Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31].Cl>C(Cl)Cl>[CH3:29][S:30]([O:1][CH2:2][CH2:3][N:4]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=1)[CH2:17][C:18]([F:19])([F:20])[F:21])(=[O:32])=[O:31]
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(CC(F)(F)F)c1ccc(C#N)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.104 g, 0.333 mmol) in CH2Cl2 (3 mL) at 0° C. was added Et3N (0.07 mL, 0.5 mmol), followed by MsCl (0.03 mL, 0.37 mmol). The resulting mixture was stirred 12 h, gradually warming to rt. The mixture was poured into 10% v/v HCl and the layers were separated. The organic layer was washed (sat'd NaHCO3, water, brine), dried over Na2SO4, filtered and concentrated to a colorless film (0.122 g), which was used without further purification: 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=8.8 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.99 (dd, J=8.7, 2.7 Hz, 1H), 4.43 (t, J=5.7 Hz, 2H), 4.10 (q, J=8.5 Hz, 2H), 3.95 (t, J=5.7 Hz, 2H), 3.02 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12].FCC(C1C=CC=CC=1)=O.[NH2:27][C:28]1[C:32]([C:33]#[N:34])=[CH:31][NH:30][N:29]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]2[N:30]=[CH:31][C:32]([C:33]#[N:34])=[C:28]2[N:27]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1F
Reactant: N#Cc1c[nH]nc1N
Agent: O=C(CF)c1ccccc1
Product: N#Cc1cnn2c(C(F)(F)F)cc(-c3ccccc3F)nc12
Yield: 27.1 %

Procedure:
Reaction of 1-(2-fluoro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (234 mg, 1.0 mmol), prepared from commercially available 2-fluoro-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a light yellow solid (83 mg, 27%). MS (ISP) 307.1 [(M+H)+]; mp 165° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:19])[C:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([N:30]2[CH:34]=[CH:33][CH:32]=[N:31]2)=[C:26]([CH:29]=1)[CH:27]=O.OOS([O-])=O.[K+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[C:15]([N:14]1[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[N:3][C:2]([NH2:1])=[N:7][CH:6]=3)=[CH:9][C:10]=2[N:19]=[C:27]1[C:26]1[CH:29]=[C:22]([O:21][CH3:20])[CH:23]=[CH:24][C:25]=1[N:30]1[CH:34]=[CH:33][CH:32]=[N:31]1)([CH3:16])([CH3:18])[CH3:17]
Reactant: COc1ccc(-n2cccn2)c(C=O)c1
Reactant: CC(C)(C)Nc1ccc(-c2cnc(N)nc2)cc1N
Agent: O=S([O-])([O-])=S
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-n2cccn2)c(-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)c1
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 4-(2-amino-pyrimidin-5-yl)-N1-tert-butyl-benzene-1,2-diamine (50 mg, 0.19 mmol) in DMF (10 mL) is added 5-methoxy-2-(1H-pyrazol-1-yl)benzaldehyde (59 mg, 0.29 mmol) at room temperature. Oxone (119 mg, 0.19 mmol) in H2O (2 mL) is added and the solution is stirred for 1 hour. Saturated sodium thiosulfate solution (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL) and H2O (5 mL). The combined organic layer is dried with MgSO4, filtered and concentrated. The residue is purified by silica gel flash column chromatography eluting with 10% MeOH in CH2Cl2 to afford the title compound (56 mg, 67%) as a white solid. LCMS (ESMS): m/z 440.20 (M++1)
Reaction SMILES: [F:1][C:2]1[C:3]([NH:20][CH3:21])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=2[O:18][CH3:19])=[N:6][CH:7]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O.CCOC(C)=O>[F:1][C:2]1[C:3]([NH:20][CH3:21])=[N:4][C:5]([NH:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:15])=[CH:11][C:10]=2[O:18][CH3:19])=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CNc1nc(Nc2ccc(C(=O)O)cc2OC)ncc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNc1nc(Nc2ccc(C(=O)N3CCOCC3)cc2OC)ncc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 100 mg 4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxybenzoic acid, 47 μL morpholine, 205 mg HATU, 188 mL diisopropylethylamine in 1 mL of dimethylformamide was stirred at room temperature overnight. The reaction was checked by LCMS and found to be complete. The reaction was diluted with EtOAc, and the organic layer washed with saturated NaHCO3 and brine. The organic layer was concentrated and purified by preparative reverse phase HPLC to yield 12 mg of (4-(5-fluoro-4-(methylamino)pyrimidin-2-ylamino)-3-methoxyphenyl)(morpholino)methanone.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH:4]=[C:5]([C:10]([CH2:12][O:13][CH2:14][CH2:15][N:16]1[C:20](=[O:21])[C:19]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:18]2[C:17]1=[O:26])=O)[C:6]([O:8][CH3:9])=[O:7].[CH2:31]([O:33][C:34](=[O:39])/[CH:35]=[C:36](\[NH2:38])/[CH3:37])[CH3:32]>CC(O)C>[Cl:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH:4]1[C:35]([C:34]([O:33][CH2:31][CH3:32])=[O:39])=[C:36]([CH3:37])[NH:38][C:10]([CH2:12][O:13][CH2:14][CH2:15][N:16]2[C:20](=[O:21])[C:19]3[C:18](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]2=[O:26])=[C:5]1[C:6]([O:8][CH3:9])=[O:7]
Reactant: CCOC(=O)/C=C(/C)N
Reactant: COC(=O)C(=Cc1ccccc1Cl)C(=O)COCCN1C(=O)c2ccccc2C1=O
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(COCCN2C(=O)c3ccccc3C2=O)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 15 °C
Reaction time: 20 h

Procedure:
87 g of methyl 2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate was dissolved in 102 ml of 2-propanol at 80° C. 33.1 g of ethyl-3-aminocrotonate was added and the mixture was heated at the same temperature for 16 hours. The mixture was evaporated to dryness. The residue was dissolved in 153 ml of glacial acetic acid at 80° C. The mixture was cooled to 15° C. and stirred at the same temperature for 20 hours. The solid was filtered off and washed with 78 ml of glacial acetic acid. The solid was suspended in 150 ml of methanol and agitated at 60° C. for 30 minutes. The solid was cooled to 20° C. and filtered off, washed with 30 ml of methanol and dried. The product was recrystallized from ethyl acetate.
Reaction SMILES: [K:1].[OH:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[C:25](O)(=[O:27])[CH3:26].C(OC(=O)C)(=O)C.S(=O)(=O)(O)O>C(OCC)C>[K:1].[C:25]([O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=[O:22])=[O:23])=[CH:17][CH:16]=2)=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])(=[O:27])[CH3:26]
Reactant: CC(=O)O
Reactant: COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)O)cc2)ccc1O
Agent: O=S(=O)(O)O
Agent: [K]
Solvent: CC(=O)OC(C)=O
Solvent: CCOCC
Product: COC(=O)c1cc(C=Cc2ccc(S(=O)(=O)O)cc2)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Methyl 2-hydroxy-5-[2-(4-sulfophenyl)ethenyl]benzoate potassium salt (57.5 g, 0.15 mol), acetic acid (35 ml) and acetic anhydride (142 ml) were refluxed until the major part of the solids had dissolved, and then more acetic anhydride (142 ml) and sulfuric acid (1 ml) were added. After boiling for 1.5 h, the mixture was cooled to room temperature and diethyl ether was added to complete precipitation. After filtration and drying, the yield was 43.4 g (69%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:22][C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2ncnc3cc(N)ncc23)c1
Temperature: 190 °C
Reaction time: 1.5 h
Yield: 43.1 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (226 mg, 1.18 mmol) (described in the previous experimental) and m-anisidine (1.00 mL, 8.90 mmol) is stirred under N2 at 190° C. for 1.5 h. The resulting product is chromatographed over silica gel (5-7% EtOH/EtOAc) to give 7-amino-4-(3-methoxyanilino)pyrido[4,3-d]pyrimidine (136 mg, 43%) as a light brown solid. 1H NMR (DMSO) δ 9.78 (1H, brs), 9.34 (1H, s), 8.40 (1H, s), 7.50 (1H, brs), 7.44 (1H, d, J=8.0 Hz), 7.28 (1H, t, J=8.2 Hz), 6.71 (1H, dd, J=8.2, 2.3 Hz), 6.61 (2H, brs), 6.45 (1H, s), 3.77 (3H, s).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][S:16][C:10]=2S[CH2:8][CH2:7]1.OO.[S:19]([O-:22])(O)=[O:20].[Na+]>C(O)=O>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][S:16][C:10]=2[S:19](=[O:22])(=[O:20])[CH2:8][CH2:7]1
Reactant: O=C1c2ccsc2SCCN1CCCCCl
Reactant: O=S([O-])O
Agent: OO
Agent: [Na+]
Solvent: O=CO
Product: O=C1c2ccsc2S(=O)(=O)CCN1CCCCCl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3.4 g of 4-(4-chlorobutyl)-2,3-dihydrothieno[3,2-f]-1,4-thiazepin-5(4H)-one in 100 ml of formic acid was added 2.9 ml of 30% hydrogen peroxide and the mixture was stirred for 3 hours at room temperature. Then, the mixture was poured into ca. 3% sodium hydrogensulfite solution and extracted with chloroform. The extract was washed with water, dried over magnesium sulfate and the solvent was distilled off to give 3.5 g of 4-(4-chlorobutyl)-2,3-dihydrothieno-[3,2-f]1,4-thiazepin-5(4H)-one 1,1-dioxide as a pale yellow oil.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[CH:12]=O.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.CCCCCC.C(OCC)(=O)C>[Br:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[CH2:12][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=Cc1ccncc1Br
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Brc1cnccc1CN1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
Acetic acid (0.1 mL) was added to a stirred solution of 3-bromo-pyridine-4-carbaldehyde (220 mg, 1.18 mmol) and pyrrolidine (0.11 mL, 1.34 mmol) in DCE (15 mL) under nitrogen atmosphere and stirred at room temperature for 2 hours. This was followed by addition of NaBH(OAc)3 (342 mg, 1.612 mmol) at 0° C. over a period of 10 minutes. The resulting reaction mass was stirred for 12 hours at room temperature. The reaction was monitored by TLC (30% ethyl acetate in hexane). The reaction mixture was washed with NaHCO3 solution and extracted using ethyl acetate. The organic layer was dried over Na2SO4 and concentrated to afford 275 mg of the product (98.2% yield).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1[O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=1[C:32](=[O:34])[CH3:33])(=O)C.[O:35]1[CH:39]=[CH:38][C:37]2[CH:40]=[C:41]([CH:44]=O)[CH:42]=[CH:43][C:36]1=2.[OH-].[K+]>C(O)C.[Pt]=O>[C@@H:6]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[C:26]=2[C:32](=[O:34])[CH:33]=[CH:44][C:41]2[CH:42]=[CH:43][C:36]3[O:35][CH:39]=[CH:38][C:37]=3[CH:40]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@H](Oc2cccc(O)c2C(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=Cc1ccc2occc2c1
Agent: O=[Pt]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(C=Cc1ccc2occc2c1)c1c(O)cccc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
2'-(2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyloxy)-6'-hydroxyacetophenone (5 g) and benzo[b]furan-5-carbaldehyde (1.81 g) are (i) treated in the same manner as in Example 1 to give crude 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)acrylophenone, which is dissolved in a mixture of ethanol (50 ml) and a 10% aqueous potassium hydroxide solution (10 ml). The mixture is subjected to catalytic hydrogenation by using as a catalyst platinum oxide (120 mg) under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is neutralized with a 10% hydrochloric acid under ice-cooling, and concentrated under reduced pressure. To the residue is added ethyl acetate, and the mixture is stirred, and the organic layer is collected; (ii) treated in the same manner as in Example 1 to give crude 2'-(β-D-glucopyranosyloxy)-6'-hydroxy-3-(5-benzo[b]furanyl)acrylophenone, which is dissolved in a mixture of ethanol (50 ml) and a 10% aqueous potassium hydroxide solution (10 ml). To the solution is added 4-N,N-diemethylaminopyridine (2.5 g) and the mixture is subjected to catalytic hydrogenation by using as a catalyst 10% palladium-carbon (1.1 g) under atmospheric pressure. The catalyst is removed by filtration, and the filtrate is neutralized with a 10% hydrochloric acid under ice-cooling, and concentrated under reduced pressure. To the residue is added ethyl acetate, and the mixture is stirred, and the organic layer is collected; or (iii) treated in the same manner as in Example 2, and the organic layer is collected.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[CH:6][CH:5]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:44])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:44])[NH:14]3)=[CH:8][CH:9]=1
Reactant: CC(=O)O
Reactant: FC(F)(F)Oc1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
To the suspension of 4-(4-trifluoromethoxy-phenyl)-1H-indole (4.93 g, 17.78 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (261 mL) was added pyridinium tribromide (17.06 g, 53.34 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (105 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (2.05 g, 39%) as a tan solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O1CCCC1>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCOCC2)nc1
Temperature: 25 °C

Procedure:
To a solution of 20 g (126 mmol) of 2-chloro-5-nitropyridine in 150 ml tetrahydrofuran were added dropwise 27 ml (315 mmol) morpholine within 10 min. The reaction mixture was refluxed for additional 2 h. After cooling to room temperature, the solvent was removed in vacuo and the residue was re-dissolved in 200 ml ethyl acetate. The organic phase was washed with 200 ml 1 N sodium bicarbonate solution, dried (magnesium sulfate) and evaporated to give 27.3 g (quantitative) of the title compound as a yellow solid. M.p. 142-143° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10]O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:10][C@@H:9]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H](CO)Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@@H]1Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
(2S)-2-(tert-Butoxycarbonylamino)-3-phenyl-1-propanol (2.0 g, 8.0 mmol) in anhydrous THF (50 mL) at 0° C. under a dry N2 atmosphere was treated with triphenylphosphine (2.5 g, 9.5 mmol) and diethyl azodicarboxylate (1.66 g, 9.5 mmol). The mixture was stirred at 0° C. for 1 hour, allowed to warm to ambient temperature and stirred overnight. The mixture was partitioned between water (50 mL) and ethyl acetate (2×50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexanes:CH2Cl2, 1:1) to provide the title compound as a colorless oil (1.4 g, 76%). Rf=0.54 (hexanes:ethyl acetate,2:1); 1H NMR (CDCl3) δ 7.32-7.19 (m, 5H), 3.01-2.90 (m, 1H), 2.70-2.56 (m, 2H), 2.30 (m, 1H), 2.03 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[S:14][N:13]=[C:12]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[OH-].[K+].[I:27]I.S(=O)(O)[O-].[Na+]>CN(C=O)C>[I:27][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]3[S:14][N:13]=[C:12]([NH:15][CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[N:11]=3)[CH:5]=2)[NH:1][CH:2]=1
Reactant: COc1ccc(CNc2nsc(-c3ccc4[nH]ccc4c3)n2)cc1
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nsc(-c3ccc4[nH]cc(I)c4c3)n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of 5-(1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (0.67 g, 1.99 mmol) in DMF (7 mL) was added KOH pellets (0.325 g, 5.95 mmol) followed by I2 (1 g, 3.98 mmol) in portions at 0° C. The reaction was stirred for 1 h at RT. 10% aq sodium bisulphite solution was added to the mixture and solid precipitate was obtained. The suspension was filtered and washed with H2O (2×20 mL) and dried under vacuum to give 5-(3-iodo-1H-indol-5-yl)-N-(4-methoxybenzyl)-1,2,4-thiadiazol-3-amine (800 mg, 87%) as an off brown solid. MS (ESI, pos. ion) m/z: 463.0 (M+1); 1H-NMR (300 MHz, CDCl3): δ 8.72 (brs, 1H), 8.02 (d, J=6 Hz, 1H), 7.77 (d, J=8.4 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.36-7.33 (m, 2H), 6.90 (d, J=8.4 Hz, 1H), 5.43 (m, 1H), 4.63 (d, J=5.7 Hz, 2H), 3.80 (s, 3H).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([CH2:10][C:11]([OH:13])=O)[CH2:3]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:38][C:39]1[CH:44]=[CH:43][C:42]([C:45]([NH2:48])([CH3:47])[CH3:46])=[CH:41][CH:40]=1.C(N(CC)CC)C>CN(C=O)C>[Br:38][C:39]1[CH:40]=[CH:41][C:42]([C:45]([NH:48][C:11](=[O:13])[CH2:10][CH:4]2[CH:5]3[CH2:6][CH2:7][N:2]([CH2:9][CH2:8]3)[CH2:3]2)([CH3:46])[CH3:47])=[CH:43][CH:44]=1
Reactant: O=C(O)CC1CN2CCC1CC2
Reactant: CC(C)(N)c1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)CC1CN2CCC1CC2)c1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 75.7 %

Procedure:
To a solution of 2-(quinuclidin-3-yl)acetic acid hydrochloride (0.97 g, 4.7 mmol) in DMF (30 mL) was added HATU (1.79 g, 4.72 mmol), 2-(4-bromophenyl)propan-2-amine (1.0 g, 4.7 mmol), and triethylamine (3.9 mL, 28 mmol). The resulting mixture was stirred at 60° C. for 16 h. The mixture was concentrated in vacuo, diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4 and evaporated to afford crude product, which was purified by silica gel column chromatography (EtOAc/methanol 50/1 to 3/1) to obtain N-(2-(4-bromophenyl)propan-2-yl)-2-(quinuclidin-3-yl)acetamide as a yellow solid (1.3 g, 76%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[CH3:10]O>>[CH3:10][O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[OH:1]
Reactant: OCc1ccccc1O
Reactant: CO
Product: COCc1ccccc1O
Yield: 58 %

Procedure:
A solution of 2-hydoxybenzyl alcohol (5 g, 40 mmol) in methanol (25 mL) was heated in a sealed vessel at 150° C. for 4 hours. The reaction mixture was then concentrated in vacuo and the residue was purified by fractional distillation (90° C./10 mm Hg) to afford the title compound as a colourless liquid in 58% yield, 3.22 g. LRMS APCI m/z 137 [M−H]−
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(OCC)OCC.[CH2:24]([C:26]1[C:31]([Br:32])=[C:30]([NH2:33])[CH:29]=[CH:28][N:27]=1)[CH3:25].ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>C(O)C.B(F)(F)F.CCOCC>[CH2:24]([C:26]1[C:31]([Br:32])=[C:30]([NH:33][C@H:10]2[CH2:11][CH2:12][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)[CH:29]=[CH:28][N:27]=1)[CH3:25]
Reactant: CCc1nccc(N)c1Br
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: CC(Cl)Cl
Solvent: CCOC(OCC)OCC
Product: CCc1nccc(N[C@H]2CC[C@@H](c3ccccc3)CC2)c1Br
Temperature: 50 °C

Procedure:
3.48 g (20 mmol) of 4-phenylcyclohexanone in 3.3 ml of ethanol are treated with 3.3 ml of triethyl orthoformate and 2 drops of boron trifluoride etherate and warmed at 50° C. for 30 min. After addition of 2.01 g (10mmol) of 2-ethyl-3-bromo-4-aminopyridine the reaction mixture is heated at 135°-140° C. for 3.5-4 hours with simultaneous removal of the low-boiling components by distillation. It is then cooled, 40 ml of dichloroethane, 3.18 g (15 mmol) of sodium triacetoxyborohydride and 0.57 ml (10 mmol) of glacial acetic acid are added, and it is heated at 50°-60° C. for 3 hours; the reaction mixture is then cooled, saturated aqueous sodium hydrogen carbonate solution is added, the 1,2-dichloroethane is evaporated and the reaction product is extracted from the aqueous phase using ethyl acetate. Purification is carried out by column chromatography. Yield: 1.46 g (41%); RF =0.59 (ethyl acetate)
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][N:15]1[C:42]2[C:37](=[CH:38][C:39]([C:43]([NH2:45])=O)=[CH:40][CH:41]=2)[C:17]2([CH2:22][CH2:21][N:20]([C:23](=[O:36])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])[CH2:19][CH2:18]2)[C:16]1=[O:46].N1C=CC=CC=1>O1CCOCC1.O>[CH3:14][N:15]1[C:42]2[C:37](=[CH:38][C:39]([C:43]#[N:45])=[CH:40][CH:41]=2)[C:17]2([CH2:22][CH2:21][N:20]([C:23](=[O:36])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:33])[F:34])[CH2:19][CH2:18]2)[C:16]1=[O:46]
Reactant: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C(N)=O)ccc21
Solvent: O
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN1C(=O)C2(CCN(C(=O)/C=C/c3ccccc3C(F)(F)F)CC2)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of trifluoroacetic anhydride (34 mg, 0.157 mmol) in dioxane (4 mL) was added dropwise to a stirred, ice-cooled solution of (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl)phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carboxamide (60 mg, 0.131 mmol) and pyridine (60 mg, 0.262 mmol). The reaction mixture was stirred at rt overnight. The mixture was diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated to afford the crude product. After purification by preparative HPLC, (E)-1-methyl-2-oxo-1′-(3-(2-(trifluoromethyl) phenyl)acryloyl)spiro[indoline-3,4′-piperidine]-5-carbonitrile was obtained (2.04 mg, 4%). 1H NMR: (400 MHz, CDCl3): δ=1.85 (m, 4H), 3.20 (m, 3H), 3.80-3.90 (m, 2H), 4.10 (m, 1H), 4.35 (m, 1H), 6.75 (m, 1H), 6.85 (m, 1H), 7.40 (m, 2H), 7.50 (m, 1H), 7.55 (m, 1H) 7.65 (m, 2H), 7.90 (m, 1H).