Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]([F:12])([F:11])[C:6]([O:8]CC)=O.[CH3:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16].C(O)(=O)C>CCOCC.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:4][C:5]([F:11])([F:12])[C:6](=[O:8])[CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: CC(=O)C(C)(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: C[O-]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)CC(=O)C(F)(F)Cl
Yield: 49 %

Procedure:
7.1 g of sodium methoxide was added to 100 ml of dry ether, and the mixture was stirred. A solution of 20 g of ethyl chlorodifluoroacetate diluted with 25 ml of dry ether was added dropwise at room temperature. Further, a solution of 12.5 g of pinacolone diluted with 25 ml of dry ether was added dropwise, and the mixture was stirred overnight at room temperature. Then, to the reaction solution, a solution of 8.4 g of glacial acetic acid diluted with 100 ml of water and a solution of 23.6 g of copper (II) acetate dissolved in a proper amount of water were added dropwise successively. The dropwise addition was followed by stirring for about 10 minutes. Then, the ether was distilled off under reduced pressure and the solid mass was filtered off. After vacuum drying, 100 ml of 6N hydrochloric acid was added, and extraction with ethyl acetate was carried out. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Then, the residue was subjected to vacuum distillation to obtain 13 g of the desired product. (b.p. 54°-57° C./5 mmHg)
Reaction SMILES: [CH:1]1([CH2:4][S:5]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH2:16][CH2:17][CH:18]([NH:30][C:31](=O)OCC)[CH:19]3[CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)=[CH:14][CH:13]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+].CC(O)C.Cl>C1COCC1.C(Cl)Cl>[CH:1]1([CH2:4][S:5]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]3[CH2:16][CH2:17][CH:18]([NH:30][CH3:31])[CH:19]([CH2:22][C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[C:20]=3[CH:21]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(=O)NC1CCc2ccc(OCCNS(=O)(=O)CC3CC3)cc2C1Cc1ccc(F)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CC(C)O
Solvent: ClCCl
Product: CNC1CCc2ccc(OCCNS(=O)(=O)CC3CC3)cc2C1Cc1ccc(F)cc1
Reaction time: 8 h

Procedure:
The synthesis was performed starting from ethyl 7-(2-(cyclopropylmethylsulfonamido)ethoxy)-1-(4-fluorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-ylcarbamate (synthesized in analogy to example 3), which was dissolved in THF (50 ml), after which LiAlH4 was added at room temperature and the mixture was stirred for 8 h under reflux. Addition of 2N aqueous NaOH, extraction with CH2Cl2, washing of the organic layers with saturated NaHCO3 solution and saturated NaCl solution and evaporation of the solvent gave a residue that was treated with iPrOH/HCl after which the product precipitated. After filtration a white salt (89 mg, 76%) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:35]#[N:36])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18][CH:17]([C:25]([OH:27])=O)[CH:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)=[C:11]([F:37])[CH:10]=1.CC1(C)[O:43][C@@H:42]([CH2:44][CH2:45][NH2:46])[CH2:41][O:40]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.Cl>C(Cl)Cl.O1CCCC1>[OH:43][C@H:42]([CH2:41][OH:40])[CH2:44][CH2:45][NH:46][C:25]([CH:17]1[CH:16]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[CH:29]=2)[C:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=2[F:37])([C:35]#[N:36])[CH:19]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:18]1)=[O:27]
Reactant: CC1(C)OC[C@H](CCN)O1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(F)c2)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)NCC[C@H](O)CO)C(c2cccc(F)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 48.7 %

Procedure:
In a manner similar to the method described in Examples 42c, 42d, rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 65c (0.46 g, 0.83 mmol) was reacted with 2-((S)-2,2-dimethyl-[1,3]dioxolan-4-yl)-ethylamine (0.36 g, 2.5 mmol), HATU (0.57 g, 1.5 mmol) and iPr2NEt (0.72 mL, 4.2 mmol) in CH2Cl2 at room temperature for 20 h, then reacted with aqueous HCl solution in tetrahydrofuran at room temperature for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-3-(3-fluoro-phenyl)-pyrrolidine-2-carboxylic acid ((S)-3,4-dihydroxy-butyl)-amide as a white solid (0.21 g, 48%).
Reaction SMILES: N1C=CN=C1CN1C(=O)COC2N=C(C3C=CC(C4(N)CCC4)=CC=3)C(C3C=CC=CC=3)=CC1=2.C(OC(=O)[NH:41][C:42]1([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[C:53]([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)=[CH:54][C:55]4[N:61]([CH2:62][CH2:63][F:64])[C:60](=[O:65])[CH2:59][CH2:58][NH:57][C:56]=4[N:66]=3)=[CH:48][CH:47]=2)[CH2:45][CH2:44][CH2:43]1)(C)(C)C>>[NH2:41][C:42]1([C:46]2[CH:47]=[CH:48][C:49]([C:52]3[C:53]([C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)=[CH:54][C:55]4[N:61]([CH2:62][CH2:63][F:64])[C:60](=[O:65])[CH2:59][CH2:58][NH:57][C:56]=4[N:66]=3)=[CH:50][CH:51]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCF)C(=O)CCN4)cc2)CCC1
Agent: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3ncc[nH]3)C(=O)CO4)cc2)CCC1
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCF)C(=O)CCN4)cc2)CCC1
Yield: 92.9 %

Procedure:
Following the procedure for 1-((1H-imidazol-2-yl)methyl)-6-(4-(1-aminocyclobutyl)phenyl)-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one, tert-butyl(1-(4-(1-(2-fluoroethyl)-2-oxo-8-phenyl-2,3,4,5-tetrahydro-1H-pyrido[2,3-b][1,4]diazepin-7-yl)phenyl)cyclobutyl)carbamate (15 mg, 0.03 mmol) was reacted to afford the title compound (12 mg, 64%). LCMS (Method D): RT=0.808 min, M+1=431. 1H NMR (500 MHz, MeOD): 7.76 (1H, s), 7.48 (2H, d), 7.41 (2H, d), 7.29-7.25 (3H, m), 7.20-7.18 (2H, m), 4.67 (2H, dt), 4.16 (2H, dt), 3.88-3.86 (2H, m), 2.79-2.73 (4H, m, 2.61-2.55 (2H, m), 2.25-2.18 (1H, m), 1.99-1.91 (1H, m).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[NH:15][C:14](=[O:20])[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[NH:15][C:14](=[O:20])[CH:13]=[CH:12]2)[CH2:7][O:8][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO[Si](C)(C)C(C)(C)C)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of (S)-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one (8K) (0.5175 g, 1.34 mmol) in DMF (5.0 mL), was added imidazole (0.204 g, 4.02 mmol), followed by tert-butyldimethylsilyl chloride (0.243 g, 1.61 mmol) at 0° C. The reaction mixture was warmed to room temperature overnight. Additional imidazole (0.2 g) and tert-butyldimethylsilyl chloride (0.30 g) were added and the mixture stirred for another 2 hours. The reaction mixture was the diluted with ethyl acetate, washed with 5% lithium chloride solution (2×), brine, dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 20 to 60% ethyl acetate/hexanes) to give a yellow foam (0.500 g). LCMS-ESI+ (m/z): calcd for C28H39ClNO3Si: 501.1;
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH2:15][OH:16])[N:12]([CH3:14])[CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1.O=[Mn]=O>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[O:16])[N:12]([CH3:14])[CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(S(=O)(=O)NC(C)(C)C)cc1CO
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: Cn1cc(S(=O)(=O)NC(C)(C)C)cc1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
A solution of 4 (6.40 g, 25.98 mmol) in dry THF (750 mL) under nitrogen was charged with MnO2 (65.0 g, 0.64 mol) and was allowed to stir at room temperature for 1 h. The mixture was filtered through celite; the filtrate was concentrated. Purification by flash chromatography on silica gel using 10-25% EtOAc/hexanes gradient as eluent afforded 1 (5.67 g, 89%) as a white solid. Mp 97-98° C. 1H NMR (300 MHz, CDCl3): δ 9.95(d, 0.8 Hz, 1H), 7.33 (bs, 1H), 7.18 (d, 1.9 Hz, 1H), 4.69 (bs, 1H), 3.97 (s, 3H), 1.27 (s, 9H). MS m/z: 243 (M−1). Analysis calcd. for C10H16N2O3S; C, 49.16; H, 6.60, N, 11.47; found, C, 48.99; H, 6.70; N, 11.45.
Reaction SMILES: ClC1C=CC([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][S:26](=[O:30])(=[O:29])[CH2:25][CH2:24]4)=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=C(F)C=1.C(=O)([O-])O.[Na+]>Cl.O>[O:30]=[S:26]1(=[O:29])[CH2:25][CH2:24][N:23]([CH2:22][CH2:21][CH2:20][O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:7](=[O:6])[NH:8][CH:9]=[N:10]3)=[CH:15][C:14]=2[O:17][CH3:18])[CH2:28][CH2:27]1
Reactant: COc1cc2c(Oc3ccc(Cl)cc3F)ncnc2cc1OCCCN1CCS(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 95 °C
Yield: 87.9 %

Procedure:
4-(4-Chloro-2-fluorophenoxy)-7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxyquinazoline (3.5 g, 7 mmol) was dissolved in 2M aqueous hydrochloric acid (56 ml) and heated at 95° C. for 2 hours. The cooled reaction mixture was treated with solid sodium hydrogen carbonate solution to give a thick paste which was diluted with water and filtered. The solid was transferred to a flask and azeotroped with toluene twice to give a dry solid. The solid was flash chromatographed on silica eluting with dichloromethane and methanol (95/5). The relevant fractions were combined and evaporated to give 7-(3-(1,1-dioxothiomorpholino)propoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (2.26 g, 87%) as a white solid.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[O:6][C:7]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:8]=2[CH:9]=1)C.C(O)=O>O>[CH:4]([C:5]1[O:6][C:7]2[CH:13]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:3]
Reactant: CCOC(OCC)c1cc2ccc(C(=O)OC)cc2o1
Solvent: O=CO
Solvent: O
Product: COC(=O)c1ccc2cc(C=O)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.9 %

Procedure:
Methyl 2-(diethoxymethyl)-1-benzofuran-6-carboxylate (2.71 g, 9.7 mmol) is treated drop-wise with formic acid (20 ml, 530 mmol) and water (5.5 ml). The reaction is stirred overnight at RT, diluted with water (50 ml), and the brown slurry is filtered. The cake is dried overnight to afford 1.86 g (94%) of methyl 2-formyl-1-benzofuran-6-carboxylate as an amber solid. 1H NMR (400 MHz, DMSO-d6): δ 3.91, 8.03, 8.28, 9.92 ppm.
Reaction SMILES: [I:1][C:2]1[C:3](=[O:21])[N:4]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH:10]=O)[CH:7]=1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([C:30]23[CH2:35][CH:34]2[CH2:33][NH:32][CH2:31]3)[CH:27]=[CH:28][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O.C([O-])(O)=O.[Na+]>[I:1][C:2]1[C:3](=[O:21])[N:4]([C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[C:5](=[O:12])[N:6]([CH2:8][CH2:9][CH2:10][N:32]2[CH2:33][CH:34]3[C:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:37])[F:36])[CH:25]=4)([CH2:35]3)[CH2:31]2)[CH:7]=1
Reactant: O=CCCn1cc(I)c(=O)n(C(=O)c2ccccc2)c1=O
Reactant: FC(F)(F)c1cccc(C23CNCC2C3)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCN2CC3CC3(c3cccc(C(F)(F)F)c3)C2)c1=O
Temperature: 0 °C
Reaction time: 4 h
Yield: 46.6 %

Procedure:
To a solution of 3-[5-iodo-2,4-dioxo-3-(phenylcarbonyl)-3,4-dihydro-1(2H)-pyrimidinyl]propanal (P38, 350 mg, 0.88 mmol) and (1-[3-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (racemate, reference procedure for preparation reported in WO2005/080382, 200 mg, 0.88 mmol) in dry DCE (10 ml), AcOH was added and the reaction mixture cooled to 0° C. Sodiumtriacetoxyborohydride (224 mg, 1.055 mmol) was added and the reaction left at 0° C. for 4 hrs. Reaction monitored by LC/MS. The mixture was diluted with a saturated solution of NaHCO3 and extracted with DCM. The solvent was evaporated and the crude purified by silica SPE column (20 g) eluting with acetone/toluene 20:80. After evaporation, 250 mg of the title compound were obtained.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:42])[CH2:20][CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:42])[CH2:20][CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:4])=[O:3]
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCCOCCOCCOCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCOCCOCCNC(=O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 121.3 %

Procedure:
Methanesulfonyl chloride (0.55 mL, 7.1 mmol) was added to a 0° C. solution of N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)-3-(tritylthio)propanamide (3.38 g, 6.45 mmol) and triethylamine (1.08 mL, 7.74 mmol) in dichloromethane (33 mL). The solution was allowed to warm to room temperature. After 4 hours, the solution was diluted with dichloromethane and washed with water (2×) and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 4.71 g of 13-oxo-17,17,17-triphenyl-3,6,9-trioxa-16-thia-12-azaheptadec-1-yl methanesulfonate, which was concentrated from toluene and used in Part C.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[O-:9][CH2:10][CH3:11].[Na+].CN(C)C=O.O>C(OCC)C>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([O:9][CH2:10][CH3:11])[CH:7]=1
Reactant: CC[O-]
Reactant: Brc1cncc(Br)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOc1cncc(Br)c1
Temperature: 65 °C
Yield: 17.9 %

Procedure:
3,5-Dibromopyridine (98%) was purchased from Lancaster Chemical Company. Sodium ethoxide (96%) and N,N-dimethylformamide (DMF) (99.9+%, HPLC grade) were purchased from Aldrich Chemical Company. Under a nitrogen atmosphere, a mixture of 3,5-dibromopyridine (5.00 g, 21.1 mmol), sodium ethoxide (2.87 g, 42.2 mmol), and DMF (10 mL) was stirred and heated at 65° C. for 15 h. The mixture was poured into water (70 mL), and anhydrous diethyl ether (155 mL) was added. Because of insoluble solids, it was necessary to filter both phases. The aqueous layer was separated and extracted with ether (2×25, 3×50 mL). The combined ether extracts were dried (MgSO4), filtered, and concentrated by rotary evaporation, producing a dark-brown syrup. The brown residue was purified by vacuum distillation, affording 0.76 g (17.9%) of an oil, bp 105° C. at 5 mm Hg. 1H NMR (CDCl3): δ 9.12 (br s, 1H), 8.83 (br s, 1H), 8.42 (dd, 1H), 4.41 (q, 2H), 1.42 (t, 3H). 13C NMR (CDCl3): δ 142.72, 136.50, 123.78, 64.31, 14.57.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2(O)[CH:18]([C:19]([O:21][CH3:22])=[O:20])[S:17][C:16]3[C:23]([C:27]([F:30])([F:29])[F:28])=[CH:24][CH:25]=[CH:26][C:15]2=3)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:22][O:21][C:19]([C:18]1[S:17][C:16]2[C:23]([C:27]([F:29])([F:30])[F:28])=[CH:24][CH:25]=[CH:26][C:15]=2[C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)=[O:20]
Reactant: COC(=O)C1Sc2c(C(F)(F)F)cccc2C1(O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc2c(C(F)(F)F)cccc2c1C1CCNCC1
Temperature: 40 °C
Reaction time: 0.08 h

Procedure:
To a room temperature solution of 4-(3-hydroxy-2-methoxycarbonyl-7-trifluoromethyl-2,3-dihydro-benzo[b]thiophen-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (6.00 g, 13.0 mmol) in DCM (30 mL) was added TFA (30 mL) causing rapid gas evolution. After 5 min, the reaction was stirred at 40° C. for 5.5 h. After cooling to room temperature, the reaction was poured into 20% aqueous potassium carbonate (400 mL) and extracted with DCM (2×200 mL). The combined extracts were dried over magnesium sulfate, filtered, and the solvent removed to give a thick oil. After drying under high vacuum 4.37 g (98%) of the desired product was obtained as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:12](=[O:21])[NH:13][CH:14]=[CH:15][C:16]=2[C:17]([F:20])([F:19])[F:18])[CH:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:29][C:30]([N:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[Cl:41])[CH3:33])=[O:31]>CN(C)C=O>[Cl:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[CH2:34][N:32]([CH3:33])[C:30](=[O:31])[CH2:29][N:13]1[CH:14]=[CH:15][C:16]([C:17]([F:18])([F:19])[F:20])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([C:5]#[N:6])[CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:12]1=[O:21]
Reactant: N#Cc1cc(Cl)cc(Oc2c(C(F)(F)F)cc[nH]c2=O)c1
Reactant: CN(Cc1ccccc1Cl)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1Cl)C(=O)Cn1ccc(C(F)(F)F)c(Oc2cc(Cl)cc(C#N)c2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a flask charged with 3-chloro-5-{[2-oxo-4-(trifluoromethyl)-1,2-dihydropyridin-3-yl]oxy}benzonitrile (3C, 0.020 g, 0.064 mmol) and potassium carbonate (0.0088 g, 0.064 mmol) was added 2-chloro-N-(2-chlorobenzyl)-N-methylacetamide in dimethylformamide (0.75 mL). The reaction mixture was allowed to stir at room temperature. After 1.5 hours, the reaction mixture was filtered and the filtrate was purified by preparative HPLC Phenomenex Luna C18 100A 10μ, eluting with 30-95% MeCN/H2O+0.1% TFA. and lyophilized to yield the title compound. 1H NMR (DMSO-d6) δ 7.90-7.84 (m, 1H), 7.76-7.74 (m, 1H), 7.54-7.43 (m, 3H), 7.42-7.32 (m, 1H), 7.31-7.26 (m, 2H), 7.23-7.19 (m, 1H), 6.68-6.62 (m, 1H), 5.09 (s, 1.35H), 4.80 (s, 0.65H), 4.72 (s, 0.65H), 4.59 (s, 1.35H), 3.06 (s, 2H), 2.82 (s, 1H). HRMS (M+1)=510.0591.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.Cl.[CH3:30][N:31]([CH3:38])[CH2:32][CH2:33][CH2:34][C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:30][N:31]([CH3:38])[CH2:32][CH2:33][CH2:34][C:35]([N:26]1[CH2:25][CH:24]=[C:23]([C:21]2[NH:20][C:16]3[N:17]=[CH:18][N:19]=[C:14]([NH:13][C:10]4[CH:11]=[CH:12][C:7]5[N:6]=[CH:5][S:4][C:8]=5[CH:9]=4)[C:15]=3[CH:22]=2)[CH2:28][CH2:27]1)=[O:36]
Reactant: CN(C)CCCC(=O)O
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CCCC(=O)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C

Procedure:
To a solution of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine trihydrochloride (50.0 mg, 0.11 mmol) in DMF (3 mL) was added 4-(dimethylamino)butyric acid hydrochloride (17 mg, 0.13 mmol), TBTU (42 mg, 0.13 mmol) and N,N-diisopropylethylamine (0.11 mL). The reaction mixture was left to stir at rt over the weekend. The crude mixture was concentrated in vacuo and purified via MDP, which afforded the title compound as a tan solid. MS (ES+): m/z: 461.99 (100) [MH+]. HPLC: tr=1.82 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, DMSO-d6): δ=1.63-1.68 (m, 2H), 2.10 (s, 3H), 2.11 (s, 3H), 2.18-2.24 (m, 2H), 2.33-2.43 (m, 2H), 2.54-2.56 (m, 2H), 3.67-3.72 (m, 2H), 4.15 (bs, 1H), 4.21 (bs, 1H), 6.45 (s, 1H), 6.84 (d, J=6.4 Hz, 1H), 7.87 (dd, J=1.6, 8.8 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 8.34 (s, 1H), 8.92 (s, 1H), 9.23 (s, 1H), 9.61 (s, 1H), 12.02 (d, J=11.2 Hz, 1H).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:6][C:7]1[N:12]=[C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([F:23])=[CH:15][CH:14]=2)[CH:10]=[C:9]([CH:24]([CH3:26])[CH3:25])[N:8]=1)[CH3:5].[CH3:28][NH2:29]>>[CH:24]([C:9]1[N:8]=[C:7]([NH:6][CH:4]([CH3:5])[C:3]([NH:29][CH3:28])=[O:2])[N:12]=[C:11]([C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([F:23])=[CH:15][CH:14]=2)[CH:10]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)C(C)Nc1nc(-c2ccc(F)c3ccccc23)cc(C(C)C)n1
Reactant: CN
Product: CNC(=O)C(C)Nc1nc(-c2ccc(F)c3ccccc23)cc(C(C)C)n1

Procedure:
2-[6-Isopropyl-4-(4-fluoronaphth-1-yl)pyrimidin-2-ylamino]-propionic acid methyl ester was dissolved in ethanolic methyl amine solution (33%) and sonicated in a Branson ultrasonic bath for 3 hours. The solution was evaporated to dryness and taken up in methanol. Sufficient water was added to cause crystallization. The impure reaction product was further purified by silica gel column chromatography, eluting with methylene chloride/methanol and recrystallized from methanol/water to give 2-[6-isopropyl-4-(4-fluoronaphth-1-yl)pyrimidin-2-ylamino]-N-methyl-propionamide, m.p. 141.1-142.0° C.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CC[N:28]([CH:32]([CH3:34])C)[CH:29](C)C.N1CCC1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:28]4[CH2:29][CH2:34][CH2:32]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCN(C(C)C)C(C)C
Agent: C1CNC1
Product: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and azetidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.84 (m, 1H), 7.56 (2H), 6.85 (1H), 4.57 (m, 1H), 4.11 (m, 4H), 3.49 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 410 [M+H]
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][C:5]=1[NH2:6])([O-])=O>C(O)C.[Pd]>[F:11][C:9]1[C:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][C:5]([NH2:6])=[C:4]([NH2:1])[CH:10]=1
Reactant: Nc1cc(N2CCCCC2)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)c(N2CCCCC2)cc1N
Yield: 97.4 %

Procedure:
The nitroaniline derivative (6.2 g, 0.026 mol) (obtained in step 1 above) was hydrogenated using 10% Pd-C (1.0 g,) in ethanol (30 mL), using an analogous procedure as described in preparation 1 (step 4) to yield 4-fluoro-5-(piperidin-1-yl)-1,2-phenylenediamine (5.3 g 98%) as brown viscous oil. IR (Neat) 3346 cm-1 ; 1H NMR (CDCl3) δ 1.54 (m, 2H, CH2), 1.70 (m, 4H, (CH2)2), 2.90 (m, 4H, N(CH2)2), 3.10 (brs, 4H, 2×NH2), 6.40 (d, J=8.8 Hz, 1H), 6.48 (d, J=13.8 Hz, 1H); Mass (m/z) 209 (M+.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:4]2([CH:6]([C:7]([O:9]CC)=[O:8])[CH2:5]2)[CH2:3]1.C1(C(OCC)=O)C2(CCCCC2)C1>>[CH3:1][CH:2]1[CH2:14][CH:13]([CH3:15])[CH2:12][C:4]2([CH:6]([C:7]([OH:9])=[O:8])[CH2:5]2)[CH2:3]1
Reactant: CCOC(=O)C1CC12CC(C)CC(C)C2
Agent: CCOC(=O)C1CC12CCCCC2
Product: CC1CC(C)CC2(C1)CC2C(=O)O

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 21B for the product from Example 1A. MS m/z 182 (M+NH4)+.