Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)[CH2:7]1.[CH3:19][Si:20]([CH3:27])([CH3:26])N1C=CN=C1>C1COCC1>[CH3:17][C:2]([O:1][Si:20]([CH3:27])([CH3:26])[CH3:19])([CH3:18])[CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][C:8]2([CH2:15][CH2:14][CH2:13][C:12](=[O:16])[CH2:11]2)[CH2:7]1
Reactant: C[Si](C)(C)n1ccnc1
Reactant: CC(C)(O)CCCC1CCC2(CCCC(=O)C2)C1
Solvent: C1CCOC1
Product: CC(C)(CCCC1CCC2(CCCC(=O)C2)C1)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of a 2-(4-hydroxy-4-methylpentyl)-spiro[4.5]decan-7-one (19a) (50 mg, 0.198 mmol) in dry THF (1 mL) was added 1-(trimethylsilyl)-imidazole (0.146 mL, 0.99 mmol). The reaction mixture was stirred at room temperature for 4 hours and the solvent was then removed in vacuo. The resulting residue was purified over silica (petroleum ether/EtOAc, 95:5) to afford the desired product which was used directly for the next reaction step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)C(C)C)(C)C.Br[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]1[CH2:11][CH2:12][N:13]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:14][CH2:15]1
Reactant: COc1ccc(C2CCNCC2)c(F)c1
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN1CCC(c2ccc(OC)cc2F)CC1

Procedure:
To a stirred solution of 4-(2-fluoro-4-methoxyphenyl)piperidine (40 mg; 0.19 mmol) in DMF (1 mL) under an atmosphere of N2 was added N,N-diisopropylethylamine (33 μL; 0.19 mmol), followed by ethyl bromoacetate (21 μL; 0.19 mmol). The resultant solution was stirred at room temperature for 2.5 h. The reaction was partitioned between EtOAc (10 mL) and H2O (10 mL). The aqueous layer was extracted with EtOAc (3×10 mL) and the combined extracts were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash silica gel chromatography (0-25% EtOAc/hexanes gradient) to afford ethyl [4-(2-fluoro-4-methoxyphenyl)piperidin-1-yl]acetate as a colorless oil. LCMS=295.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.14 (t, J=8.7 Hz, 1 H), 6.65 (dd, J=8.5, 2.5 Hz, 1 H), 6.58 (dd, J=12.43, 2.5 Hz, 1 H), 4.20 (q, J=7.1 Hz, 2 H), 3.77 (s, 3 H), 3.26 (s, 2H), 3.06 (d, J=11.4 Hz, 2 H), 2.80 (tt, J=12.1, 3.7 Hz, 1 H), 2.32 (t, J=11.2 Hz, 2 H), 1.87 (qd, J=12.3, 3.3 Hz, 2 H), 1.78 (d, J=12.1 Hz, 2 H), 1.29 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:13]2[C:8](=[C:9]([OH:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[CH2:15](I)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH2:15]([O:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH:12]=[CH:11][CH:10]=[C:9]2[OH:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCI
Reactant: Oc1cccc2c(O)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCOc1cccc2c(O)cccc12
Reaction time: 4 h

Procedure:
12 g (0.3 Mol) sodium hydroxide are dissolved while heating in 500 ml ethanol and a solution of 25 g (0.15 Mol) 1,5-dihydroxynaphthalene 97% is added to the cooled solution within 20 minutes. Afterwards 40.23 g (0.15 Mol) n-decyl iodide is added dropwise within 20 minutes and it is subsequently boiled for 4 hours under reflux. After aspiration of the inorganic residue, the filtrate is concentrated in a vacuum and the dark-brown, semi-crystalline residue is purified by column chromatography on silica gel 60 (Merck). Mobile solvent: toluol/methanol=7:1. After recrystallization from n-heptane the corresponding eluate yields 11.5 g (25.3% of the theroretical yield) product, light-brown crystals, Fp 85°-87° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([OH:16])=O)[O:10][C:11]=1[CH2:12][CH3:13].[NH2:18][C@@H:19]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40])[CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:8]=[C:9]([C:14]([NH:18][C@@H:19]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:39]([F:42])([F:40])[F:41])[CH2:20][N:21]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]2=[O:31])=[O:16])[O:10][C:11]=1[CH2:12][CH3:13]
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Reactant: CCc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1oc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.9 %

Procedure:
To a solution of 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-furancarboxylic acid (145 mg, 0.57 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (219 mg, 0.57 mmol) [prepared according to Preparation 6] and N,N-diisopropylethylamine (0.50 ml, 2.85 mmol) in dichloromethane (4.6 ml) at 25° C. was added bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (292 mg, 0.63 mmol) in one portion. The solution stirred at 25° C. for 1 h and was then dry loaded onto silica and purified via column chromatography (silica, 30-70% EtOAc in hexanes) yielding 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-N-((1S)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-{[2-(trifluoromethyl)phenyl]methyl}ethyl)-5-ethyl-2-furancarboxamide (250 mg, 0.41 mmol, 71% yield) as a white solid: LCMS (ES) m/e 585, 587 (M, M+2)+.
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH2:6]([C:8]1([CH2:17][CH3:18])[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10](=[O:16])[CH2:9]1)[CH3:7].[NH4+].[Cl-]>CCOCC>[CH2:3]([C:10]1([OH:16])[CH2:11][C:12]([CH3:14])([CH3:15])[CH2:13][C:8]([CH2:6][CH3:7])([CH2:17][CH3:18])[CH2:9]1)[CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: CCC1(CC)CC(=O)CC(C)(C)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC1(O)CC(C)(C)CC(CC)(CC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a stirred 1 M etheral solution of allylmagnesium bromide (20 ml, 20 mmol) was added dropwise a solution of 3,3-diethyl-5,5-dimethylcyclohexanone (25) (1.47 g, 8.06 mmol) in dry ether (5 ml). The mixture was stirred for 1 h at ambient temperature and boiled at reflux for 10 min. Then it was cooled with ice water and treated with saturated aqueous NH4Cl (40 ml). The organic layer was separated and washed with water and brine. After drying over anhydrous MgSO4, the solution was concentrated in vacuo. The residue was purified by column chromatography on silica gel (light petroleum ether). A fraction with Rf 0.7 (Hexane:EtOAc, 13:2) was collected. Evaporation of the solvent afforded 26 (1.35 g, 74%) as a colorless oil. 1H NMR (CDCl3, TMS): 0.74 (6H, t, 7 Hz, 2CH3 of ethyl); 0.88 (3H, s, 5-CH3eq); 1.19 (3H, s, 5-CH3ax); 0.80-2.05 (10H, m, 2,4,6-CH2 and 2CH2 of ethyl); 2.14 (2H, d, 7 Hz, CH2C═); 4.95-5.30 (2H, m, ═CH2) and 5.65-6.20 ppm (1H, m, ═CH).
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]2[N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:18][C:17]=1[F:35])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:22][C:20]1[C:19]([O:23][C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:18][C:17]([F:35])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(O[C@H]2CCCC[C@H]2n2ccnc2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(O[C@H]2CCCC[C@@H]2n2ccnc2)cc1F
Yield: 104.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the tert-butyl[(5-chloro-2-fluoro-4-{[(1S*,2R*)-2-(1H-imidazol-1-yl)cyclohexyl]oxy}phenyl)sulfonyl](1,3-thiazol-4-yl)carbamic acid (340 mg, 0.610 mmol) prepared in Example 13a, trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (292 mg, 67%) as a colorless solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]([C:27]#[N:28])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]([CH3:20])[CH3:19])[CH2:10][CH:9]1[C:29]([O:31][CH2:32][CH3:33])=[O:30])C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[C:27]([C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:15][CH2:14][N:11]1[CH2:12][CH2:13][NH:8][CH:9]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:10]1)#[N:28]
Reactant: CCOC(=O)C1CN(CCCC(C#N)(c2ccccc2)C(C)C)CCN1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1CN(CCCC(C#N)(c2ccccc2)C(C)C)CCN1
Yield: 93.4 %

Procedure:
Ethyl 1-benzyl-4-(4-cyano-5-methyl-4-phenylhexyl)-2-piperazinecarboxylate (857 mg) was dissolved in ethanol (15 ml), and 770 mg of 10% Pd-C was added. After replacing the atmosphere with hydrogen, the mixture was stirred. After completion of the reaction, the solution was evaporated, to give 639 mg (93%) of the title compound as a crude product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[C:13]3[C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)=[C:5]([N+:32]([O-])=O)[CH:4]=1)#[N:2].[CH2:35](OC=C(C#N)C#N)C.CC(C)=O>C(O)C.C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]2[N:9]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=3)[CH:35]=[N:32][C:5]=2[CH:4]=1)#[N:2]
Reactant: CCOC=C(C#N)C#N
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(Nc4ccc(C#N)cc4[N+](=O)[O-])cc23)CC1
Solvent: ClCCl
Solvent: CCO
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc(-n4cnc5cc(C#N)ccc54)cc23)CC1
Yield: 10 %

Procedure:
5-(4-Cyano-2-nitrophenyl)amino-3-(N-t-butoxycarbonyl-1,2,5,6-tetrahydropyrid-4-yl)-1H-indole was used. Reduction was by aqueous FeSO4 in ethanol, the cyclization reaction used ethoxymethylene malononitrile, and the cyclization reaction was heated for 56 hours. Chromatography using 5% acetone in methylene chloride afforded the title compound (10%) as a brown foam: Rf =0.5 in 5% acetone in methylene chloride; HRMS calculated for C26H25N5O2 439.2011, found 439.1999.
Reaction SMILES: [CH2:1]1[CH2:7][S:4](=[O:6])(=[O:5])[O:3][CH2:2]1.[CH:8]1([NH2:11])[CH2:10][CH2:9]1>C1COCC1>[CH:8]1([NH:11][CH2:2][CH2:1][CH2:7][S:4]([OH:3])(=[O:6])=[O:5])[CH2:10][CH2:9]1
Reactant: NC1CC1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: O=S(=O)(O)CCCNC1CC1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 16.6 %

Procedure:
To a solution of 1,3-propane sultone (2.246 g, 18.39 mmol) in THF (20.0 mL) was added cyclopropanamine (1.214 mL, 17.51 mmol) at room temperature. Upon completion of addition, the reaction mixture was stirred at 40° C. for 30 min, at which point the mixture became a thick white paste. At the conclusion of this period, the reaction mixture was vigorously stirred at 65° C. for 2 h. After cooling to room temperature, the resulting solid was collected by filtration to afford the tilted compound (0.522 g, 17% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (br. s, 1H), 3.12 (t, J=6.9 Hz, 2H), 2.72-2.63 (m, 1H), 2.60 (t, J=6.8 Hz, 2H), 2.51-2.46 (m, 1H), 1.97-1.85 (m, 2H), 0.79-0.70 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[NH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:40][C:39]([F:41])([F:42])[C:36]1[CH:35]=[CH:34][C:33]([NH:32][C:28]([CH:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:38][CH:37]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
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: ClCCl
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(F)(F)F)cc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 14.5 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (0.2 g, 0.43 mmol) was reacted with 4-aminobenzotrifluoride (Alfa) (0.14 g, 0.86 mmol), HATU (0.29 g, 0.77 mmol) and iPr2NEt (0.15 mL, 0.86 mmol) in CH2Cl2 at room temperature to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (4-trifluoromethyl-phenyl)-amide as a white solid (38 mg, 15%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:35]2[CH:36]=[C:37]3[C:41](=[CH:42][CH:43]=2)[NH:40][N:39]=[CH:38]3)O1.COCCOC>C(Cl)Cl.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[NH:40]1[C:41]2[C:37](=[CH:36][C:35]([C:2]3[CH:3]=[CH:4][N:5]4[C:10]([C:11]=3[CH3:12])=[C:9]([CH:13]3[CH2:15][CH2:14]3)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]4=[O:20])=[CH:43][CH:42]=2)[CH:38]=[N:39]1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc4[nH]ncc4c3)ccn2c1=O
Temperature: 150 °C
Yield: 73.3 %

Procedure:
Methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol), cesium carbonate (335 mg, 1.03 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (92 mg, 0.38 mmol) were added to a mixture of 1,2-dimethoxyethane (3 mL) and water (1 mL). The mixture was degassed with argon. 1,1′-Bis-(diphenylphosphino)-ferrocene) palladium dichloride (28 mg, 0.03 mmol) was added. The reaction mixture was heated at 150° C. in a microwave oven under argon atmosphere for 0.25 h. The reaction mixture was cooled. The mixture was diluted with DCM (3 mL) and water was added (3 mL). The layers were separated using a phase separator and the aqueous layer was extracted with DCM (2×5 mL). The combined organic layers were concentrated in vacuum. The crude product was purified by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) and dried in vacuum to afford the title compound as a yellow solid (93 mg, 72%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:7][NH2:8])[S:5][CH:6]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29](O)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][N:20]([C:23]2[S:24][C:25]([C:29]([NH:8][CH2:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=3)=[O:30])=[C:26]([CH3:28])[N:27]=2)[C:19](=[O:32])[CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Cc1nc(-n2ccc(OCc3ccccc3)cc2=O)sc1C(=O)O
Reactant: Cc1csc(CN)c1
Product: Cc1csc(CNC(=O)c2sc(-n3ccc(OCc4ccccc4)cc3=O)nc2C)c1
Yield: 46 %

Procedure:
Following the procedure as described in Example 22, making variation only as required to use (4-methylthiophen-2-yl)methanamine in place of benzo[b]thiophen-2-ylmethanamine to react with 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 46% yield: 1H NMR (300 MHz, DMSO-d6) δ 8.83 (t, J=5.8 Hz, 1H), 8.60 (d, J=8.1 Hz, 1H), 7.50-7.31 (m, 5H), 6.91 (s, 1H), 6.77 (s, 1H), 6.38 (dd, J=8.1, 2.6 Hz, 1H), 6.22 (d, J=2.6 Hz, 1H), 5.15 (s, 2H), 4.46 (d, J=5.7 Hz, 2H), 2.53 (s, 3H), 2.12 (s, 3H); MS (ES+) m/z 452.2 (M+1).
Reaction SMILES: [C:1]1([C@H:7]([CH2:11][CH2:12][OH:13])C(O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:14]([O-])=O.[Na+]>OS(O)(=O)=O>[C:1]1([C@@H:7]([NH2:14])[CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=N[O-]
Reactant: O=C(O)[C@@H](CCO)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@@H](CCO)c1ccccc1
Temperature: 2.5 °C

Procedure:
The hydrazide of (S)-2-phenyl-4-hydroxybutanoic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (S)-1-phenyl-3-hydroxypropylamine is isolated as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:21]1([S:27]([Cl:30])(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>>[ClH:30].[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=3)[N:10]([S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CC=C(c2c[nH]c3ccc(C(F)(F)F)cc23)CC1
Agent: Cl
Product: CN1CC=C(c2cn(S(=O)(=O)c3ccccc3)c3ccc(C(F)(F)F)cc23)CC1

Procedure:
(14.9 mg, 46%); from 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-trifluoromethyl-1H-indole (Example 4i, 20 mg, 0.071 mmol) and phenylsulfonyl chloride (18.9 mg, 0.107 mmol). HRMS-FAB+ for C21H19N2O2SF3.HCl, calculated MH+ (--HCl): 421.11975; found: 421.11923.
Reaction SMILES: Br[C:2]1[C:3]([C:8]([NH2:10])=O)=[N:4][N:5]([CH3:7])[CH:6]=1.CN(C=O)C.S(Cl)(Cl)=O.[Cl:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[C:22]=1[C@H:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38](B3OC(C)(C)C(C)(C)O3)[CH:39]=2)[NH:34][CH:33]=1)[CH3:31].C([O-])([O-])=O.[K+].[K+].O>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[Cl:20][C:21]1[C:26]([F:27])=[CH:25][CH:24]=[C:23]([O:28][CH3:29])[C:22]=1[C@H:30]([C:32]1[C:40]2[C:35](=[N:36][CH:37]=[C:38]([C:2]3[C:3]([C:8]#[N:10])=[N:4][N:5]([CH3:7])[CH:6]=3)[CH:39]=2)[NH:34][CH:33]=1)[CH3:31]
Reactant: Cn1cc(Br)c(C(N)=O)n1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(-c3cn(C)nc3C#N)cc12
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-1-methyl-1H-pyrazole-3-carboxamide (10.0 mg, 0.0490 mmol) in DMF (2 mL, 20 mmol) was added thionyl chloride (0.1 mL, 1 mmol) at 0° C., and the mixture was allowed to warm to rt. The material was extracted with EtOAc, and washed with sat. NaHCO3 (3×). The organic layer was concentrated in vacuo. 3-[(S)-1-(2-Chloro-3-fluoro-6-methoxyphenyl)-ethyl]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (10.0 mg, 0.0232 mmol), (1,1′bis-(diphenylphosphino)-ferrocene) palladium dichloride (1.79 mg, 0.00245 mmol), K2CO3 (10.0 mg, 0.0724 mmol) and 4:1 dioxane:H2O (1 mL, 10 mmol) were added, and the mixture was heated in a microwave reactor at 100° C. for 30 min. The solution was used directly for HPLC purification, and the fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. 1H NMR (400 MHz, CD3OD): δ=1.80 (d, J=7.3 Hz, 3H), 3.72 (br. s., 3H), 4.00 (s, 3H), 5.15 (q, J=6.7 Hz, 1H), 6.90 (dd, J=9.1, 4.3 Hz, 1H), 7.05 (t, J=8.8 Hz, 1H), 7.37 (d, J=1.3 Hz, 1H), 7.82 (s, 1H), 7.98 (s, 1H), 8.31 (d, J=2.0 Hz, 1H). MS (ES+): m/z=410.05/412.06 (100/50) [MH+]. HPLC: tR=4.08 min (polar—5 min, ZQ3).
Reaction SMILES: [O:1]1[CH2:5]C[CH2:3][CH2:2]1.[C:6]([C:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:12]([CH3:29])[NH:11][C:10]=1[CH3:30])(=[O:8])[CH3:7].[H-].[Na+].ClCOCC>C1C=CC=CC=1.CC(C)=O.C(O)(=O)C>[C:6]([C:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=2)[C:13]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:12]([CH3:29])[N:11]([CH2:5][O:1][CH2:2][CH3:3])[C:10]=1[CH3:30])(=[O:8])[CH3:7]
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(C)=O)C1c1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: c1ccccc1
Product: CCOCN1C(C)=C(C(C)=O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OCC)=C1C
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
In 7 ml. of tetrahydrofuran was dissolved 0.5 g. of ethyl 3-acetyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine- 5-carboxylate and after adding to the solution 0.2 g. of a 50% oil dispersion of sodium hydride, the mixture was stirred for 30 minutes at room temperature. After cooling the mixture to -10° C., 0.5 ml. of chloromethoxyethane was added thereto, the temperature of the mixture was elevated to room temperature over a period of about 20 minutes, and after 15 minutes the mixture was cooled again to -10° C. Then, after adding to the reaction product 0.5 ml. of glacial acetic acid and 20 ml. of water, the product was extracted three times each time with 5 ml. of ether. The extracts were combined, washed with 5 ml. of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then ether was distilled away. The residue formed was subjected to a silica gel column chromatography, using a 10:1 benzene-acetone mixed solvent as an eluant, the effluent was examined by a thin layer chromatography, and then the effluent of the main fraction was concentrated. By recrystallizing the residue thus obtained from a 10:1 benzene-hexane mixed solvent, 0.45 g. of faint yellow acicular crystals of ethyl 3-acetyl-1-ethoxymethyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-5-carboxylate melting at 110°-111° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9]C(=O)C(C)(C)C)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.O.N1C=CC=CC=1.[OH-].[Na+]>Cl>[Cl:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: Nc1nc(Cl)ccc1Cl
Temperature: 115 °C

Procedure:
A slurry of N-(3,6-dichloropyridin-2-yl)pivalamide (1.83 g, 7.41 mmol) in 75 mL 5N aq HCl with water cooled reflux pyridine was heated in a 115° C. bath overnight, to give a clear yellow solution. The reaction mixture was cooled and poured onto ice, and was basified with 10 N NaOH. The resulting white precipitate was extracted with DCM, and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vauco to give 3,6-dichloropyridin-2-amine as an off-white solid. MS (ESI) m/z: calculated: 162.0; Observed: 163.0 (M++1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].C1C(=O)N([I:18])C(=O)C1>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:18])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1N
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: CC(=O)c1cc(I)ccc1N
Temperature: 0 °C

Procedure:
A flask charged with 1-(2-aminophenyl)ethanone (405 mg) and DCM (20 mL) was cooled in an ice/water bath and NIS (675 mg) was added in three portions. The reaction was stirred at 0° C. The reaction mixture was diluted with 30 mL DCM, washed with sat. aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by preparative RP-HPLC, affording the title compound. MS (ESI+): m/z 262.06 (MH+). 1H NMR (400 MHz, CDCl3): δ 7.94 (s, 1H), 7.44 (d, J=8.8 Hz, 1H), 6.43 (d, J=8.8 Hz, 1H), 6.32 (br, 2H), 2.53 (s, 3H).