Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][CH:64]1[CH2:69][N:68]([C:70]2[CH:76]=[CH:75][C:73]([NH2:74])=[C:72]([O:77][CH3:78])[CH:71]=2)[CH2:67][CH:66]([CH3:79])[O:65]1>>[CH3:63][CH:64]1[O:65][CH:66]([CH3:79])[CH2:67][N:68]([C:70]2[CH:76]=[CH:75][C:73]([NH:74][C:30]([CH:20]3[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]4([C:12]5[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=5)[NH:15][C:16]4=[O:38])[CH:21]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])=[O:31])=[C:72]([O:77][CH3:78])[CH:71]=2)[CH2:69]1
Reactant: COc1cc(N2CC(C)OC(C)C2)ccc1N
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC(C)OC(C)C2)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 37.4 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.43 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.89 mmol), then reacted with 4-(2,6-dimethylmorpholino)-2-methoxyaniline (Bionet) (0.11 g, 0.44 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2,6-dimethyl-morpholin-4-yl)-2-methoxy-phenyl]-amide as a white solid (Yield 0.11 g, 37%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:19](C(OC(C)(C)C)=O)[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.Cl>C1COCC1>[C:23]([O:22][C:20](=[O:19])[NH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Nc1cnccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.9 %

Procedure:
To a solution of 3-amino-4-chloropyridine (6.56 g, 51 mmol) in THF (46 mL) is added 2 M NaHMDS in THF (50 mL, 100 mmol). After stirring at rt for 15 min BOC2O (10.1 g, 46.4 mmol) in THF (26 mL) is added in one portion and the mixture is stirred for 3 h at rt. 0.1% aqueous HCl (590 mL) is added. The mixture is extracted with EtOAc. The organic layer is dried (Na2SO4), filtered and concentrated. The residue is purified by silica gel chromatography eluting with 0-50% EtOAc in heptane to afford (4-chloro-pyridin-3-yl)-carbamic acid tert-butyl ester (6.78 g, 76%). MS: 229 (M+H); 1H NMR (300 MHz, CDCl3): δ 9.38 (ms 1H), 8.23 (d, 1H), 7.30 (dd, 1H), 6.85 (broad s, 1H), 1.57 (s, 9H).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([OH:27])[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:47]1[CH:51]=[CH:50][CH:49]=[C:48]1[CH2:52]O>C1COCC1>[CH2:13]([O:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[C:24]([O:27][CH2:52][C:48]1[O:47][CH:51]=[CH:50][CH:49]=1)[CH:23]=[CH:22][CH:21]=2)=[O:17])[CH3:14]
Reactant: OCc1ccco1
Reactant: CCOC(=O)c1cc2c(O)cccc2[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(OCc3ccco3)cccc2[nH]1
Reaction time: 2 h

Procedure:
DEAD (2.1 ml, 13.65 mmol) is slowly added to a solution of 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester 79 (2 g, 9.75 mmol), triphenylphosphine (3.58 g, 13.65 mmol) and furan-2-yl-methanol (1.18 ml, 12.26 mmol) in 10 ml of THF, so that the temperature always remained below 30° C. Stirring is continued for 2 hours and the solvent is then evaporated. The crude residue is purified by chromatography (cyclohexane:EtOAc/95:5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([C:28]1[C:29]([N:35]=[CH:36][N:37]([CH3:39])C)=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1)#N.NC1C=C(OCC2C=CC(OC)=CC=2)C=CC=1SC1C=CC(O)=CC=1>>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([S:18][C:19]2[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=2)=[C:2]([NH:1][C:39]2[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[N:30][C:29]=3[N:35]=[CH:36][N:37]=2)[CH:7]=1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Reactant: COc1cccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)c1
Agent: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Product: COc1cccc(COc2ccc(Sc3ccc(O)cc3)c(Nc3ncnc4nc(C)ccc34)c2)c1
Yield: 26 %

Procedure:
The product of Example 31A was reacted with the product of Example 10B using the procedure of Example 10F substituting the product of Example 31A for the product of Example 10E to provide a solid which was triturated with methanol to provide the title compound (24 mg, 26%). 1H NMR (300 MHz, DMSO-D6) δ ppm 9.93 (s, 1H), 9.63 (s, 1H), 8.71 (d, J=8.09 Hz, 1H), 8.55 (s, 1H), 7.53 (d, J=8.09 Hz, 1H), 7.26-7.35 (m, 2H), 7.15 (d, J=8.46 Hz, 1H), 7.07-7.13 (m, 2H), 6.98-7.04 (m, J=5.15 Hz, 2H), 6.96 (s, 1H), 6.90 (dd, J=8.09, 2.57 Hz, 1H), 6.62-6.71 (m, 2H), 5.08 (s, 2H), 3.75 (s, 3H), 2.67 (s, 3H); MS (ESI+) m/z 497.2 (M+H)+ (ESI−) m/z 495.2 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[C:12]([CH3:15])[CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[OH:19][CH2:20][C:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])(C)[CH2:22][CH:23]([CH3:25])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][N:11]=1)[C:8](=[O:16])[N:7]([CH3:17])[C:6]1[CH:18]=[C:2]([O:19][CH2:20][C@@H:21]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH:3]=[CH:4][C:5]2=1
Reactant: CC(C)CC(C)(CO)NC(=O)OC(C)(C)C
Reactant: Cc1cc2c(cn1)c(=O)n(C)c1cc(Cl)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1cc2c(cn1)c(=O)n(C)c1cc(OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)ccc21
Temperature: 100 °C
Yield: 44.2 %

Procedure:
To the stirred solution of 8-chloro-2,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (100 mg, 0.387 mmol) and tert-butyl (1-hydroxy-2,4-dimethylpentan-2-yl)carbamate (168 mg, 0.773 mmol) in toluene (5 mL) was added cesium carbonate (189 mg, 0.580 mmol) and 2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (9.85 mg, 0.023 mmol). The reaction mixture was degassed with argon for 5 minutes and palladium(II) acetate (26 mg, 0.116 mmol) was added. The reaction mixture was heated to 100° C. for 18 h. The reaction mixture was filtered through diatomaceous earth (Celite®) and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography using ethyl acetate-petroleum ether to afford (S)-tert-butyl (1-((2,6-dimethyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.171 mmol, 44% yield) as a dark yellow semi-solid. LC/MS (ESI) m/e 440.6 [(M+H+)+, calcd for C25H34N3O4 440.2]; LC/MS retention time (method D): tR=0.89 min.
Reaction SMILES: Br[C:2]1[N:3]([CH3:24])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=2.[OH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH:11]1([C:10]2[C:9]3[C:4](=[CH:5][C:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:7][CH:8]=3)[N:3]([CH3:24])[C:2]=2[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[OH:25])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Cn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Reactant: OB(O)c1ccccc1O
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Cn1c(-c2ccccc2O)c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Temperature: 100 °C

Procedure:
A solution of tert-butyl 2-bromo-3-cyclohexyl-1-methyl-1H-indole-6-carboxylate (24, 500 mg, 1.27 mmol), 2-hydroxy-phenylboronic acid (211 mg, 1.53 mmol) and potassium carbonate (1.35 g, 12.74 mmol) in 100 mL of 1,2-dimethoxyethane/water (4:1) was thoroughly flushed with argon. Then trans-bis(triphenylphosphine)palladium(II) chloride (0.147 g, 0.127 mmol) was added and the reaction was heated at 100° C. under argon for 12 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethylacetate (EtOAc). Combined organic layers were washed with a saturated solution of NaHCO3 and brine, dried over anhydrous Na2SO4 and filtered. The filtered solution was concentrated under vacuum to give tert-butyl 3-cyclohexyl-2-(2-hydroxyphenyl)-1-methyl-1H-indole-6-carboxylate 25: m/z=406 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[C:3]#[CH:4].[H][H]>[Pd].[O-2].[Al+3].[O-2].[O-2].[Al+3]>[CH3:1][C:2]([OH:11])([CH2:5][CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[CH2:3][CH3:4]
Reactant: C#CC(C)(O)CCC(C)CC
Reactant: [H][H]
Agent: [Pd]
Agent: [Al+3]
Agent: [O-2]
Product: CCC(C)CCC(C)(O)CC
Yield: 91 %

Procedure:
0.5 g of an 0.5% strength palladium/aluminum oxide catalyst is added to 154 g (1 mole) of 3,6-dimethyl-oct-1-yn-3-ol and hydrogenation is carried out at 20°-50° C. and 0.5 bar hydrogen pressure. When hydrogen absorption has ceased (after 6-8 hours), the catalyst is filtered off and the filtrate is fractionated. 145 g of main fraction, boiling at 42°-43° C./0.01 mbar, are obtained; nD25 =1.4345. This corresponds to a yield of 91%. Scent: fresh, floral, lavender-like.
Reaction SMILES: N1CCCCC1.FC(F)OC1C(OC)=CC(C=O)=CC=1OC.C(CC(N[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=O)(O)=O>C1(C)C=CC=CC=1>[C:32]([OH:34])(=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:30]=1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: COc1cc(C=O)cc(OC)c1OC(F)F
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Yield: 163.8 %

Procedure:
Piperidine (110 μL, 1.10 mmol) was added to a suspension of 4-(difluoromethoxy)-3,5-dimethoxybenzaldehyde (200 mg, 1.10 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (233 mg, 1.05 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (4 mL) and water (2 mL) and the solution was acidified with 20% aqueous AcOH. The crude product was collected by filtration and recrystallised from EtOH/water and filtered to afford (E)-2-[[4-(difluoromethoxy)-3,5-dimethoxyphenyl)-1-oxo-2-propenyl]amino]benzoic acid (210 mg, 51%) as a pale yellow crystalline solid; mp 211-215° C.; δH (400 MHz, DMSO-d6) 3.87 (s, 6H, OCH3), 6.87 (t, J=75 Hz, 1H, OCHF2), 6.98 (d, J=15.6 Hz, 1H, CH═CHCO), 7.17 (s, 2H, H2′, H6′), 7.18 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.61 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 8.00 (d, J5,6=8.0 Hz, 1H, H6), 8.61 (d, J3,4=8.0 Hz, 1H, H3), 11.33 (s, 1H, NH), 13.60 (s, 1H, CO2H); δC (100 MHz, DMSO-d6) 56.4, 105.5, 116.8 117.2 (t, J=259 Hz), 120.4, 122.9, 123.1, 129.6, 131.1, 132.9, 134.0, 140.8, 141.1, 152.6, 163.7, 169.4; νmax 1153, 1113, 1224, 1506, 1593, 1694, 2602, 2946 cm−1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([F:12])=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1)[CH3:2].[OH-].[Na+].[Br:15]N1C(=O)CCC1=O>CN(C=O)C>[Br:15][C:5]1[C:6]2[C:7](=[N:8][C:9]([F:12])=[CH:10][CH:11]=2)[N:3]([CH2:1][CH3:2])[CH:4]=1
Reactant: CCn1ccc2ccc(F)nc21
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCn1cc(Br)c2ccc(F)nc21
Yield: 96.6 %

Procedure:
A solution of 1-ethyl-6-fluoro-1H-pyrrolo[2,3-b]pyridine (16.38 g, 99.77 mmol) in DMF (300 mL) is cooled to 15° C. with stirring. To this is added sodium hydroxide (4.39 g, 109.7 mmol), followed by N-bromosuccinimide (19.53 g, 109.7 mmol) portionwise over 5 minutes, and then the reaction is allowed to stir at room temperature overnight. The reaction is poured onto brine (ca. 500 mL) and the product extracted with CHCl3 (ca. 2×300 mL). The combined organic phase is dried over magnesium sulphate, filtered, and concentrated in vacuo to give a brown oil. This is purified by column chromatography on silica, eluting with 0 to 60% DCM in hexane, to give the title compound as a light yellow oil (23.4 g, 96.4 mmol). MS (m/z): 243/245 (M+1).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:14]=1[OH:15])[CH:10]=[O:11])([CH3:6])([CH3:5])[CH3:4].[CH3:20][C:21]([CH3:23])=[O:22].Cl>C(O)C.O>[CH3:20][C:21]([CH:23]=[CH:10][C:9]1[CH:8]=[C:7]([C:3]([CH3:4])([CH3:6])[CH3:5])[C:14]([OH:15])=[C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=1)=[O:22].[C:16]([C:13]1[CH:12]=[C:9]([CH:8]=[C:7]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:14]=1[OH:15])[CH:10]=[O:11])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)=O
Agent: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)C=Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
3,5-di tert.butyl-4-hydroxystyryl methyl ketone was prepared by adding a solution of 8 grams of sodium hydroxide in 100 milliliters of absolute ethanol to a mixture of 23.4 grams of 3,5-di tert.butyl-4-hydroxybenzaldehyde and 58 grams of acetone. The reaction mixture was stirred at room temperature for 14 hours and then at reflux temperature for 71/2 hours. After cooling, it was poured into 500 milliliters of water and the resulting mixture was neutralized by the addition of dilute hydrochloric acid. The sticky solid which precipitated was filtered off and mixed with petroleum ether. Filtration yielded 11 grams of unreacted 3,5-di tert.butyl-4-hydroxybenzaldehyde. From the filtrate was isolated 5.5 grams of the desired product which melted at 101° to 105° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[NH:8][CH2:7][C:6]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][C@@H:30]1[O:32][CH2:31]1>CC(C)=O.C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[S:9](=[O:19])(=[O:18])[N:8]([CH2:28][CH2:29][C@H:30]3[CH2:31][O:32]3)[CH2:7][C:6]=2[CH:20]=1
Reactant: BrCC[C@H]1CO1
Reactant: O=S1(=O)NCc2cc(F)ccc2N1c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: O=S1(=O)N(CC[C@H]2CO2)Cc2cc(F)ccc2N1c1ccccc1F
Temperature: 45 °C
Reaction time: 14 h
Yield: 160 %

Procedure:
A solution 6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.13 g, 0.29 mmol) in acetone (3 mL) was treated with potassium carbonate (0.11 g, 0.81 mmol), (S)-(−)-4-Bromo-1,2-epoxybutane (0.14 mL, 1.41 mmol) and was heated to 45° C. for two h then at room temperature for 14 h. The reaction mixture was diluted with ethyl ether (40 mL) and washed with sat. sodium bicarbonate (2×20 mL), the organic layer was isolated, dried with MgSO4 and evaporated. The crude reaction product was purified by flash chromatography (SiO2, 3-50% ethyl acetate/heptane) to provided 6-fluoro-1-(2-fluorophenyl)-3-{2-[(2S)-oxiran-2-yl]ethyl}-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.17 g, 67%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH:25]1([C:28]2[CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32][CH:33]=2)[CH2:27][CH2:26]1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:32]4[CH:31]=[CH:30][CH:29]=[C:28]([CH:25]5[CH2:27][CH2:26]5)[CH:33]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CC1(C)OB(c2cccc(C3CC3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(-c4cccc(C5CC5)c4)cc32)N=C1N
Yield: 2.9 %

Procedure:
Pd(PPh3)2Cl2 (5 mg, 0.01 mmol) in a 10 mL of flask under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (110 mg, 0.29 mmol) in 1,4-dioxane (5.0 mL), Cs2CO3 (2 N, 1 mL) and 2-(3-cyclopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (70 mg, 0.29 mmol) The mixture was refluxed for 2 hour. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and HPLC to give 2′-amino-6-(3-cyclopropylphenyl)-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (3.6 mg, 3%). 1H-NMR (MeOD): 0.71 (m, 1H), 0.98 (m, 1H), 1.97 (m, 1H), 2.31 (m, 1H), 2.65 (m, 0.8H), 2.75 (m, 0.2H), 3.32 (m, 3H), 5.24 (m, 0.2H), 5.86 (m, 0.8H), 6.99 (m, 1H), 7.12 (m, 2H), 7.23 (m, 2H), 7.28 (m, 2H), 7.46 (m, 6H).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][N:12]=[CH:11][C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(O)=O>[C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][NH:12][CH2:11][C:10]=3[N:9]=[CH:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-n2cnc3cnccc32)cc1
Solvent: CC(=O)O
Product: C1=Cc2c(ncn2-c2ccccc2)CN1
Reaction time: 5 h
Yield: 17.7 %

Procedure:
A solution of Intermediate 2 (196 mg, 1.00 mmol) in AcOH (25 ml) was passed through a Pt2O catalyst cartridge on an H-Cube hydrogenation apparatus at a pressure of 80 bar and a flow rate of 1 ml/min at 100° C. The reaction was looped through the apparatus for 5 h. The crude reaction mixture was concentrated and purified on 16 g SiO2 column with 0-10% NH3MeOH CH2Cl2 to give the desired compound (35 mg, 17%). MS (ESI): mass calcd. for C12H11N3, 197.1. m/z found, 198.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C@@H:4]([C:5](O)=[C:6]([S:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C@H:3]1[C:15]([OH:17])=[O:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[CH:3]2[CH:4]1[CH:5]([CH:6]([S:12][CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[O:16][C:15]2=[O:17]
Reactant: CCOC(=O)C(SC)=C(O)[C@H]1[C@@H](C(=O)O)C1(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCOC(=O)C(SC)C1OC(=O)C2C1C2(C)C

Procedure:
A mixture of 9.67 g of the product of Step A, 80 mg of p-toluene sulfonic acid and 120 ml of benzene was refluxed and 60 ml of benzene were distilled over 90 minutes equipped with a flask of Dean Stark apparatus containing silica gel. The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 6-4 hexane-ethyl acetate mixture yielded 7.36 of 6,6-dimethyl-4-[methylthio-ethoxycarbonyl-methyl]-3-oxa-bicyclo [3,1,0]-hexane-2-one.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[I:11]I.O>O1CCCC1.C([Li])CCC.CCCCCC>[I:11][C:9]1[N:4]2[N:3]=[C:2]([CH3:1])[N:10]=[C:5]2[CH:6]=[CH:7][CH:8]=1
Reactant: II
Reactant: Cc1nc2ccccn2n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Cc1nc2cccc(I)n2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a solution of 2-methyl[1,2,4]triazolo[1,5-a]pyridine (63.2 g, 475 mmol) in tetrahydrofuran (1.37 L) was added dropwise 2.5 M n-butyllithium/hexane solution (5.62 mL, 8.99 mmol) at −78° C. and the mixture was stirred at −78° C. for 30 min. A solution of iodine (181 g, 712 mmol) in tetrahydrofuran (1.00 L) was added, and the mixture was stirred at −78° C. for 30 min, and at room temperature for 1 hr. Water (500 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/2) to give the title compound (45.0 g, yield 37%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)[O:11][CH:12]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:42][N:43]([CH2:50][C@H:51]1[CH2:56][CH2:55][C@H:54]([NH2:57])[CH2:53][CH2:52]1)[CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10](/[CH:13]=[CH:14]/[C:15]([NH:57][C@H:54]3[CH2:53][CH2:52][C@H:51]([CH2:50][N:43]([CH3:42])[CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)[CH2:56][CH2:55]3)=[O:17])[O:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2coc(/C=C/C(=O)O)c2)cc1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1ccc(-c2coc(/C=C/C(=O)N[C@H]3CC[C@H](CN(C)C4CCOCC4)CC3)c2)cc1
Reaction time: 2 h

Procedure:
Into a suspension of (E)-3-[4-(4-methylphenyl) furan-2-yl]acrylic acid (150 mg) and 1-hydroxybenzotriazole (133 mg) in acetonitrile (15 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (189 mg), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (295 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (0.3 g) and triethylamine (0.18 ml) in acetonitrile (15 ml), and the resulting mixture was stirred for 4 days. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the residue was subjected to purification using column chromatography (ethanol/ethyl acetate 1:3→1:2) and to recrystallization (ethyl acetate/hexane) to obtain (trans, E)-3-[4-(4-methylphenyl)furan-2-yl]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]acrylamide (compound 74) (137 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:34])[CH2:3][CH2:4][N:5]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([N+:26]([O-])=O)=[C:12]([NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:13]=1)=[O:7]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:26][C:11]1[CH:10]=[CH:9][C:8]([C:6]([N:5]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:4][CH2:3][CH:2]([CH3:34])[CH3:1])=[O:7])=[CH:13][C:12]=1[NH:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc([N+](=O)[O-])c(NCCCNC(=O)OC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCCNC(=O)OC(C)(C)C)c1
Temperature: 20 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
Tert-butyl 3-[(5-{[bis(3-methylbutyl)amino]carbonyl}-2-nitrophenyl)amino]propylcarbamate (1.65 g) in solution in a mixture of ethyl acetate/ethanol 2:1 (130 ml), and 10% palladium on carbon (165 mg) are introduced into an autoclave. After stirring for 3 hours under a hydrogen atmosphere (3 bar) at a temperature of approximately 20° C., the catalyst is eliminated by filtration on celite and the filtrate is concentrated under reduced pressure at 40° C. in order to produce the expected compound in the form of an oil (1.35 g; 89% yield).