Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]([NH2:14])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([Br:13])[CH:7]=1.O=C1CCC(=O)N1[O:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH2:36]2)[CH2:27]1)=O.C(N(CC)CC)C.[Cl-].[NH4+]>CN(C)C=O.ClCCl>[Br:13][C:8]1[CH:7]=[C:6]([CH:5]([NH:14][C:24]([C@@H:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:48])[CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37][CH2:36]3)[CH2:27]2)=[O:23])[CH2:4][C:3]([O:2][CH3:1])=[O:15])[CH:11]=[C:10]([F:12])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)ON3C(=O)CCC3=O)C2)CC1
Reactant: COC(=O)CC(N)c1cc(F)cc(Br)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cc(F)cc(Br)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 124.4 %

Procedure:
587.2 mg (2.13 mmol) 3-amino-3-(3-bromo-5-fluoro-phenyl)-propionic acid methyl ester were dissolved in 8.2 ml N,N-dimethylformamide and cooled to 0° C. To this solution was added a solution of 1100 mg (2.36 mmol) tert-butyl 4-{3-[(3R)-3-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5c) and 0.89 ml (6.38 mmol) triethylamine in 8.2 ml dichloromethane. The mixture was kept at 6° C. for 20 hours. Saturated ammonium chloride solution was added and the mixture extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated in vacuum to give 1.66 g (125%) tert-butyl 4-{3-[(3R)-3-{[1-(3-bromo-5-fluorophenyl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate with 80% purity.
Reaction SMILES: [Br:1][CH:2]([Si:4]([O:9][CH3:10])([O:7][CH3:8])[O:5][CH3:6])[CH3:3].[CH3:11][N:12]([CH3:14])[CH3:13]>>[Br-:1].[CH3:11][N+:12]([CH3:14])([CH3:13])[CH:2]([Si:4]([O:9][CH3:10])([O:7][CH3:8])[O:5][CH3:6])[CH3:3]
Reactant: CN(C)C
Reactant: CO[Si](OC)(OC)C(C)Br
Product: CO[Si](OC)(OC)C(C)[N+](C)(C)C
Product: [Br-]
Temperature: 80 °C

Procedure:
One quarter mole of the alpha-bromoethyltrimethoxysilane (57.3g) is placed in an autoclave along with 17.7g of trimethylamine. The mixture is heated to 80° C. for 6 hours under 200 p.s.i. nitrogen. The excess trimethylamine is allowed to evaporate after the product has been removed from the autoclave, leaving the bromide salt of alpha-trimethylammonioethyltrimethyoxysilane bromide.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:5](=[O:11])[N:6]([CH2:8][S:9][CH3:10])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:25])C=1.[OH2:28]>C(Cl)Cl>[Br:1][C:2]1[C:3]([O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[CH:4][C:5](=[O:11])[N:6]([CH2:8][S:9]([CH3:10])(=[O:25])=[O:28])[CH:7]=1
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCn1cc(Br)c(OCC2CC2)cc1=O
Solvent: ClCCl
Product: CS(=O)(=O)Cn1cc(Br)c(OCC2CC2)cc1=O
Temperature: 15 °C
Reaction time: 2.5 h
Yield: 72 %

Procedure:
To a solution of the title compound from Step 3 (150 mg, 0.5 mmoL) in DCM (5 mL), was added mCPBA (340 mg, 1.9 mmol). The mixture was stirred at 15° C. for 2.5 hours. Water (30 mL) was added and the resulting mixture was extracted with EtOAc (120 mL×3). The combined organic phases were washed with saturated brine (40 mL×2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (PE: EA=5:1 to 2:1) to afford the title compound (120 mg, 72%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 7.60 (s, 1H), 5.91 (s, 1H), 5.10 (s, 2H), 3.89 (d, J=6.8 Hz, 2H), 2.98 (s, 3H), 0.90-0.86 (m, 1H), 0.75-0.70 (m, 2H), 0.45-0.42 (m, 2H). LCMS: 335.9 (M+1)+; 337
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:6][CH:5]=1.[H-].[Na+].Br[CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24]>CN(C)C=O>[F:24][C:23]([F:26])([F:25])[CH2:22][CH2:21][C:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:16])([F:17])[F:1])=[CH:15][CH:14]=1)([C:12]#[N:13])[C:10]#[N:11]
Reactant: N#CC(C#N)Cc1ccc(OC(F)(F)F)cc1
Reactant: FC(F)(F)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1ccc(OC(F)(F)F)cc1
Yield: 20 %

Procedure:
Using 0.50 g of (4-(trifluoromethoxy)benzyl)malononitrile, 8 ml of N,N-dimethylformamide, 96 mg of sodium hydride (60% in oil), and 0.74 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.14 g of 2-(3,3,3-trifluoropropyl)-2-(4-(trifluoromethoxy)benzyl)malononitrile (the present compound (50)).
Reaction SMILES: [C:1]([N:8](C1C=CC=CC=1)[CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:19]1[CH:20]=[CH:21][C:22]2N(O)N=N[C:23]=2[CH:24]=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:42][C:43]1[N:47]2[C:48](=[O:57])[N:49]([CH:51]3[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)[CH2:50][C:46]2=[CH:45][N:44]=1>C(#N)C.C(N(CC)CC)C>[CH3:42][C:43]1[N:47]2[C:48](=[O:57])[N:49]([CH:51]3[CH2:56][CH2:55][N:54]([C:10](=[O:12])[CH:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:23]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:24]=4)[CH2:53][CH2:52]3)[CH2:50][C:46]2=[CH:45][N:44]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N(CC(=O)O)c1ccccc1
Reactant: Cc1ncc2n1C(=O)N(C1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ncc2n1C(=O)N(C1CCN(C(=O)C(NC(=O)OC(C)(C)C)c3ccccc3)CC1)C2
Yield: 95.9 %

Procedure:
Boc-phenylglycine (0.25 g) was dissolved in acetonitrile (10 ml). HOBt (0.23 g), WSC (0.29 g), triethylamine (0.2 ml) and 5-methyl-2-(4-piperidinyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.29 g) were added thereto, and mixed at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a green oil (0.43 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH3:9])[CH:5]=[N:6][CH:7]=1.[CH3:16]I.[H-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:10]([CH3:16])[S:11]([CH2:14][CH3:15])(=[O:12])=[O:13])[CH3:9])[CH:5]=[N:6][CH:7]=1
Reactant: CI
Reactant: CCS(=O)(=O)NC(C)c1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: CCS(=O)(=O)N(C)C(C)c1cncc(Br)c1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-41, N-(1-(5-bromopyridin-3-yl)ethyl)ethanesulfonamide (intermediate A-37) was reacted with MeI in presence of NaH (60% in mineral oil) to give the title compound as a light yellow solid. MS: 307.1 and 309.2 (M+H+).
Reaction SMILES: S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[C:11]([C:15]1[CH:20]=[C:19]([N:21]=O)[CH:18]=[C:17]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]=1[OH:27])([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+].C1C=CC=CC=1>O>[C:11]([C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[C:17]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]=1[OH:27])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(N=O)cc(C(C)(C)C)c1O
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reaction time: 0.75 h

Procedure:
2,6-di tert.butyl-4-aminophenol was prepared by adding in a nitrogen atmosphere, a solution of 70 grams of sodium dithionate in 300 milliliters of water to a mixture of 23.5 grams of 2,6-di tert.butyl-4-nitrosophenol, 80 milliliters of 5 N sodium hydroxide solution and 160 milliliters of water. The addition was accomplished in 45 minutes at 24° C. to 41° C. After stirring for 21/4 hours, 100 milliliters of benzene was added to dissolve the solid product, and the layers were separated.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1.[CH3:25][O-:26].[Na+].Cl>CN(C)C=O.CCOCC>[ClH:1].[CH:25]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1)=[O:26]
Reactant: CN1CCC2(CC1)CN(c1ccccc1N)c1ccccc12
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN1CCC2(CC1)CN(c1ccccc1NC=O)c1ccccc12
Temperature: 90 °C

Procedure:
To a mixture of 15.0 g of 1-(2-aminophenyl)-1'-methylspiro-[indoline-3,4'-piperidine] dihydrochloride, Example 16, in 75 ml of dimethylformamide at 90° C. under nitrogen is added 8.6 g of sodium methoxide. Following this addition the reaction temperature is increased to 110°-115° C. and maintained at this temperature for 40 minutes. The resulting dark brown mixture is permitted to cool to 90° C. and then poured onto 800 ml of ice-water. The mixture is filtered and the filter cake is washed with water and then dissolved in chloroform. The chloroform solution is successively washed with brine, dried and concentrated leaving a red colored glass. The glass is dissolved in ether, where it is converted to its hydrochloric acid salt which is collected by filtration and then washed with ether and finally dried. The salt is recrystallized from a methyl alcohol-ether mixture to provide the product, mp 287.5° C., dec of 1-(2-formamidophenyl)-1'-methylspiro[indoline-3,4'-piperidine] hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: Cc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C(=CN(C)C)c2ccccc2)cc1

Procedure:
A solution of 1-(4-methylphenyl)-2-phenylethanone (11-1) (8.4 g, 39.95 mmol) and N,N-dimethylformamide dimethylacetal (11.9 g, 99.87 mmol) in DMF (40 mL) was heated to 100° C. for 1 h. Concentrated in vacuo to give crude 3-(dimethylamino)-1-(4-methylphenyl)-2-phenylprop-2-en-1-one (11-2) as a red oil. LRMS m/z (M+H) Calcd: 266.4, found: 266.2.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Si]([O:29][CH2:30][C:31]1[C:39]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:38][C:37]2[N:36]3[CH2:44][CH2:45][NH:46][CH:47]([CH:48]([CH3:50])[CH3:49])[C:35]3=[CH:34][C:33]=2[CH:32]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl>[CH:48]([CH:47]1[C:35]2=[CH:34][C:33]3[CH:32]=[C:31]([CH2:30][OH:29])[C:39]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:38][C:37]=3[N:36]2[CH2:44][CH2:45][N:46]1[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1)([CH3:50])[CH3:49]
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: CC(C)C1NCCn2c1cc1cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc12
Solvent: CC(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C1c2cc3cc(CO)c(S(C)(=O)=O)cc3n2CCN1c1nccc(C(F)(F)F)n1
Temperature: 110 °C
Reaction time: 30 h
Yield: 72 %

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyrimidine (80 mg, 0.44 mmol), 8-(((tert-butyldiphenylsilyl)oxy)methyl)-1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (crude, from step 9), and DIEA (115 μL, 0.66 mmol) in i-PrOH/CH2Cl2 (2 mL/1 mL) was stirred at 110° C. for 30 h. The solvent was removed under reduced pressure and the crude residue was purified by silica chromatography and SFC separation on a chiral column to give isomers of (1-isopropyl-7-(methylsulfonyl)-2-(4-(trifluoromethyl)pyrimidin-2-yl)-1,2,3,4-tetrahydropyrazino[1,2-a]indol-8-yl)methanol (75 mg, 72% yield for two steps).
Reaction SMILES: C([N:3](CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2C=[C:19]3[C:25]([NH:26][C:27](=[O:59])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:38][CH2:37][C@H:36]([NH:39]C(=O)C(F)(F)F)[CH2:35]5)=[CH:30][C:29]=4[N:46]([CH:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)C(=O)C(F)(F)F)=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1.C(O)CCC.C(=O)([O-])[O-].[K+].[K+]>CO>[NH2:39][C@H:36]1[CH2:37][CH2:38][N:34]([C:31]2[CH:32]=[CH:33][C:28]([C:27]([NH:26][C:25]3[C:19]4[C:20](=[N:21][CH:22]=[C:17]([S:16][C:11]5[CH:10]=[C:9]([F:8])[CH:14]=[C:13]([F:15])[CH:12]=5)[N:3]=4)[NH:23][N:24]=3)=[O:59])=[C:29]([NH:46][CH:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)[CH:30]=2)[CH2:35]1
Reactant: O=C(Nc1n[nH]c2ncc(Sc3cc(F)cc(F)c3)cc12)c1ccc(N2CC[C@H](NC(=O)C(F)(F)F)C2)cc1N(C(=O)C(F)(F)F)C1CCOCC1
Reactant: CCN(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CO
Product: N[C@H]1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)nc34)c(NC3CCOCC3)c2)C1
Temperature: 65 °C
Reaction time: 4 h
Yield: 49 %

Procedure:
876 μl (20 eq) of triethylamine is added to a solution of 238 mg (0.314 mmol) of (S)—N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl) acetamido)-4-(3-(2,2,2-trifluoroacetamido)pyrrolidin-1-yl)benzamide in 6 ml of methanol. The reaction medium is stirred at 65° C. for 4 hours. After returning to room temperature, 8 ml of n-butanol and 260 mg (6 eq) of potassium carbonate are added. The reaction medium is stirred at 80° C. for 24 hours. After returning to room temperature, the solvents are evaporated, water is added and the product is extracted with dichloromethane. The organic phase is washed with saturated sodium chloride solution, dried on magnesium sulfate, filtered and evaporated. The residue is purified by silica gel chromatography (8:2 dichloromethane/methanol as eluent) to yield 87 mg (yield=49%) of (S)-4-(3-aminopyrrolidin-1-yl)-N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyrazine-3-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a brown powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][N:24]2[CH2:25][CH2:26][CH:21](/[CH:20]=[CH:19]/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[F:12])[CH2:22][CH2:23]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: Fc1ccccc1/C=C/C1CCNCC1
Reactant: COc1ncc(F)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ncc(F)cc1CN1CCC(/C=C/c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
117 mg of 5-fluoro-2-methoxy-3-pyridinecarboxaldehyde and 291 mg of 4-[(E)-2-(2-fluorophenyl)-1-ethenyl]piperidine were dissolved in 3 ml of 1,2-dichloroethane, 0.06 ml of acetic acid and 238 mg of sodium triacetoxyborohydride were added thereto, and the mixture was stirred at room temperature overnight. An aqueous saturated sodium carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=8:1), to give 221 mg of the title compound as a colorless oil.
Reaction SMILES: [CH2:1]([CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:2]#[CH:3].Br[CH2:16]/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].[H-].[Na+]>C1COCC1>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:18]=[CH:17][CH2:16][C:4]([CH2:1][C:2]#[CH:3])([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: C#CCC(C(=O)OCC)C(=O)OCC
Reactant: Clc1ccccc1/C=C/CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCC(CC=Cc1ccccc1Cl)(C(=O)OCC)C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
An oven-dried, 100 mL three-necked round-bottomed flask under a nitrogen atmosphere was charged with diethyl 2-(prop-2-yn-1-yl)malonate S13 (1.8 g, 9.1 mmol), (E)-1-(3-bromoprop-1-en-1-yl)-2-chlorobenzene S14 (2.1 g, 11.0 mmol), and THF (60 mL). The solution was cooled to 0° C. in an ice bath for 15 min, then NaH (0.43 g of a 60% dispersion in mineral oil, 11.0 mmol) was added in one portion. The solution was stirred at 0° C. for 2 h. The consumption of the starting material was monitored by TLC (AcOEt/n-hexane 0.5:9.5). The reaction was then quenched with sat'd aq ammonium chloride solution (70 mL). The layers were separated and the aqueous phase was extracted with AcOEt (3×50 mL). The combined organic layers were dried over Na2SO4, gravity filtered, and concentrated under reduced pressure. The reaction residue was purified by silica gel flash chromatography, eluting with AcOEt/n-hexane 0.5:9.5, to provide 2.55 g of the title compound as a yellow oil in 81% yield.
Reaction SMILES: [F:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([CH2:8]O)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.CS([Cl:23])(=O)=O>ClCCl.C(OCC)C>[Cl:23][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[O:10][CH3:11]
Reactant: COc1c(F)cccc1CO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1c(F)cccc1CCl
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A solution of (3-fluoro-2-methoxyphenyl)methanol (3.02 g, 19.3 mmol) and triethylamine (6.74 mL, 48.4 mmol) in dichloromethane (20 mL) is treated with methanesulfonyl chloride (2.99 mL, 38.7 mmol) slowly at room temperature and stirred under nitrogen for 3 h. The reaction is the diluted with diethyl ether, washed with 0.5 M hydrochloric acid twice, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the title compound as a yellow oil (2.71 g, 80%). 1H NMR (400 MHz, CDCl3) δ 7.15-6.93 (m, 3H), 4.61 (s, 2H), 4.00 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][C:8]=1[O:18][CH2:19][CH3:20])(=O)=O.[I-:23].[Na+].CCOC(C)=O>CS(C)=O>[CH2:19]([O:18][C:8]1[CH:9]=[C:10]([CH:11]=[C:12]([N+:13]([O-:15])=[O:14])[C:7]=1[I:23])[CH:16]=[O:17])[CH3:20]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOc1cc(C=O)cc([N+](=O)[O-])c1I
Temperature: 6.5 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of 2-ethoxy-4-formyl-6-nitrophenyl trifluoromethanesulfonate (4.7 g, 13.7 mmol) in DMSO (10 mL) was added sodium iodide (6.2 g, 41.1 mmol). The mixture was stirred under N2 atmosphere at 3-10° C. overnight. EtOAc/aqueous workup. Purified by silica gel column chromatography (PE:EtOAc=50:1 to PE:EtOAc=10:1) (4.0 g, yield 91%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH2:15]C)[CH2:13]C)[C:6]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:5]2[Cl:24].[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30]([C:33]([C:35]2[N:39]([CH3:40])[CH:38]=[N:37][CH:36]=2)=[O:34])=[CH:29][CH:28]=1>>[Cl:24][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:33]([C:30]3[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)([C:35]3[N:39]([CH3:40])[CH:38]=[N:37][CH:36]=3)[OH:34])[CH:3]=2)[N:8]=[C:7]([N:12]([CH3:15])[CH3:13])[C:6]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Oc1ccccc1
Reactant: COc1ccc(C(=O)c2cncn2C)cn1
Product: COc1ccc(C(O)(c2ccc3nc(N(C)C)c(Oc4ccccc4)c(Cl)c3c2)c2cncn2C)cn1

Procedure:
The title compound was prepared using 6-bromo-4-chloro-N,N-dimethyl-3-phenoxyquinolin-2-amine (Intermediate 5, step e) and (6-methoxypyridin-3-yl)(1-methyl-1H-imidazol-5-yl)methanone (Intermediate 4, step d) according to the procedure of Example 3a. 1H NMR (400 MHz, MeOH-d4) δ 8.01 (d, J=2.02 Hz, 1H), 7.93 (d, J=2.02 Hz, 1H), 7.72-7.86 (m, 2H), 7.68 (dd, J=2.53, 8.59 Hz, 1H), 7.56 (dd, J=2.02, 9.09 Hz, 1H), 7.25-7.32 (m, J=7.07, 8.59 Hz, 2H), 7.01-7.07 (m, 1H), 6.81 (d, J=8.59 Hz, 1H), 6.72-6.78 (m, 2H), 6.37 (br. s., 1H), 3.91 (s, 3H), 3.51 (s, 3H), 3.11 (s, 6H); MS m/e 516.9 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3][C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH3:20])([CH3:19])[C@@H:10]([OH:18])[C@H:11]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[C:6]=2[CH:5]=1.[OH:25]OS([O-])=O.[K+].[OH2:31]>CO>[F:24][C:2]([F:1])([F:23])[S:3]([C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH3:20])([CH3:19])[C@@H:10]([OH:18])[C@H:11]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[C:6]=2[CH:5]=1)(=[O:25])=[O:31].[F:24][C:2]([F:1])([F:23])[S:3]([C:4]1[CH:22]=[CH:21][C:7]2[O:8][C:9]([CH3:20])([CH3:19])[C@@H:10]([OH:18])[C@H:11]([N:12]3[CH2:16][CH2:15][CH2:14][C:13]3=[O:17])[C:6]=2[CH:5]=1)=[O:25]
Reactant: O
Reactant: O=S([O-])OO
Reactant: CC1(C)Oc2ccc(SC(F)(F)F)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Agent: [K+]
Solvent: CO
Product: CC1(C)Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Product: CC1(C)Oc2ccc(S(=O)C(F)(F)F)cc2[C@@H](N2CCCC2=O)[C@@H]1O
Yield: 55 %

Procedure:
0.2 g (5.5 mmol) of 6-trifluoromethylthio-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol are dissolved in 7 ml of methanol and a suspension of 1 g of Oxone® in 5 ml of water is added at 0° C. with stirring. After stirring for 5 days at room temperature, the mixture is diluted using 20 ml of water and extracted using chloroform (3×50 ml). After drying and evaporating, 0.2 g of white crystals remain. By means of HPLC (eluent chloroform:methanol 98 : 2), 120 mg (55 % of theory) of 6-trifluoromethylsulphonyl-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)pyran-3-ol and 15 mg of 6-trifluoromethylsulphinyl-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidinyl)-2H-benzo(b)-pyran-3-ol are obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:14][C:15]1([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH2:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:18]1[CH2:19][CH2:20][C:15]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)([F:14])[CH2:16][CH2:17]1)=[O:9]
Reactant: CCc1cc(C)c(N)cc1C(=O)O
Reactant: N#Cc1ccc(C2(F)CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(C)c(N)cc1C(=O)N1CCC(F)(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.5 %

Procedure:
A mixture of 5-amino-2-ethyl-4-methylbenzoic acid (compound 48.4, 100 mg, 0.56 mmol, 1.00 equiv), 4-(4-fluoropiperidin-4-yl)benzonitrile (compound 11.2, 140 mg, 0.69 mmol, 1.23 equiv), HBTU (320 mg, 0.84 mmol, 1.51 equiv), and DIEA (150 mg, 1.16 mmol, 2.08 equiv) in DMF (20 mL) was stirred for 48 h at room temperature. Water (30 mL) was added and the resulting mixture was extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 1×50 mL of brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with PE:EtOAc (1:1) to yield 130 mg (38%) of the title compound as a light yellow solid.