Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[Br:29][CH2:30][C:31](Cl)=[O:32]>C(OCC)C.CC(OC)(C)C>[Br:29][CH2:30][C:31]([N:9]([C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=1)[CH2:10][CH2:11][C:12]1[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)=[O:32]
Reactant: O=C(Cl)CBr
Reactant: Cc1ccc(NCCc2ccc(C(F)(F)F)nc2)cc1C
Solvent: CCOCC
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: Cc1ccc(N(CCc2ccc(C(F)(F)F)nc2)C(=O)CBr)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A solution of (3,4-dimethyl-phenyl)-[2-(6-trifluoromethyl-pyridin-3-yl)-ethyl]-amine (220 mg, 0.75 mmol) in diethylether (2 mL) was cooled to 0° C. and triethylamine (114 μL, 0.82 mmol) and bromoacetyl chloride (81 μL, 0.97 mmol) were added. After stirring for 15 min. at this temperature the ice bath was removed and the suspension was stirred for 2 h at ambient temperature. Further bromoacetyl chloride (16 μL, 0.2 mmol) was added and the resulting suspension was stirred for 1 h at this temperature. It was diluted with TBME (10 mL) and washed with water (15 mL) and brine (15 mL). The combined aqueous layers were extracted with TBME (15 mL) and the combined organic layers dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 70:30) afforded the title compound (134 mg, 43%) as a light brown oil. MS m/e: 417.1 [M+H]+.
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.C(N(CC)C(C)C)(C)C.[F:28][C:29]([F:39])([F:38])[C@H:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[CH3:40][CH:41]([S:43]([C:46]1[CH:47]=[C:48]2[C:53](=[CH:54][CH:55]=1)[N:52]=[C:51]([C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=1)[C:50]([CH2:66][N:67]1[CH2:72][CH2:71][C:70](=[O:73])[CH:69]([CH3:74])[CH2:68]1)=[C:49]2[C:75](O)=[O:76])(=[O:45])=[O:44])[CH3:42].CCCP(=O)=O>C(OCC)(=O)C.ClCCl>[CH3:42][CH:41]([S:43]([C:46]1[CH:47]=[C:48]2[C:53](=[CH:54][CH:55]=1)[N:52]=[C:51]([C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:63])([F:65])[F:64])[CH:57]=1)[C:50]([CH2:66][N:67]1[CH2:72][CH2:71][C:70](=[O:73])[CH:69]([CH3:74])[CH2:68]1)=[C:49]2[C:75]([NH:37][C@H:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:29]([F:38])([F:39])[F:28])=[O:76])(=[O:44])=[O:45])[CH3:40]
Reactant: N[C@H](c1ccccc1)C(F)(F)F
Reactant: CC1CN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(=O)(=O)C(C)C)cc3c2C(=O)O)CCC1=O
Agent: CCCP(=O)=O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(Cc2c(-c3cccc(C(F)(F)F)c3)nc3ccc(S(=O)(=O)C(C)C)cc3c2C(=O)N[C@H](c2ccccc2)C(F)(F)F)CCC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67 %

Procedure:
T3P (propylphosphonic anhydride) (0.698 mL of a 50% solution in ethyl acetate, 1.185 mmol), N,N-diisopropylethylamine (0.478 mL, 2.73 mmol), and [(1R)-2,2,2-trifluoro-1-phenylethyl]amine (0.251 g, 1.185 mmol) were added to a suspension of 6-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (0.5 g, 0.911 mmol) in dichloromethane (14.02 mL) at 0° C. After 90 min, additional T3P (propylphosphonic anhydride, 0.349 mL of a 50% solution in ethyl acetate, 0.593 mmol) was added. The mixture was stirred overnight at room temperature. The mixture was diluted with methylene chloride (30 mL), and the solution was washed with 10% Na2CO3, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was loaded onto florisil and purified using column chromatography (ISCO, 12 g silica, 5-40% ethyl acetate/hexanes) to afford 6-[(1-methylethyl)sulfonyl]-3-[(3-methyl-4-oxo-1-piperidinyl)methyl]-2-[3-(trifluoromethyl)phenyl]-N-[(1R)-2,2,2-trifluoro-1-phenylethyl]-4-quinolinecarboxamide (0.431 g, 67% yield). MS (m/z) 706.3 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:21][C:20]3[C:19](=[O:22])[NH:18][C:17]([CH:23]4[CH2:27][CH2:26][CH2:25][N:24]4[CH2:28][C:29](OCC)=[O:30])=[N:16][C:15]=3[CH:14]=2)[C:10]([CH3:34])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.[OH-].[Na+]>O.C(OCC)(=O)C.C(O)C.O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:21][C:20]3[C:19](=[O:22])[NH:18][C:17]([CH:23]4[CH2:27][CH2:26][CH2:25][N:24]4[CH2:28][CH2:29][OH:30])=[N:16][C:15]=3[CH:14]=2)[C:10]([CH3:34])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CN1CCCC1c1nc2cc(-c3cn(Cc4ccccc4)nc3C)sc2c(=O)[nH]1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1nn(Cc2ccccc2)cc1-c1cc2nc(C3CCCN3CCO)[nH]c(=O)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
A mixture of ethyl {2-[6-(1-benzyl-3-methyl-1H-pyrazol-4-yl)-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl]pyrrolidin-1-yl}acetate (80 mg) produced in Example 152, step A, sodium borohydride (63 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) was stirred at room temperature for 2 hr. 1M Hydrochloric acid (2 mL) was added to the reaction mixture under ice-cooling, and the mixture was neutralized with 1M aqueous sodium hydroxide solution (2 mL), ethyl acetate (20 mL) and water (20 mL) were added, and the separated aqueous layer was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure and the mixture was crystallized from diethylether to give the title compound (73 mg) as a white powder.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][C@H:43]1[CH2:48][CH2:47][CH2:46][N:45]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:44]1=[O:55]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:10])[NH:42][C@H:43]1[CH2:48][CH2:47][CH2:46][N:45]([C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:44]1=[O:55])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CCCN(c2ccccc2)C1=O
Agent: Cl
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@H]3CCCN(c4ccccc4)C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-oxo-6-((S)-2-oxo-1-phenylpiperidin-3-ylamino)hexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (10 mg, 0.018 mmol) and Intermediate 32 (3.4 mg, 0.018 mmol) to give a white solid (5.0 mg, 36% yield). Anal. Calcd. for C42H50N4O6S m/z 738.4. found: 739.4 (M+H)+; 1H NMR (500 MHz, CD3OD) δ ppm 7.46-7.35 (m, 2H), 7.32-7.25 (m, 3H), 7.23-7.08 (m, 10H), 5.49 (dd, J=6.32, 3.02 Hz, 1H), 5.08-5.02 (m, 1H), 4.98-4.91 (m, 1H), 4.17 (dd, J=11.00, 6.05 Hz, 1H), 3.97 (s, 1H), 3.73 (d, J=7.15 Hz, 1H), 3.64 (s, 3H), 3.09 (s, 1H), 2.89-2.76 (m, 2H), 2.76-2.65 (m, 3H), 2.65-2.51 (m, 2H), 2.31 (br. s., 1H), 2.11-1.91 (m, 5H), 1.90-1.80 (m, 1H), 1.77-1.55 (m, 7H), 1.57-1.46 (m, 2H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:27]([F:30])([F:29])[F:28])=[C:10]([CH2:14][O:15][CH:16]3[CH2:19][N:18]([C:20]([NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]3)[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.B1([C:37]2[CH:42]=[CH:41][CH:40]=[N:39][CH:38]=2)OCCCO1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:39]1[CH:40]=[CH:41][CH:42]=[C:37]([C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:9]([C:27]([F:29])([F:30])[F:28])=[C:10]([CH2:14][O:15][CH:16]4[CH2:19][N:18]([C:20]([NH:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:21])[CH2:17]4)[CH:11]=[CH:12][CH:13]=3)=[CH:6][CH:7]=2)[CH:38]=1
Reactant: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(I)cc3)c2C(F)(F)F)C1
Reactant: c1cncc(B2OCCCO2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(-c4cccnc4)cc3)c2C(F)(F)F)C1
Temperature: 65 °C
Yield: 8.4 %

Procedure:
To a solution of aryl iodide (191) (100 mg, 0.19 mmol), pyridine-3-boronic acid 1,3-propanediol cyclic ester (61 mg, 0.38 mmol), palladium acetate (4 mg, 0.019 mmol) and triphenylphosphine (10 mg, 0.38 mmol) in tetrahydrofuran (10 mL) was added sodium bicarbonate (10 mL, saturated aqueous). The reaction mixture was heated to reflux (65° C.) for 4 h, cooled, filtered and partitioned between water (20 mL) and ethyl acetate (20 mL). The organic phase was separated and washed with brine (20 mL), dried (Na2SO4), filtered and the solvent removed under reduced pressure to afford the crude product as a yellow oil. Purification by silica gel chromatography (50% ethyl acetate/iso-hexane eluant) followed by preparative HPLC gave the title compound (194) as a colourless gum (7.7 mg, 8.5% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][C:24]=2[O:25][CH3:26])[N:21]=[CH:20][N:19]=[C:18]3[NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2[F:35])[CH2:10][C@H:9]1[C:36]([OH:38])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1CCOCC1.CN>C1COCC1.C(Cl)Cl>[Cl:34][C:30]1[C:29]([F:35])=[C:28]([NH:27][C:18]2[C:17]3[C:22](=[CH:23][C:24]([O:25][CH3:26])=[C:15]([O:14][C@H:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:36]([NH:40][CH3:39])=[O:38])[CH2:10]4)[CH:16]=3)[N:21]=[CH:20][N:19]=2)[CH:33]=[CH:32][CH:31]=1
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C1
Reactant: CN1CCOCC1
Agent: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNC(=O)[C@@H]1C[C@@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 100.2 %

Procedure:
A stirred solution of (2S,4S)-1-(tert-butoxycarbonyl)-4-({-4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)piperidine-2-carboxylic acid (4 g, 7.31 mmol, prepared as described in Example 1) in THF (50 ml) was cooled to −15° C. (acetone/ice). NMM (1.21 ml, 11.0 mmol) was added to the solution followed by IBCF (1.24 ml, 9.51 mmol). The reaction mixture was held at −15° C. (the formation of the mixed anhydride was monitored by TLC (THF)). After 5-10 minutes, the reaction mixture was treated with a 2.0M solution of methylamine in THF (10 ml) at −15° C. and allowed to warm to room temperature. The reaction mixture was diluted with DCM (250 ml), washed with water (2×20 ml) and concentrated to give tert-butyl (2S,4S)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-2-[(methylamino)carbonyl]piperidine-1-carboxylate (4.1 g, 100%) as pale yellow foam which was used without further purification; Mass Spectrum: (M+H)+ 560.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O1CCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>C(OCC)(=O)C.CCCCCC.O>[C:10]([C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:17])[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])#[N:11]
Reactant: CC(C)(C)[Si](C)(C)OCCC(C#N)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(C#N)(CCO[Si](C)(C)C(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Combine 2-(3,4-dichlorophenyl)-4-(t-butyldimethylsilyloxy)butyronitrile (13.35 g, 38.8 mmol) and anhydrous tetrahydrofuran (50 mL). Cool in a dry-ice/acetone bath. Add dropwise a solution of lithium bis(trimethylsilyl)amide (42.6 mL, 1 M in THF, 42.6 mmol). Add dropwise, ethyl 3-bromopropionate (7.71 g, 42.6 mmol). Warm the reaction mixture to ambient temperature. After 18 hours, add water. Separate the aqueous layer and extract three times with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 90% ethyl acetate/hexane to give the title compound: Rf=0.35 (silica gel, 10% ethyl acetate/hexane).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][NH:13]1)=[O:11].[C:21](OC(C)(C)C)(=[O:26])[CH2:22][C:23]([CH3:25])=[O:24]>C(N(CC)CC)C>[CH3:8][O:9][C:10]([C@@H:12]1[CH2:16][C@@H:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:14][N:13]1[C:21](=[O:26])[CH2:22][C:23](=[O:24])[CH3:25])=[O:11]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-methanesulfonyl-pyrrolidine-2-carboxylic acid methyl ester trifluoroacetate was reacted with tert-butyl acetoacetate in the presence of triethylamine to give the title compound. MS (ESI): m/z=292.2 [M+H]+.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:20])[O:17][CH2:18][CH3:19])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:21](Cl)(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1>>[C:21]([N:20]=[C:16]([N:7]1[CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=2[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[CH2:8]1)[O:17][CH2:18][CH3:19])(=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: CCOC(=NC(=O)c1ccc(OC)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from ethyl 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate and p-anisoyl chloride, there is obtained ethyl N-(p-anisoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 71°-78° C.;
Reaction SMILES: [OH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[C:12]1[S:13][CH:14]=[C:15]([Br:17])[N:16]=1.CC([O-])=O.[K+]>N1C=CC=CC=1.[Cu].Cl[Cu]>[Br:17][C:15]1[N:16]=[C:12]([N:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[NH:6][C:2]2=[O:1])[S:13][CH:14]=1
Reactant: Brc1csc(Br)n1
Reactant: Oc1nc2ccccc2[nH]1
Agent: Cl[Cu]
Agent: [Cu]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: O=c1[nH]c2ccccc2n1-c1nc(Br)cs1
Temperature: 60 °C

Procedure:
A mixture of 2-hydroxybenzimidazole (1.20 g, 8.95 mmol), 2,4-dibromothiazole (6.50 g, 26.8 mmol), copper powder (1.42 g, 22.4 mmol), CuCl (177 mg, 1.79 mmol), and KOAc (2.20 g, 22.4 mmol) in pyridine (10 mL) were heated at 60° C. for 2 h. The cooled mixture was partitioned between EtOAc (40 mL) and 10% aqueous citric acid (20 mL) and the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=298 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3].[Br:30]Br>CCOC(C)=O.[Al+3].[Cl-].[Cl-].[Cl-]>[Br:30][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[OH:11])=[O:10]
Reactant: CC(=O)c1ccc(F)cc1O
Reactant: BrBr
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CBr)c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(4-fluoro-2-hydroxy-phenyl)-ethanone (15.4 g, Aldrich) in EtOAc (100 mL) was treated with AlCl3 (133 mg), stirred at r.t. for 30 min, treated with montmorillonite K10 (2.5 g) stirred an additional 30 min then treated with a solution of bromine (7.05 mL) in EtOAc (100 mL) (added dropwise via addition funnel over 1.5 h). The reaction was stirred at r.t. for 1 h, cooled in a an ice bath and quenched with water added dropwise. The mixture was diluted with EtOAc, filtered through celite and the filtrate was extracted with EtOAc (2×). The combined organic extracts were dried (Na2SO4), concentrated and teh crude product was purified via silica gel chromatography eluting with 5% EtOAc-hexanes to give 3.31 g of the title compound. MS (ESI) m/e 437(2M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[CH:10]([CH:17]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]([F:16])([F:15])[F:14])[CH:10]([CH2:17][N:29]2[CH2:30][CH2:31][CH:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=3)[CH2:27][CH2:28]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2CCNCC2)cc1
Reactant: O=CC1CN(Cc2ccccc2)CC1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Fc1ccc(C2CCN(CC3CN(Cc4ccccc4)CC3C(F)(F)F)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 702.8 %

Procedure:
To a solution of 1.46 g (5.6 mmol) of 1-benzyl-3-(RS)-formyl-4-(RS)-trifluoromethylpyrrolidine and 0.13 g (0.67 mmol) of 4-(4-fluorophenyl)piperidine (Example 1, Step 1) in 30 mL of dichloroethane at rt was added 2.37 g (11.2 mmol) of sodium triacetoxyborohydride. After stirring for 18 h at rt, the reaction mixture was partitioned between CH2Cl2 and sat'd NaHCO3. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by chomatography (silica, acetone:hexanes, 1:8) to give 1.98 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26].O>C(Cl)Cl>[CH3:24][S:25]([O:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[CH:12][CH:11]=1)(=[O:27])=[O:26]
Reactant: OCc1ccc(-c2cnccn2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccc(-c2cnccn2)cc1
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred solution of (4-(pyrazin-2-yl)phenyl)methanol (40 mg, 0.22 mmol) and DIEA (56 μL, 0.32 mmol) in DCM (1 mL) was added methanesulfonyl chloride (29.5 mg, 0.258 mmol) at 0° C. The reaction mixture was stirred at that temperature for 1 h, poured into water, and extracted with DCM. The combined organics were dried and concentrated to give the title compound (50 mg) without further purification. LCMS m/z=265.1 [M+H]+.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][C:13]=2[CH3:18])[C:9]([Cl:19])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:20].[BrH:21].N([O-])=O.[Na+].[OH-].[Na+]>O1CCCC1.[Cu]Br>[Br:21][C:2]1[CH:11]=[C:10]([C:12]2[N:16]([CH3:17])[N:15]=[N:14][C:13]=2[CH3:18])[C:9]([Cl:19])=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][C:7]2=[O:20]
Reactant: Cc1nnn(C)c1-c1cc(N)c2c(c1Cl)C(=O)NCC2
Reactant: Br
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nnn(C)c1-c1cc(Br)c2c(c1Cl)C(=O)NCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.4 %

Procedure:
To a solution of 5-amino-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293 g, 300 mg, 1.03 mmol) in tetrahydrofuran (5 mL) chilled in an ice-water bath was added 40% aqueous hydrobromic acid (6.86 g, 33.93 mmol). The mixture was allowed to stir at room temperature for three hours, and then cooled again to 0° C. Copper (I) bromide (295 mg, 2.06 mmol) was added, followed by sodium nitrite (78 mg, 1.13 mmol), and the resulting mixture stirred at 0° C. for two hours. The mixture was neutralized with solid sodium hydroxide and extracted with ethyl acetate (2×100 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography to give 5-bromo-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293h, 60 mg, 16.5% yield) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1B(O)O.[Cl-].[Li+].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1
Reactant: OB(O)c1ccco1
Reactant: OCc1cncc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: OCc1cncc(-c2ccco2)c1
Temperature: 25 °C
Yield: 41.9 %

Procedure:
To a solution of 0.10 g of (5-bromopyridin-3-yl)methanol in 5 mL of dioxane, 72 mg of 2-furanboronic acid, 67 mg of lithium chloride, 0.51 g of cesium carbonate, 5.4 mg of palladium acetate and 20 mg of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl were added at room temperature, and the mixture was heated under reflux for 1 hour 30 minutes under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and the solvent was then distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=95:5 to 90:10 to obtain 39 mg of (5-(2-furyl)pyridin-3-yl)methanol as a yellow oily substance.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH3:35])=[CH:4][N:3]=1.CCN(CC)CC.[CH3:49][S:50](Cl)(=[O:52])=[O:51].[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[N:13]=[C:12]([CH3:14])[N:11]=[C:10]([N:15]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:9]=2)=[CH:6][C:5]([C@H:34]([N:36]2[CH2:37][CH2:38][N:39]([S:50]([CH3:49])(=[O:52])=[O:51])[CH2:40][CH2:41]2)[CH3:35])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCNCC4)cnc3F)nc(C)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)CC4)cnc3F)nc(C)n2)cc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
A solution of 6-(2-fluoro-5-((1R)-1-(1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.448 g, 0.805 mmol) in CH2Cl2 (4 mL) at −20° C. was treated with NEt3 (1.122 mL, 8.05 mmol) followed by methanesulfonyl chloride (0.190 mL, 2.414 mmol). The mixture stirred at −20° C. for 30 minutes and then 1 M NaOH (aq.) and CH2Cl2 were added. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (12 g), eluting with a gradient of 75% to 100% EtOAc in hexane, to provide 6-(2-fluoro-5-((1R)-1-(4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-2-methyl-4-pyrimidinamine (0.317 g, 0.499 mmol, 62.1% yield) as a white foam. m/z (ESI, +ve) 635.2 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J=9.00 Hz, 1H); 8.18 (s, 1H); 7.17 (d, J=7.63 Hz, 4H); 6.83-6.89 (m, 5H); 4.74 (br. s., 4H); 3.80 (s, 6H); 3.65 (m, 1H); 3.18-3.30 (m, 4H); 2.77 (s, 3H); 2.64 (s, 5H); 2.50-2.58 (m, 2H); 1.44 (d, J=6.65 Hz, 3H).