=1[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNC1
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc(N2CCCC2)c(Cl)c1
Temperature: 130 °C
Yield: 91.2 %

Procedure:
A mixture of 5,6-dichloronicotinic acid ethyl ester (1.00 g, 4.57 mmol), pyrrolidine (325 mg, 4.57 mmol), potassium carbonate (632 mg, 4.57 mmol) and copper powder (34 mg) in DMF (6.8 mL) was heated at 130° C. in the microwave for 20 min. Further pyrrolidine (163 mg, 2.29 mmol) was added and the reaction heated at 130° C. for 20 min. Water (7 mL) was added and the mixture extracted with ethyl acetate (2×14 mL). The combined organic extracts were washed with water (7 mL) and brine (7 mL) before being dried (phase separator) and concentrated in vacuo to give the title compound as an orange oil (1.06 g, 4.17 mmol). δH (methanol-d4, 400 MHz): 8.45 (1H, d), 7.98 (1H, d), 4.31 (2H, q), 3.82-3.75 (4H, m), 2.0-1.93 (4H, m), 1.36 (3H, t) ppm. MS (ES): C12H15ClN2O2 requires 254, 256; found 255, 257 (MH+).
Reaction SMILES: C(O[C:4](=[O:43])[CH2:5][NH:6][C:7]1[C:12]([NH2:13])=[C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:21]([CH2:36][CH2:37][N:38]4[CH2:42][CH2:41][CH2:40][CH2:39]4)[CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[C:27]([C:32]([F:35])([F:34])[F:33])[CH:26]=4)[N:24]=3)[CH2:16][CH2:15]2)[N:10]=[CH:9][N:8]=1)C>CCO>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:24]=[C:20]([CH:17]3[CH2:18][CH2:19][N:14]([C:11]4[C:12]5[NH:13][C:4](=[O:43])[CH2:5][NH:6][C:7]=5[N:8]=[CH:9][N:10]=4)[CH2:15][CH2:16]3)[N:21]([CH2:36][CH2:37][N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:22]=2)=[CH:26][C:27]=1[C:32]([F:35])([F:34])[F:33]
Reactant: CCOC(=O)CNc1ncnc(N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3CCN3CCCC3)CC2)c1N
Solvent: CCO
Product: O=C1CNc2ncnc(N3CCC(c4nc(-c5ccc(F)c(C(F)(F)F)c5)cn4CCN4CCCC4)CC3)c2N1
Yield: 75.7 %

Procedure:
The solution of (5-amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamino)-acetic acid ethyl ester (80.00 mg; 0.13 mmol; 1.00 eq.) in EtOH (10 mL) was refluxed for 15 hours. After reverse phase HPLC purification, 4-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-(2-pyrrolidin-1-yl-ethyl)-1H-imidazol-2-yl]-piperidin-1-yl}-7,8-dihydro-5H-pteridin-6-one (55 mg, 74% yield) was obtained; LC/MS: 559 (M+H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:11]([CH2:12][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[S:26]([CH3:25])(=[O:28])=[O:27]
Reactant: COc1ccc(NCc2cccnc2)c(OC)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc(N(Cc2cccnc2)S(C)(=O)=O)c(OC)c1

Procedure:
A 7.3 g. portion of 3-(2,4-dimethoxyphenylaminomethyl)pyridine was dissolved in 25 ml. of dichloromethane, and 5.5 g. of potassium carbonate and 3.1 ml. of methanesulfonyl chloride were added. The mixture was stirred under reflux overnight. Then it was cooled, diluted with 25 ml. of dichloromethane and washed with 25 ml. of aqueous sodium bicarbonate. The organic layer was separated, washed with water, dried over magnesium sulfate and evaporated under vacuum. The residue was suspended in ethyl acetate, and filtered. The filtrate was evaporated, and the residue was triturated with diethyl ether, filtered and dried under vacuum to obtain 6.7 g. of the desired product, m.p. 117°-119°.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:21]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]1=[O:34])=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26][Si:27]([C:30]([CH3:32])([CH3:31])[CH3:33])([CH3:28])[CH3:29])[CH:21]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]1=[O:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccccc2-c2cccc(O[Si](C)(C)C(C)(C)C)c2)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)Oc1cccc(-c2ccccc2N2CC[C@H](N)C2=O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
(S)-3-(tert-Butoxycarbonylamino)-1-[3′-(tert-butyldimethylsilyloxy) biphen-2-yl]-2-oxopyrrolidine, as described above in Step E, (888 mg, 1.84 mmol) was dissolved in CH2Cl2 (20 mL), cooled to 0° C., and trifluoroacetic acid (4 mL) was added. After 3 hours, the reaction mixture was poured into saturated aqueous NaHCO3 and extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered and concentrated in vacuo, to yield the above-titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:21])[CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[CH2:36][S:37][CH3:38]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([C:8]2([F:22])[C:16]3[C:11](=[CH:12][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:14][CH:15]=3)[N:10]([CH2:36][S:37][CH3:38])[C:9]2=[O:21])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C1(F)C(=O)Nc2cc(C(F)(F)F)ccc21
Reactant: CSCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C1(F)C(=O)N(CSC)c2cc(C(F)(F)F)ccc21
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a 1 L, 3-necked round bottom flask equipped with an addition funnel was added 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-6-trifluoromethyl-1,3-dihydro-indol-2-one (25 g, 69.8 mmol) and anhydrous THF (150 mL). The solution was cooled to 0° C. and potassium bis(trimethylsilyl)amide (0.5M in toluene, 153.6 mL, 76.8 mmol) was added over 25 minutes in order to keep the reaction temperature between 0° C. and 5° C. The reaction mixture immediately turned dark orange. The solution was allowed to warm to room temperature after which chloromethyl methylsulfide (6.39 mL, 76.8 mmol) was added. The dark brown reaction was then allowed to stir at reflux. After 3 hours, the reaction mixture contained 84% (AP) of the desired product. The reaction was allowed to reflux overnight. No further reaction took place during this period (82% AP of product after overnight stirring). The reaction mixture was then allowed to cool, and 1 N HCl (100 mL) was added slowly in order to keep the reaction temperature under 30° C. After stirring for 5 minutes, heptane (200 mL) was added and the layers were separated. The organic layer was then washed with saturated NaCl (200 mL), dried over anhydrous sodium sulfate and concentrated to yield crude product (29.3 g). The crude material was then recrystallized from heptane: THF (15:1) to provide 3-(5-chloro-2-methoxy-phenyl)-3-fluoro-1-methylsulfanylmethyl-6-trifluoromethyl-1,3-dihydro-indol-2-one as a light yellow powder (19.5 g, 67%). 1H NMR (CDCl3, 400 MHz): δ=7.78 (dd, 1H, J=2.7, 0.9 Hz), 7.32 (m, 2H), 7.21 (m, 2H), 6.73 (dd, 1H, J=8.9, 1.2 Hz), 4.95 (d, 1H, J=14.6 Hz), 4.79 (d, 1H, J=14.6 Hz), 3.48 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:23])[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])[CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCOC1CCCCO1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Br)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N(CCOC2CCCCO2)c2ccccc2Br)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(2-Bromo-phenylcarbamoyl)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.60 mmol) was dissolved in dry N,N-dimethylformamide (10.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 127.3 mg, 3.18 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C., 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.6 g, 2.86 mmol). The reaction mixture was stirred at 0° C. for one hour, then at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was then partitioned with water-ice and methylene chloride. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was purified via flash chromatography (25% ethyl acetate/hexanes) to yield the title compound as a gum.
Reaction SMILES: [CH:1]1[C:6]([SH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Br[CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17]>>[C:3]1([CH3:8])[CH:4]=[CH:5][C:6]([S:7][CH2:10][CH:11]=[C:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:1][CH:2]=1
Reactant: CC(C)=CCCC(C)=CCBr
Reactant: Cc1ccc(S)cc1
Product: CC(C)=CCCC(C)=CCSc1ccc(C)cc1

Procedure:
thio-p-cresol is reacted with 1-bromo-3,7-dimethyl-octa- 2,6-diene to produce 3,7-dimethyl-octa-2,6-dienyl p-tolyl sulphide (boiling point = 116°-118°C/0.1 mmHg);
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]=[C:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=1.CO.[BH4-].[Na+]>O>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH:7]2[C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=1
Reactant: FC(F)(F)c1ccc(C2=NCCc3c(Br)cccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: FC(F)(F)c1ccc(C2NCCc3c(Br)cccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL round-bottomed flask was added 5-bromo-1-(4-(trifluoromethyl)-phenyl)-3,4-dihydroisoquinoline (1.18 g, 3332 μmol, from step 2), MeOH (5 mL), sodium borohydride (117 μL, 3332 μmol, Aldrich). The reaction mixture was stirred at RT for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (2×40 mL). The organic extract was washed with water (20 mL), saturated NaCl (20 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 40% EtOAc/hexanes to give 5-bromo-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline. MS (ESI pos. ion) m/z: 356 (M+1).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][CH2:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.O[N:19]1C2C=CC=CC=2N=N1.C(Cl)CCl>ClCCl>[C:1]([NH:8][C@H:9]([C:14]([NH2:19])=[O:16])[CH2:10][CH2:11][CH2:12][CH3:13])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(N)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred mixture of 3.47 g (15 mmol) of BOC-norleucine (Bachem), 3.44 g (22.5 mmol) of 1-hydroxybenzotriazole monohydrate and 50 mL of dichloromethane at 0° C. was added 3.45 g (1.2 mmol) of EDC. The resulting mixture was stirred at 0° C. for 1 hour and then ammonia gas was bubbled through the mixture for 10 min. The cooling bath was allowed to warm to room temperature and the mixture stirred for 18 hours. The mixture was evaporated to dryness, triturated with 20% Na2CO3. The resulting solid was collected by filtration and washed with water to yield 2.69 g (11.7 mmol, 78%) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:36])=[CH:20][N:19]=1>>[Cl:36][C:21]1[C:22]([NH:24][C:25]2[C:34]([F:35])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidine-4-ylamino}-3-fluoro-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (52 mg, 31%). LCMS (m/e) 499 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.70 (bs, 1H), 8.05 (s, 1H), 7.34-7.22 (m, 2H), 7.14 (s, 1H), 7.09 (d, 1H, J=8.1 Hz), 6.88 (d, 1H, J=8.1 Hz), 6.82 (s, 1H), 6.10-6.0 (m, 1H), 3.59-3.52 (m, 2H), 3.37 (s, 3H), 2.90 (d, 3H, J=4.8 Hz), 2.89-2.60 (m, 10H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:10][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)C[C@@H](CBr)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)C[C@@H](CN1CCOCC1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
To a stirred mixture of N-tert-butoxycarbonyl-1-bromo-2-(S)-amino-4-methylpentane 1.76 g, 6.3 mmol) and triethylamine (0.96 ml, 6.9 mmol) in THF (50 ml) at room temperature was added morpholine (0.60 ml, 6.9 mmol). The mixture was stirred overnight and the solvent removed under reduced pressure. The residue was partitioned between saturated aqueous ammonium chloride (50 ml) and ethyl acetate (2×100 ml). The crude N-tert-butoxycarbonyl-1-morpholino-2-(S)-amino-4-methylpentane was then used directly in the next step.