Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][S:9][C@@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:12]([C:13](=[CH2:30])[CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:29])[CH2:11]1)=[O:4].C[N+]1([O-])CC[O:37]CC1>CC#N.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[F:32][C:2]([F:1])([F:31])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][S@@:9]([C@@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[CH:12]([C:13](=[CH2:30])[CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@H:16]3[CH2:17][CH2:18][C:19]2=[O:29])[CH2:11]1)=[O:37])=[O:4]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CC[C@@H](SCCCNC(=O)C(F)(F)F)CC12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CC[C@@H]([S@@](=O)CCCNC(=O)C(F)(F)F)CC12
Yield: 34 %

Procedure:
To a solution of 3α-(3-trifluoroacetamidopropylthio)-6-methyleneandrostane-17-one (Prepn. 82, 286 mg) in dry CH3CN (14 mL), NMO (213 mg) and molecular sieves (4 Å, 280 mg) were added followed by the addition of TPAP (10.6 mg). After 1 h at room temperature the mixture was evaporated to dryness. The residue was purified by flash chromatography (SiO2, n-hexane/acetone 65/35) to give 3α-[(S)-3-trifluoroacetamidopropylsulfinyl]-6-methyleneandrostane-17-one (100 mg, 34% yield). 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 9.43 (1H, bb), 4.72 (1H, m), 4.41 (1H, m), 3.24 (3H, m), 2.50-0.86 (24H, m), 0.75 (3H, s), 0.65 (3H, s).
Reaction SMILES: II.[CH2:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:15])(=[O:14])=[O:13])[CH:4]=[CH2:5].C(=O)([O-])[O-].[K+].[K+].O>N#N>[CH2:5]1[CH:4]2[N:15]1[S:12](=[O:13])(=[O:14])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:3]2
Reactant: C=CCc1ccccc1S(N)(=O)=O
Agent: II
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: O
Product: O=S1(=O)c2ccccc2CC2CN21
Reaction time: 0.33 h

Procedure:
Iodine (6.51 g, 26.7 mmol) was added in one portion to a solution of 2-(2-propenyl)benzenesulfonamide (2.53 g, 12.8 mmol) in N2-degassed dichloromethane (125 mL) containing potassium carbonate (7.09 g, 51.3 mmol). After stirring for 20 min, water (50 mL, containing 2 g of sodium metabisulfite) was carefully added. The layers were separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined organic layers were washed with water (25 mL). To the combined organic layers were added methanol (50 mL) and 0.25 N potassium carbonate in 70% aqueous methanol. After stirring for 10 min, sodium metabisulfite (100 mg) was added to discharge the color. The volatile organic solvents were removed in vacuo. The residue was partitioned between dichloromethane (100 mL) and additional water (30 mL). The aqueous layer was extracted with dichloromethane (25 mL). The combined organic layers were dried (magnesium sulfate) and concentrated in vacuo to provide 8,8a-dihydro-1H-azirino[1,2-b][1,2]benzothiazine 3,3-dioxide as a pale yellow oil which solidified (2.25 g, 90%): LCMS (pos. ion spectrum) m/z 237 (M+H+CH3CN).
Reaction SMILES: [C:1]([C@H:3]1[NH:6][C:5](=[O:7])[C@H:4]1[NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)#[N:2].[OH-:28].[Na+].Cl>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C@H:3]1[NH:6][C:5](=[O:7])[C@H:4]1[NH:8][C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:28])[NH2:2]
Reactant: N#C[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: NC(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C

Procedure:
In 2 ml of dichloromethane is dissolved 160 mg of (3S,4S)-4-cyano-3-triphenylmethylamino-2-azetidinone and, following addition of 154 mg of tetra-n-butylammonium hydrogen sulfate, 0.103 ml of 30% aqueous peroxide and 0.68 ml of 1 N sodium hydroxide are added under ice-cooling and stirring. The mixtire is stirred vigorously for 30 minutes and poured into ice water containing 0.22 ml of 1 N hydrochloric acid. After phase separation, the aqueous layer is extracted twice with chloroform. The organic layers are combined, washed with aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on a silica gel column [eluant: chloroform-ethyl acetate-methanol (50:50:5)] to give 75 mg of (3S,4S)-4-carbamoyl-3-triphenylmethylamino-2-azetidinone. The IR and NMR spectra of this compound are identical with those of the compound obtained in Example 17.
Reaction SMILES: [N:1]1([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[CH3:25]O>>[N:1]1([C:11]2[CH:19]=[CH:18][C:14]([C:15]([O:17][CH3:25])=[O:16])=[CH:13][CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(N2CCNc3ccccc32)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(N2CCNc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3.8 g of 4-(3,4-dihydroquinoxalin-1(2H)-yl)benzoic acid and 70 ml of methanol are introduced into a 250 ml round-bottomed flask equipped with a magnetic stirrer. 4.4 ml of 97% sulfuric acid are added dropwise and the reaction medium is stirred at ambient temperature for 18 h. The methanol is partially evaporated. The remaining solution is poured onto a water-plus-ice mixture, neutralized by slow addition of sodium hydrogencarbonate and extracted 3 times with ethyl acetate. The organic phases are combined, washed with water and with a saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure. The residue is chromatographed on silica gel eluted with a gradient of ethyl acetate from 10% to 20% in heptane. 2.8 g of methyl 4-(3,4-dihydroquinoxalin-1(2H)-yl)benzoate are obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:5][C:4]=1[N+:17]([O-])=O)=[O:2].[H][H]>CO.[Pd]>[NH2:17][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:7]=[CH:8][C:3]=1[CH:1]=[O:2]
Reactant: [H][H]
Reactant: COC(=O)CCC#Cc1ccc(C=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCc1ccc(C=O)c(N)c1

Procedure:
Methyl 5-(4-formyl-3-nitrophenyl)pent-4-ynoate (522 mg) was reduced by 5% Pd/C (53 mg) in MeOH with hydrogen balloon at room temperature. Filtration followed by concentration under reduced pressure afforded methyl 5-(3-amino-4-formylphenyl)pentanoate. MS-ESI m/z 236.28 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[CH2:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4]>C(O)C.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH2:11][CH3:12])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4]
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Reaction time: 4 h
Yield: 62.2 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylic acid methyl ester (200 mg, 0.7 mmol) was dissolved in ethanol (10 mL), palladium hydroxide (20% on carbon, 50 mg) was added, and the reaction mixture was stirred under an atmosphere of hydrogen for 4 h. The catalyst was then filtered off, the filtrate concentrated, and the product purified by flash chromatography on silica gel (hexane/ethyl acetate gradient) to yield the title compound (148 mg, 62% yield): mp 144-146° C.: 1H NMR (CDCl3) δ 7.61 (m, 1H), 7.20 (m, 1H), 5.19 (br s, 2H), 3.99 (d, 3H), 3.98 (s, 3H), 2.68 (q, 2H), 1.28 (t, 3H).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:15]2[CH:14]=[C:13]([C:16]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[CH:12]=[CH:11][C:10]=2[C:9]2[N:24]([CH:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:25]=[CH:26][C:8]=2[C:7]1=[O:33]>C(O)(C(F)(F)F)=O>[CH3:22][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:23])[C:16]=1[C:13]1[CH:12]=[CH:11][C:10]2[C:9]3[N:24]([CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[N:25]=[CH:26][C:8]=3[C:7](=[O:33])[NH:6][C:15]=2[CH:14]=1
Reactant: COc1ccc(Cn2c(=O)c3cnn(C4CCOCC4)c3c3ccc(-c4c(C)cccc4C)cc32)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C)c1-c1ccc2c(c1)[nH]c(=O)c1cnn(C3CCOCC3)c12
Temperature: 65 °C
Reaction time: 2 h
Yield: 18.7 %

Procedure:
7-chloro-5-(2,4-dimethoxybenzyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one obtained in Preparation Example 2 (100 mg) was dissolved in DMF (3.3 mL). 2,6-dimethylphenylboronic acid (33 mg), Pd(PPh3)4 (13 mg), potassium carbonate (91 mg) and water (0.7 mL) were added to the solution, and the mixture was reacted using a microwave reactor at 150° C. for two hours. The reaction mixture was returned to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 30% to 50% to 80%) to give 5-(2,4-dimethoxybenzyl)-7-(2,6-dimethylphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (80 mg). The 5-(2,4-dimethoxybenzyl)-7-(2,6-dimethylphenyl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-c]quinolin-4(5H)-one (75 mg) was dissolved in TFA. (1 mL), and the mixture was stirred at 65° C. for two hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was neutralized by adding a saturated aqueous sodium bicarbonate solution. The aqueous solution was extracted with DCM. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 50% to 70% to 80%) to give the title compound (10 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:12][C:13](/[CH:16]=[C:24]3\[C:25](=[O:30])[NH:26][C:27]4[C:23]\3=[CH:22][C:21]([F:20])=[CH:29][CH:28]=4)=[C:14]([CH3:15])[C:7]=2[C:6]1=[O:18]
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Reactant: O=C1Cc2cc(F)ccc2N1
Product: Cc1c(/C=C2\C(=O)Nc3ccc(F)cc32)[nH]c2c1C(=O)N(CCN(C)C)CCC2
Yield: 68 %

Procedure:
The title compound was prepared under the same conditions as described in step 4 of Example 23 with 5-(2-dimethylamino-ethyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 23c obtained from step 3 of Example 23 and 5-fluoro-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-5-(2-dimethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 25 (205 mg, yield 68%) as a red solid.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:15][N:16]1[C:20](B2OC(C)(C)C(C)(C)O2)=[C:19]([CH3:30])[CH:18]=[N:17]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][N:16]1[C:20]([C:2]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:19]([CH3:30])[CH:18]=[N:17]1
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1c(Br)cccc1OC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1c(OC)cccc1-c1c(C)cnn1C
Temperature: 100 °C
Yield: 95.2 %

Procedure:
In a microwave vial was dissolved ethyl 2-bromo-6-methoxybenzoate (500 mg, 1.54 mmol) and 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (377 mg, 1.70 mmol) in DME (10 mL) and water (2 mL). Na2CO3 (259 mg, 3.09 mmol) was then added followed by Pd(PPh3)4 (89 mg, 0.077 mmol) and the reaction mixture was degassed with N2 for 10 minutes. The reaction mixture was then heated at 100° C. for 1 h in the microwave. The mixture was cooled to room temperature, filtered through Celite and washed with EtOAc and DCM. The crude solution was concentrated in vacuo and directly purified via silica gel chromatography (10-80% EtOAc in hexanes) to afford the title compound (402 mg, 95%). MS (ESI) mass calcd. for C15H18N2O3, 274.1; m/z found 275.2 [M+H]+. 1H NMR (400 MHz, Chloroform-d) 7.45 (dd, J=8.4, 7.6 Hz, 1H), 7.29 (s, 1H), 7.04 (dd, J=8.5, 0.9 Hz, 1H), 6.84 (dd, J=7.6, 0.9 Hz, 1H), 4.07 (qd, J=7.2, 1.5 Hz, 2H), 3.90 (s, 3H), 3.61 (s, 3H), 1.86 (s, 3H), 1.01 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[N:20][C:19]=2[O:24]C)[CH2:13][CH2:12]1)=[O:10].[OH-].[Na+].ClCCl>Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([CH:11]1[CH2:12][CH2:13][N:14]([CH2:17][C:18]2[C:19](=[O:24])[NH:20][N:21]=[CH:22][CH:23]=2)[CH2:15][CH2:16]1)=[O:10]
Reactant: COc1nnccc1CN1CCC(C(=O)Cc2ccccc2F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(Cc1ccccc1F)C1CCN(Cc2ccn[nH]c2=O)CC1
Yield: 38 %

Procedure:
After dissolving 74 mg of 2-(2-fluorophenyl)-1-[1-(3-methoxy-4-pyridazinylmethyl)piperidin-4-yl]ethanone in 2 ml of 5N hydrochloric acid, the mixture was heated to reflux for 4.5 hours. A 5N sodium hydroxide solution was added to the reaction solution for neutralization, and extraction was performed with dichloromethane. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (27 mg, 38% yield).
Reaction SMILES: FC1C([O:8][C:9](=O)[C@H:10]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[NH:11][C:12]([O:14][CH2:15][CH:16]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])=C(F)C(F)=C(F)C=1F.[N+:46]([O:49][CH2:50][CH2:51][CH2:52][CH2:53][OH:54])([O-:48])=[O:47]>CN(C=O)C>[CH:18]1[C:17]2[CH:16]([CH2:15][O:14][C:12](=[O:13])[NH:11][C@H:10]([C:9]([O:54][CH2:53][CH2:52][CH2:51][CH2:50][O:49][N+:46]([O-:48])=[O:47])=[O:8])[CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:34](=[O:35])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: O=[N+]([O-])OCCCCO
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCCCCO[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Commercial N(α)-Fmoc-N(ε)-Boc-L-lysine pentafluorophenyl ester (6.51 mmol) and 4-(nitrooxy)-1-butanol (6.55 mmol) were dissolved in DMF (12 ml) and the mixture was cooled to 0° C. N,N-dimethylaminopyridine (DMAP) (6.55 mmol) were added and the reaction was slowly warmed to room temperature and stirred for 4 hours. Then the mixture was concentrate under reduced pressure and diluted with EtOAc, washed with 5% aqueous Na2HPO4 and brine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1)=[O:15]>>[CH3:12][CH:13]([CH3:29])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:25][CH2:24]2)[CH:18]=1)=[O:15]
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: ClCCCSc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCSc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using [(3-chloropropyl)sulfanyl]benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: 1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.48 (s, 1H), 7.33 (m, 3H), 7.27 (t, 2H, J=7.5 Hz), 7.20 (t, 1H, J=7.9 Hz), 7.15 (tt, 1H, J=7.2, 1.4 Hz), 6.95 (d, 1H, J=7.6 Hz), 2.97 (t, 4H, J=7.3 Hz), 2.46 (m, 4H), 1.99 (dt, 2H, J=11.4, 3.0 Hz), 1.84 (qt, 2H, J=7.3 Hz), 1.77 (m, 4H), 1.21 (d, 6H, J=6.8 Hz); ESMS m/e: 396.8 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][C:10]=2[NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:37][C:38]([NH:40][CH3:41])=[O:39]>CC#N.CCOC(C)=O>[NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)[CH:12]=[CH:11][C:10]=2[N:20]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:7])=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CNC(=O)CN(C(=O)OC(C)(C)C)c1ccc(-c2cccs2)cc1NC(=O)c1ccc(N)cc1

Procedure:
To a solution of tert-butyl [2-[(4-aminobenzoyl)amino]-4-(2-thienyl)phenyl]carbamate (mg, mmol) in CH3CN was added K2CO3 and 2-chloro-N-methylacetamide. The reaction was allowed to stir at reflux overnight. The crude reaction mixture was diluted with EtOAc (20 mL) and then washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (10-100% MeCN/H2O with 0.05% TFA). The appropriate fractions were combined and concentrated in vacuo and gave the desired tert-butyl [2-[(4-aminobenzoyl)amino]-4-(2-thienyl)phenyl][2-(methylamino)-2-oxoethyl]carbamate which was confirmed by MS: cal'd 481.2 (MH+), exp 481.2 (MH+).
Reaction SMILES: [CH2:1]([O:5][C:6](=[O:18])[CH:7]=[CH:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[C:11]([F:17])[CH:10]=1)[CH2:2][CH2:3][CH3:4].C>[Pd].CO>[CH2:1]([O:5][C:6](=[O:18])[CH2:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([CH3:16])=[C:11]([F:17])[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)C=Cc1cc(F)c(C)c(F)c1
Agent: [Pd]
Solvent: CO
Product: CCCCOC(=O)CCc1cc(F)c(C)c(F)c1
Temperature: 25 °C

Procedure:
A mixture of 3-(3,5-difluoro-4-methyl-phenyl)-acrylic acid butyl ester (7.651 g; 30.089 mmol) and 10% palladium over activated charcoal (0.760 g) was placed under nitrogen before MeOH (100 ml) was carefully added. The resulting suspension was placed under vacuum, then under hydrogen (1 atm), and the reaction mixture was vigorously stirred at rt for 2 h45. The reaction mixture was filtered over a pad of celite, and concentrated under reduced pressure to give the expected product 3-(3,5-difluoro-4-methyl-phenyl)-propionic acid butyl ester as a yellow oil which was further dried under HV (6.960 g; 90%). LC-MS: tR=1.10 min; [M+H]+: no ionisation.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:6][OH:7])[CH2:5][CH2:4]1.C[O:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)=[C:14](Cl)[N:13]=1)=[O:11]>CN(C=O)C>[CH:3]1([CH2:6][O:7][C:14]2[N:13]=[C:12]([C:10]([OH:11])=[O:9])[CH:17]=[CH:16][C:15]=2[N:18]2[CH2:21][C:20]([F:23])([F:22])[CH2:19]2)[CH2:5][CH2:4]1
Reactant: OCC1CC1
Reactant: COC(=O)c1ccc(N2CC(F)(F)C2)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
Sodium hydride (0.29 g, 8.4 mmol) was added in portion to a solution of cyclopropylmethanol (CAN 2516-33-8, 0.36 g, 5 mmol) in DMF (3 mL) and the mixture was stirred at room temperature for 2 h. 6-Chloro-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid methyl ester (0.44 g, 1.68 mmol) was added to the mixture and the resulting solution was stirred at 110° C. overnight. After concentration, water (20 mL) was added to the residue and the solution was acidified with an aqueous solution of hydrochloride (6 N), then extracted with ethyl acetate (2×20 mL). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by prep-TLC (eluting with 50% ethyl acetate in petroleum ether) to give the target compound (0.07 g, 14%); MS (EI): m/e=285.1 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10](Br)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([Cl:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:19][CH:20]=1)=[CH:11][C:10]([C:41]1[CH:42]=[C:37]([Cl:36])[C:38]([OH:53])=[C:39]([Cl:52])[CH:40]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Yield: 100.7 %

Procedure:
Following general procedure M, tert-butyl (1-(5-((3-acetyl-6-bromoquinolin-4-yl)amino)pyridin-2-yl)pyrrolidin-3-yl)(methyl)carbamate (80 mg, 0.15 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (72 mg, 0.25 mmol) to afford the desired product (94 mg, 100%) as a brown solid. ESI MS m/z 622 [C32H33Cl2N5O4+H]+
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)(=O)=O.[Br:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>>[Br:12][C:13]1[CH:14]=[N:15][N:16]([CH:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH:17]=1
Reactant: CS(=O)(=O)OC1CCOCC1
Reactant: Brc1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cnn(C2CCOCC2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
The mixture of tetrahydro-2H-pyran-4-yl methanesulfonate (U-2) (1.8 g, 10 mmol), 4-bromo-1H-pyrazole (1.46 g, 10 mmol) and K2CO3 (1.4 g, 10 mmol) in DMF (10 mmol) was stirred at 80° C. overnight, then purified by chromatography to afford the title compound (861 mg). MS (m/z): 231 (M+1)+.
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:26]=2[NH:25][CH:24]=[C:23]3[Cl:27])(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1>CN(C)C=O>[Cl:27][C:23]1[C:22]2[C:26](=[C:18]([NH:17][S:14]([C:11]3[CH:12]=[CH:13][C:8]([S:5](=[O:7])(=[O:6])[NH:4][CH2:3][CH2:2][N:28]4[CH:32]=[CH:31][N:30]=[CH:29]4)=[CH:9][CH:10]=3)(=[O:16])=[O:15])[CH:19]=[CH:20][CH:21]=2)[NH:25][CH:24]=1
Reactant: c1c[nH]cn1
Reactant: O=S(=O)(NCCBr)c1ccc(S(=O)(=O)Nc2cccc3c(Cl)c[nH]c23)cc1
Solvent: CN(C)C=O
Product: O=S(=O)(NCCn1ccnc1)c1ccc(S(=O)(=O)Nc2cccc3c(Cl)c[nH]c23)cc1
Temperature: 80 °C
Reaction time: 48 h
Yield: 59.7 %

Procedure:
557 mg (1.13 mmol) of 4-[N-(2-bromoethyl)sulfamoyl]-N-(3-chloro-1H-indole-7-yl)benzenesulfonamide and 820 mg (12.0 mmol) of imidazole were added to 10 ml of dimethylformamide and the mixture was stirred at 80° C. for 2 days. After concentrating, the residue was dissolved in ethyl acetate. The mixture was washed with water, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography, to give 324 mg of the title compound.