Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[N:24][N:23]=[N:22]1)[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][NH2+:15][CH2:14][CH2:13]1.Cl[C:27]1[N:32]=[CH:31][C:30]([CH2:33][O:34][CH3:35])=[CH:29][N:28]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.O>[F:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[N:21]1[CH:25]=[N:24][N:23]=[N:22]1)[CH2:6][O:7][CH2:8][C@@H:9]1[CH2:11][C@@H:10]1[CH:12]1[CH2:17][CH2:16][N:15]([C:27]2[N:32]=[CH:31][C:30]([CH2:33][O:34][CH3:35])=[CH:29][N:28]=2)[CH2:14][CH2:13]1
Reactant: COCc1cnc(Cl)nc1
Reactant: Fc1cc(COC[C@@H]2C[C@@H]2C2CC[NH2+]CC2)ccc1-n1cnnn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(-n4cnnn4)c(F)c3)CC2)nc1
Temperature: 55 °C
Yield: 57.8 %

Procedure:
4-((1R,2R)-2-((3-fluoro-4-(1H-tetrazol-1-yl)benzyloxy)methyl)cyclopropyl)piperidinium chloride (Step D product, 45 mg, 0.122 mmol) and 2-chloro-5-(methoxymethyl)pyrimidine (Intermediate 18, 22 mg, 0.136 mmol) were dissolved in DMF (600 uL), to which was added cesium carbonate (100 mg, 0.306 mmol). The reaction was heated at 55° C. overnight. The reaction mixture was cooled to rt and diluted with EtOAc (5 mL) and water (5 mL). The layers were cut and the aqueous phase extracted with EtOAc (5 mL×2). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was loaded onto 2×2000 micron silica preparative TLC plates (uv 254 active) which were developed using 50% EtOAc/Hex as the solvent system. The desired silica (Rf=0.4 @ 50% EtOAc/Hex) was collected and extracted to give the title compound (32 mg, 57%). 1H NMR (500 MHz, CDCl3) δ 9.14 (s, 1H), 8.39 (s, 2H), 7.94 (t, 1H), 7.40 (dd, 2H), 4.73 (t, 2H), 4.65 (q, 2H), 4.29 (s, 2H), 3.61 (td, 2H), 3.38 (s, 3H), 2.95 (m, 2H), 1.95 (dd, 2H), 1.43 (m, 2H), 1.28 (m, 1H), 1.22 (m, 1H), 0.85-0.73 (m, 2H), 0.11 (q, 1H). LC/MS (m/z): 454 (M+H)+, GPR119 Human EC50: 1.1 nM.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[CH2:26]([O:28][CH:29]([O:39][CH2:40][CH3:41])[C:30]1[S:34][CH:33]=[C:32](/[CH:35]=[CH:36]/[C:37]#[N:38])[CH:31]=1)[CH3:27].C1CCN2C(=NCCC2)CC1>O>[CH2:26]([O:28][CH:29]([O:39][CH2:40][CH3:41])[C:30]1[S:34][CH:33]=[C:32]([CH:35]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:36][C:37]#[N:38])[CH:31]=1)[CH3:27]
Reactant: CCOC(OCC)c1cc(/C=C/C#N)cs1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(OCC)c1cc(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)cs1
Yield: 43.2 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (200 mg, 0.0007 mol) in ACN (2 mL, 0.04 mol) and (2E)-3-[5-(diethoxymethyl)-3-thienyl]acrylonitrile (160 mg, 0.00067 mol) (mixture of regioisomers) DBU (80 μL, 0.0005 mol) was added. The reaction was stirred overnight than water was added and the product was extracted with ethyl acetate. The combined extracts were washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel eluting (50% EtOAc/Hexane) to give 3-[5-(diethoxymethyl)-3-thienyl]-3-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (160 mg, 43%). 1H NMR (400 MHz, CDCl3): δ 8.92 (s, 1H), 8.41 (s, 1H), 8.29 (b, 1H), 7.45 (d, 1H), 7.41 (d, 1H), 7.15 (s, 1H), 7.05 (d, 1H), 6.82 (m, 1H), 5.74 (d, 2H), 3.74 (m, 2H), 3.71 (m, 8H), 3.59 (m, 1H), 1.32 (m, 4H), 0.95 (m, 2H), −0.08 (s, 9H); MS(ES): 553(M+1).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43](OC)=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH:27]=1.CCN(C(C)C)C(C)C.[CH3:63][O:64][CH2:65][CH2:66][NH2:67]>CN(C=O)C>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[C:34]3[C:41]([CH3:42])=[C:40]([C:43]([NH:67][CH2:66][CH2:65][O:64][CH3:63])=[O:44])[S:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[C:28]([O:47][CH:48]2[CH2:49][CH2:50][O:51][CH2:52][CH2:53]2)[CH:27]=1
Reactant: COCCN
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCNC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCOCC3)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
HATU (0.052 g, 0.138 mmol) was added into a mixture of methyl 4-(4-fluoro-2-(tetrahydro-2H-pyran-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.050 g, 0.125 mmol) and Hünig's base (22 μL, 0.125 mmol) in DMF (2.0 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 hours. 2-Methoxyethylamine (54.3 μL, 0.625 mmol) was added and the coolant removed. The reaction mixture was stirred at ambient temperature overnight. The product was purified by reverse phase preparative HPLC to yield white solid (0.029 g, 50%)
Reaction SMILES: [CH:1]([C:3]1([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:2].C[Li].[C:28](=O)(O)[O-].[Na+]>C1COCC1.CCOCC>[OH:2][CH:1]([C:3]1([CH2:16][CH2:17][O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][CH2:8]1)[CH3:28]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)(CCO[Si](C)(C)C(C)(C)C)CC1
Agent: [Li]C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)C1(CCO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-formyl-4-(2-(tert-butyldimethylsilyloxy)eth-1-yl)piperidine-1-carboxylate (6.3 g, 17 mmol) in THF (170 mL) at −70° C. was added 1.4M methyl lithium in ether (13.3 mL, 19 mmol). After 2 h, an additional amount of 1.4M methyl lithium in ether (2.5 mL) was added. After an additional 30 min, the reaction was poured into aq. sodium bicarbonate and extracted three times with ether. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title product (6.6 g) which was used directly in the next step.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([OH:13])[C:10]([C:14]2[N:15]=[N:16][C:17]([O:20][CH:21]3[CH2:26][C:25]([CH3:28])([CH3:27])[NH:24][C:23]([CH3:30])([CH3:29])[CH2:22]3)=[CH:18][CH:19]=2)=[C:9]([F:31])[CH:8]=1)(=O)=[O:4].CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][N:45](C([O-])=O)[CH:46]=2)O1>>[OH2:4].[F:31][C:9]1[C:10]([C:14]2[N:15]=[N:16][C:17]([O:20][CH:21]3[CH2:22][C:23]([CH3:30])([CH3:29])[NH:24][C:25]([CH3:27])([CH3:28])[CH2:26]3)=[CH:18][CH:19]=2)=[C:11]([OH:13])[CH:12]=[C:7]([C:42]2[CH:43]=[N:44][NH:45][CH:46]=2)[CH:8]=1
Reactant: CC1(C)OB(c2cnn(C(=O)[O-])c2)OC1(C)C
Reactant: CC1(C)CC(Oc2ccc(-c3c(O)cc(OS(=O)(=O)C(F)(F)F)cc3F)nn2)CC(C)(C)N1
Product: CC1(C)CC(Oc2ccc(-c3c(O)cc(-c4cn[nH]c4)cc3F)nn2)CC(C)(C)N1
Product: O

Procedure:
Following the representative procedure GENERAL METHOD 1-6 for Suzuki cross-coupling, 3-fluoro-5-hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenyl trifluoromethanesulfonate and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate were reacted and the crude product was purified via reverse phase preparative HPLC (10% CH3CN to 30% in H2O). After salt formation, the hydrochloride salt of 3-fluoro-5-(1H-pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)oxy)pyridazin-3-yl)phenol hydrate was afforded as a yellow solid (49 mg, 25%). LCMS Rt=0.49 min; [M+H]: 412.3; 1H NMR (400 MHz, MeOD) δ 8.51 (d, J=9.5 Hz, 1H), 8.26 (s, 2H), 7.87 (d, J=9.5 Hz, 1H), 7.21 (dd, J=12.0, 1.5 Hz, 1H), 7.16 (s, 1H), 5.77 (tt, J=10.5, 4.0 Hz, 1H), 2.52 (dd, J=14.0, 4.0 Hz, 2H), 1.93 (dd, J=14.0, 10.5 Hz, 2H), 1.64 (s, 6H), 1.59 (s, 6H).
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[CH2:5]([C:7]([OH:14])([CH2:10][CH2:11][CH:12]=C)[CH2:8][OH:9])[CH3:6].C(=O)=[O:16].O=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.CC(C)=O>[CH2-:1][C:2]([CH3:4])=[O:3].[CH2:5]([C:7]([OH:14])([CH2:8][OH:9])[CH2:10][CH2:11][CH:12]=[O:16])[CH3:6]
Reactant: O=C=O
Reactant: C=CCCC(O)(CC)CO
Agent: O=[O+][O-]
Agent: [CH2-]C(C)=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCC(O)(CO)CCC=O
Temperature: 25 °C
Yield: 76 %

Procedure:
A solution of 2S 2-ethyl-2-hydroxyhex-5-enol acetonide (1.2 g, 6.52 mmol) in dichloromethane (25 mL) was brought to -78° C. (dry ice, acetone) and ozone was bubbled through until the reaction mixture turned a pale blue (approx. 15 min.). The reaction mixture was then flushed with nitrogen for 1 h, triphenylphosphine (850 mg, 3.26 mmole) was added and the mixture was allowed to slowly warm to room temperature. The solvent was removed under reduced pressure and the residue was taken up in hexane, filtered and again concentrated. Flash chromatography on 50 g of silica gel, eluting with 3:2 hexane/ether, gave 0.92 g (76%) of the title aldehyde. TLC Rf 0.39 (silica gel, 3:2 hexane-ether).
Reaction SMILES: Cl[S:2]([OH:5])(=[O:4])=[O:3].[C:6]1([CH2:12][NH:13][CH2:14][CH2:15][OH:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)(Cl)Cl.C(Cl)(Cl)Cl.C(O)C>[S:2]([OH:5])([O:16][CH2:15][CH2:14][NH:13][CH2:12][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(O)Cl
Reactant: OCCNCc1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=S(=O)(O)OCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
Chlorosulfonic acid (13.3 mL, 0.2 mol) was added very slowly to (2-[(phenylmethyl)amino]ethanol (30.2 g, 0.2 mol) in carbon tetrachloride (100 mL) in an ice bath. The resulting thick white suspension was stirred at room temperature overnight The suspension was diluted with chloroform and ethanol, warmed to 45° C. and then cooled in an ice bath. The precipitate was collected by filtration, washed with ethanol and dried under vacuum for 16 hrs at 40° C. to afford the desired compound (34 g, 74%). MS (ES)+ m/z 232 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([S:44]([CH3:47])(=[O:46])=[O:45])[CH2:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31](=[O:43])[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:26]=[CH:25]4)[N:18]=[CH:17][N:16]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:42][C:39]([F:40])([F:41])[C:35]1[CH:34]=[C:33]([NH:32][C:31]([N:27]2[C:28]3[C:24](=[CH:23][C:22]([O:21][C:19]4[CH:20]=[C:15]([CH2:14][N:13]([S:44]([CH3:47])(=[O:46])=[O:45])[CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)[N:16]=[CH:17][N:18]=4)=[CH:30][CH:29]=3)[CH:25]=[CH:26]2)=[O:43])[CH:38]=[CH:37][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)ncn2)S(C)(=O)=O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N(Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ncn1)C1CCNC1

Procedure:
(±)-3-(Methanesulfonyl-{6-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-amino)-pyrrolidine-1-carboxylic acid tert-butyl ester (12 mg, 0.018 mmol) is stirred in a solution of DCM (2 mL) and TFA (0.5 mL) overnight. After removal of solvents, the residue is quenched with saturated aqueous sodium bicarbonate. The mixture is extracted with EtOAc (3×). The combined organic layers are washed with water and brine and the organic layer is dried with Na2SO4, filtered, and condensed. The residue is then separated by FCC (0-10%, 2 M NH3 in MeOH/DCM) to provide the title compound. MS (ESI) m/z 574.8 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[C:7](B(O)O)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].Br[C:22]1[CH:29]=[CH:28][C:25]([CH2:26][OH:27])=[CH:24][CH:23]=1.C1(C)C=CC=CC=1.[OH-].[Na+]>CCOC(C)=O.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.C(O)C>[OH:27][CH2:26][C:25]1[CH:28]=[CH:29][C:22]([C:7]2[CH:6]=[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:9][C:8]=2[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:23][CH:24]=1
Reactant: CC(C)Cc1cc(B(O)O)c(S(=O)(=O)NC(C)(C)C)s1
Reactant: OCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)Cc1cc(-c2ccc(CO)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Yield: 75.7 %

Procedure:
5-iso-Butyl-2-(N-tert-butylaminosulfonyl)thiophene-3-boronic acid (319.3 mg, 1.00 mmol, see Example 1(c) above), 4-bromobenzyl alcohol (374.1 mg, 2.00 mmol), toluene (20 mL), ethanol (4 mL), NaOH (1.0M, 4 mL, 4 mmol) and Pd(PPh3)4 (34 mg, 0.030 mmol) were mixed together under N2. The mixture was warmed to reflux for 2 hours and was then diluted with EtOAc (50 mL), washed with water and brine and dried over MgSO4. The solvent was removed and the residue was separated by column chromatography using CHCl3:MeOH (40:1) as eluent to give 289 mg of the sub-title compound (yield: 76%).
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[CH3:20][N:21]=[C:22]=[O:23].[NH2:24][C:25]1[C:33]([Cl:34])=[CH:32][C:28](C(O)=O)=[C:27]([O:35][CH3:36])[CH:26]=1>>[NH2:24][C:25]1[C:33]([Cl:34])=[CH:32][C:28]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:22]([NH:21][CH3:20])=[O:23])[CH2:11]2)=[O:7])=[C:27]([O:35][CH3:36])[CH:26]=1
Reactant: CN=C=O
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: CNC(=O)NCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (1.00 g) as starting compound was reacted and treated in the same manner as in Example 34 using methyl isocyanate (0.24 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.74 g) to give 4-amino-5-chloro-2-methoxy-N-(1-(4-(3-methylureido)butyl)pyrrolidin-3-ylmethyl)benzamide.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12]CC3C=CC=CC=3C(F)(F)F)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[CH3:24][C:25]1[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32]Cl)=[C:27]([CH3:34])[CH:26]=1>>[C:1]([C:3]1[S:4][C:5]2[CH:11]=[C:10]([O:12][CH2:32][C:28]3[C:29]([CH3:31])=[CH:30][C:25]([CH3:24])=[CH:26][C:27]=3[CH3:34])[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2]
Reactant: Cc1cc(C)c(CCl)c(C)c1
Reactant: N#Cc1nc2ccc(OCc3ccccc3C(F)(F)F)cc2s1
Product: Cc1cc(C)c(COc2ccc3nc(C#N)sc3c2)c(C)c1

Procedure:
This compound was synthesized in a similar way to 2-cyano-6-(2-trifluoromethylbenzyloxy)benzothiazole with α2-chloroisodurene (100 mg, 0.852 mmol). 168 mg product was obtained.
Reaction SMILES: [CH2:1]([CH:8]1[CH:13]=[CH:12][NH:11][NH:10][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Se](=O)=O.O>C(O)C>[CH2:1]([C:8]1[C:9](=[O:14])[NH:10][N:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NNC=CC1Cc1ccccc1
Agent: O=[Se]=O
Solvent: CCO
Solvent: O
Product: O=c1[nH]nccc1Cc1ccccc1
Yield: 52.4 %

Procedure:
To a solution of 1-methyl 2-benzylsuccinate (0.78 g) in tetrahydrofuran (12 mL) was added borane tetrahydrofuran complex (0.93 mol/L solution in tetrahydrofuran, 3.8 mL) at 0° C. The temperature was raised to room temperature, and the mixture was stirred for 15 hours. To the reaction mixture were added water and potassium carbonate, and the mixture was extracted with diethyl ether. After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. After the residue was dissolved in dichloromethane (20 mL), a Dess-Martin reagent (1,1,1-tri-acetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one)(1.2 g), and the mixture was stirred for 2 hours at room temperature. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. After the residue was dissolved in ethanol (5 mL), hydrazine monohydride (0.14 mL) was added to the solution, and the mixture was heated under reflux for 30 minutes. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=2/1-1/1) to give 4-benzyl-3,4-dihydro-2H-pyridazin-3-one (0.31 g). To a solution of the obtained 4-benzyl-3,4-dihydro-2H-pyridazin-3-one (0.16 g) in ethanol (5 mL-) was added selenium dioxide (0.48 g), and the mixture was heated under reflux for 41 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue was added diethyl ether, and the resulting precipitated crystals were collected by filtration and dried under reduced pressure to give 4-benzyl-2H-pyridazin-3-one (0.083 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[C:9]=2[CH:21](C2C=NC=CC=2)[OH:22])[CH:5]=[CH:6][CH:7]=1.C(O[C:33](=[O:35])[CH3:34])(=O)C.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[C:9]=2[CH2:21][O:22][C:33](=[O:35])[CH2:34][C:38]2[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccncc1
Reactant: OC(c1cccnc1)c1c(-c2ccc(Cl)cc2Cl)noc1-c1cccc(Cl)c1
Reactant: CC(=O)OC(C)=O
Product: O=C(Cc1cccnc1)OCc1c(-c2ccc(Cl)cc2Cl)noc1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 43 mg (0.10 mmol) of 5-(3-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole in 2 mL of pyridine was added 19 μL (0.20 mmol) of acetic anhydride. The reaction was stirred overnight at room temperature, and then the pyridine was removed under vacuum. The residue was taken up in ethyl acetate, washed with saturated sodium chloride, and the ethyl acetate fraction dried over magnesium sulfate. The drying agent was filtered off, and the ethyl acetate was removed by rotoevaporation. The crude product was purified by preparative thin layer chromatography (prep TLC) to give 35 mg (0.074 mmol) of 5-(3-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)acetoxymethyl]isoxazole.
Reaction SMILES: [CH3:1][C:2](/[CH:4]=[N:5]/O)=O.[CH3:7][C:8]1([CH3:16])[CH2:13][C:12](=O)[CH2:11][C:10](=[O:15])[CH2:9]1>OC(C)=O.O.[Zn]>[CH3:1][C:2]1[C:11]2[C:10](=[O:15])[CH2:9][C:8]([CH3:7])([CH3:16])[CH2:13][C:12]=2[NH:5][CH:4]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(=O)/C=N/O
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c[nH]c2c1C(=O)CC(C)(C)C2
Temperature: 25 °C
Yield: 44.2 %

Procedure:
To a solution of anti-pyruvic aldehyde-1-oxime (10 g, 1 eq) and 5,5-dimethyl-1,3-cyclohexanedione (16.1 g, 1 eq) in HOAc—H2O (7:3, 200 mL) was added zinc powder (14.95 g, 2 eq) slowly with cooling by a water bath at room temperature. The mixture then was refluxed overnight, concentrated to dryness, partitioned between brine (300 mL) and dichloromethane (300 mL). The pH was adjusted to ca. 6 with saturated aqueous NaHCO3, then the mixture was extracted with dichloromethane (3×200 mL). The organic layers were combined, dried over Na2SO4, filtered, concentrated. The crude product was purified by flash chromatography eluting with 5% ethyl acetate in dichloromethane. The combined organic fractions were concentrated, triturated in ether-hexane (2:1) for 1 hour, then filtered, washed with hexane to give the pure title compound (9 g, 45% yield) as a solid. LCMS m/z: (M+H)=178.1.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([NH2:11])=[C:6]([F:12])[C:5]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[C:22](O)(=O)C.C(N)=N>CCO.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])=[C:6]([F:12])[C:7]2[N:11]=[CH:22][NH:10][C:8]=2[CH:9]=1)=[O:21]
Reactant: COC(=O)c1cc(N)c(N)c(F)c1Nc1ccccc1Cl
Reactant: CC(=O)O
Agent: N=CN
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2[nH]cnc2c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.4 %

Procedure:
4,5-Diamino-2-(2-chloro-phenylamino)-3-fluoro-benzoic acid methyl ester 6a (0.125 g, 0.404 mmol) is suspended in EtOH (2 mL) and formamidine acetate (63 mg, 0.605 mmol) is added. The reaction mixture is heated to reflex. After 16 hours, the reaction mixture is cooled to rt and diluted with ethyl acetate. The organic layer is washed with water, saturated NaHCO3, 10% K2CO3 and brine. The organic layer is dried (MgSO4) and concentrated under reduced pressure to give 0.109 g (85%) pure desired product.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:19][C:20]([NH2:22])=[O:21])=[C:7]([CH3:18])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][O:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:19][C:20]([NH2:22])=[O:21])=[C:7]([CH3:18])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1)[CH3:34]
Reactant: Cc1c(CC(N)=O)c2ccc(O)cc2n1Cc1ccccc1
Reactant: CCOC(=O)CCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCOc1ccc2c(CC(N)=O)c(C)n(Cc3ccccc3)c2c1
Yield: 710 %

Procedure:
Using the procedure in Example 33, 147 mg (0.5 mmol) of 6-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide was reacted with 20 mg (0.5 mmol) of 60% NaH/mineral oil and 0.08 mL (0.05 mmol) of ethyl 5-bromovalerate. After chromatography on silica (eluting first with 50% EtOAc/hexane, then EtOAc) and crystallization from MeOH/CH2Cl2 there was obtained 150 mg (71% yield) of 5-[[3-(2-amino-2-oxoethyl)-2-methyl-1-(phenylmethyl)-1H-indol-6-yl]oxy]pentanoic acid ethyl ester, mp, 123-135° C.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:5]([C:14]([OH:16])=O)[CH2:4][CH2:3]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:39][C:40]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:50][NH2:51]>ClCCl>[Cl:39][C:40]1[C:45]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:50][NH:51][C:14](=[O:16])[C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1Cl)[C@@H]1CCC(=O)N1Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
5-oxo-1-(3-pyridinylmethyl)proline (0.210 g, 1 mmol, prepared as described below), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.383 g, 2 mmol), and 1-hydroxybenzotriazole (0.306 g, 2 mmol) were stirred together in dichloromethane (10 ml) at room temperature for 30 minutes. The mixture was then treated with {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (0.314 g, 1.5 mmol) and the mixture was stirred overnight at room temperature. The mixture was concentrated and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous layer was separated and extracted with more ethyl acetate and then the combined ethyl acetate fractions were washed sequentially with 3 portions of water and then with saturated aqueous sodium chloride solution. Drying over magnesium sulphate and concentration gave a solid residue which was purified by mass-directed automated HPLC to give pure N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-5-oxo-1-(3-pyridinylmethyl)prolinamide (0.031 g).