Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCO.CO>[NH2:15][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Reactant: Nc1ccccc1
Solvent: CCCCO
Solvent: CO
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Yield: 84.9 %

Procedure:
Step-1 A solution of N2-(6-chloropyrimidin-4-yl)pyridine-2,6-diamine (1) (0.25 g, 1.1 mmol) and aniline (2) (0.16 g, 1.7 mmol) in n-BuOH (25 mL) was heated at 120° C. for 12 h in a pressure tube. The reaction mixture was cooled, was dissolved in methanol (10 mL) and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (35 mL) and was washed successively with 10% sodium bicarbonate solution (20 mL), water (20 mL), and saturated brine (20 mL). The ethyl acetate extract was dried over Na2SO4 and was concentrated under reduced pressure to give a residue, which was triturated with diethyl ether to give (260 mg, 83%) N4-(6-aminopyridin-2-yl)-N6-phenylpyrimidine-4,6-diamine (3) as an off-white solid. Step-2 To a stirred solution of 3 (0.2 g, 0.7 mmol) in NMP (10 mL) was added acryloyl chloride (0.097 g, 1 mmol), drop wise at 0° C. The reaction mixture was allowed to stir at the same temperature for 20 min and then warmed to rt for 1.5 h. It was quenched with 10% sodium bicarbonate solution (4 mL) and was extracted with ethyl acetate (2×35 mL). The combined ethyl acetate layer was washed with water (20 mL), saturated brine (20 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was further purified by column chromatography (SiO2, 60-120, Petroleum ether/EtOAc: 90/10) to give N-6-(6-(phenylamino)pyrimidin-4-ylamino)pyridine-2-yl)acrylamide (I-72) as a brown solid. 1H NMR (DMSO-d6) δ ppm: 5.80 (dd, J=1.84 & 10.12 Hz, 1H), 6.31 (dd, J=1.8 & 16.96 Hz, 1H), 6.64 (dd, J=10.08 & 16.88 Hz, 1H), 6.96 (t, J=7.32 Hz, 1H), 7.15-7.20 (m, 1H), 7.28 (t, J=7.52 Hz, 2H), 7.34 (s, 1H), 7.60-7.70 (m, 4H), 8.30 (s, 1H), 9.08 (s, 1H), 9.66 (s, 1H), 10.06 (s, 1H); LCMS: m/e 332.6 (M+).
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:44][C:45](=[O:52])[C@H:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[NH2:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[C:29]([CH:37]=[CH:38][CH:39]=2)[O:30][CH2:31][CH2:32][CH2:33][C:34]([NH:47][C@H:46]([C:45]([OH:44])=[O:52])[CH2:48][CH:49]([CH3:51])[CH3:50])=[O:35])=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)O)c2)cc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2cccc(OCCCC(=O)N[C@@H](CC(C)C)C(=O)O)c2)cc1

Procedure:
The product from Example 116B (57 mg, 0.10 mmole) and L-leucine methyl ester hydrochloride (36 mg, 0.20 mmole) were processed as in Example 279A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.22-12.61 (br.s, 1 H), 8.95 (s, 1 H), 8.06 (d, 1 H), 7.24 (m, 8 H), 7.03 (m, 1 H), 6.94 (m, 4 H), 6.67 (dd, 1 H), 6.49 (m, 2 H), 4.22 (m, 1 H), 4.06 (s, 2 H), 4.03 (s, 2 H), 3.91 (m, 2 H), 2.91 (s, 3 H), 2.40 (s, 3 H), 2.26 (m, 2 H), 1.90 (m, 2 H), 1.60 (m, 1 H), 1.47 (m, 2 H), 0.85 (d, 3 H), 0.81 (d, 3 H); MS (APCI+) m/z 688.7 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([OH:12])[CH:4]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>S(=O)(=O)(O)O.O>[CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[C:5]([O:12][C:13](=[O:15])[CH3:14])[CH:4]=1
Reactant: CSc1ccc(C(=O)O)c(O)c1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CSc1ccc(C(=O)O)c(OC(C)=O)c1
Temperature: 75 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a mixture of 4-methylthio-2-hydroxybenzoic acid (50.0 g, 272 mmol) and acetic anhydride (77.0 mL, 815 mmol) was added 36 N sulfuric acid (0.45 mL, 8.16 mmol) and the mixture was heated to 75° C. for 1 h. To the reaction mixture was added H2O (200 mL), and it was stirred for 18 h. A white precipitate was collected, triturated with dichloromethane, (100 mL), diluted with 20% Et2O/hexanes (300 mL), and filtered to give the title compound as a white solid (49 g, 80%).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:4]=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:11])[CH3:1])[C:4]=1[B:17]([OH:20])[OH:18]
Reactant: COB(OC)OC
Reactant: COc1cccc(N(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(N(C)C)c1B(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5.3 g (35 mmol) of 3-dimethylamino-anisole in 25 mL of dry THF at −78° C. was added 19 mL (47 mmol) of a 2.5M solution of n-butyl lithium in hexanes. The reaction mixture was stirred for 1 hour before removing the ice bath and warming to room temperature for 90 minutes. The solution was cooled to −78° C., treated with 8.75 g (84 mmol) of trimethyl orthoborate, and then stirred for one hour before warming to room temperature for one hour. The reaction was quenched by the addition of 20 mL of water and sufficient acetic acid to neutralize the mixture. The reaction mixture was extracted with ethyl acetate (3×30 mL), and the combined organic extracts were extracted with 1N NaOH solution (4×15 mL). The combined aqueous extracts were acidified with acetic acid and extracted with EtOAc (3×20 mL). The organic phase was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give 2-methoxy-6-dimethylamino-phenylboronic acid.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[C:29]([C:30]#[N:31])=[C:28]([CH:32]=O)[NH:27][C:26]2=[N:34][NH:35][CH:36]=[C:25]12.O>C(COC)OC>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]1[C:29]([C:30]#[N:31])=[C:28](/[CH:32]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:27][C:26]2=[N:34][NH:35][CH:36]=[C:25]12
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: N#CC1=C(C=O)Nc2n[nH]cc2C1c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)/C=C/C1=C(C#N)C(c2ccccc2Cl)c2c[nH]nc2N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.1 %

Procedure:
To a suspension of sodium hydride (94 mg) in dimethoxyethane (10 ml) was added ethyl diethylphosphonoacetate (528 mg) and the mixture was stirred at room temperature for 15 minutes. Under ice-cooling, 4-(2-chlorophenyl)-5-cyano-6-formyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (670 mg) was added to the mixture, and the mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give the title compound (560 mg) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-]>C(=S)=S>[Cl:13][CH2:14][C:15]([C:7]1[C:6]([CH3:8])=[CH:5][C:4]([NH:9][C:10](=[O:12])[CH3:11])=[CH:3][C:2]=1[CH3:1])=[O:16]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)Nc1cc(C)cc(C)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)Nc1cc(C)c(C(=O)CCl)c(C)c1
Yield: 57.9 %

Procedure:
To a solution of N-(3,5-dimethylphenyl)acetamide (4.0 g, 24.5 mmol) and ClCH2COCl (4.2 g, 37 mmol) in CS2 (30 mL), AlCl3 (10.0 g, 74.9 mmol) was added in portions. The resulting mixture was refluxed overnight. The reaction mixture was then cooled down to room temperature before the CS2 layer was decanted. The resulting complex was decomposed by pouring onto a mixture of ice (500 g) and concentrated HCl (30 mL). The solid was collected by suction, washed with 1N HCl and water, and recrystallized in EtOH to afford N-(4-(2-chloroacetyl)-3,5-dimethylphenyl)acetamide as a brown powder (3.4 g, 57.9%), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:30])[C:5]([O:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(C)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)cc1
Reaction time: 20 h

Procedure:
2-(p-Tolyloxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: C([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[NH:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19](=[O:28])[NH:20][C:21]3[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=3)=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C(Nc1ccc(Br)cc1)Oc1ccc2c(c1)CCCN2Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: O=C(Nc1ccc(Br)cc1)Oc1ccc2c(c1)CCCN2

Procedure:
Nitrogen flushed mixture of 4-bromo-phenyl-carbamic acid 1-benzyl-1,2,3,4-tetrahydro-quinolin-6-yl ester (0.655 g., 1.5 mmol) and 5% Pd—C (0.06 g.) in absolute ethanol (20 ml) was shaken in a par apparatus at room temperature (40° C.) under 50 psi pressure of hydrogen for 5 hours. Then Pd—C was discarded through filtration. The reaction mixture was concentrated under reduced pressure and the residue was washed with dichloromethane (2×3ml) to give 2f; yield: 0.48 g. (92.3%), m.p: 198° C., C16H15BrN2O2; 1H NMR δ ppm (DMSO): 1.82-2.00 (bs, 2H), 2.76 (t, 2H), 3.27 (t, 2H), 7.01-7.08 (m, 3H), 7.25-7.39 (m, 4H), 10.14 (s, 1H), IR vmax (KBr) (cm−1): 506, 608, 690, 749, 814, 884, 927, 1005, 1211, 1265, 1319, 1354, 1401, 1440, 1501, 1550, 1601, 1748, 1938, 2370, 2779, 2725, 2767, 2823, 2922, 3262, 3420, 3774.
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])S[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:14][C:5]1=2)[CH3:2].Cl.OO[S:22]([O-:24])=[O:23].[K+]>CO.O>[CH2:1]([NH:3][CH:4]1[CH2:9][C:8]([CH3:11])([CH3:10])[S:22](=[O:24])(=[O:23])[C:6]2[S:12][C:13]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:14][C:5]1=2)[CH3:2]
Reactant: CCNC1CC(C)(C)Sc2sc(S(N)(=O)=O)cc21
Reactant: O=S([O-])OO
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCNC1CC(C)(C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21

Procedure:
A solution of 5,6-dihydro-4-ethylamino-6,6-dimethyl-4H-thieno[2,3-b]thiopyran-2-sulfonamide (3.95 g, 0.013 mol) in methanol (85 ml) was acidified with 6.25N methanolic hydrogen chloride (2.1 ml). With stirring, a solution of `Oxone` (11.68 g, 0.019 mol) in water (65 ml) was added 15 minutes. After stirring at ambient temperature for 17.5 hours, the mixture was filtered and the solid was washed with methanol. The combined filtrate and washings were concentrated in vacuo below 55° C. to remove methanol and the cloudy aqueous solution was basified with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (150 ml and 2×100 ml), and the combined extracts were washed twice with water, dried over sodium sulfate and evaporated in vacuo. The amorphous residue was converted to the crystalline hydrochloride salt using ethanolic hydrogen chloride to yield 2.16 g (44%) of analytically pure product melting at 255°-255.5° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:24]([O:27][CH2:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=[CH:31][C:30]=1[N:44]1[CH2:56][CH2:55][N:47]2[C:48]3[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=3[CH:54]=[C:46]2[C:45]1=[O:57])(=[O:26])[CH3:25].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.C(Cl)Cl>[C:24]([O:27][CH2:28][C:29]1[C:30]([N:44]2[CH2:56][CH2:55][N:47]3[C:48]4[CH2:49][CH2:50][CH2:51][CH2:52][C:53]=4[CH:54]=[C:46]3[C:45]2=[O:57])=[CH:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:26])[CH3:25]
Reactant: CN1CCC(c2ccc(Nc3cc(Br)cn(C)c3=O)nc2)CC1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
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: ClCCl
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C4CCN(C)CC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O

Procedure:
To a microwave tube equipped with a stirring bar, 130c (250 mg, 0.663 mmol), 2-(2-(hydroxymethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-1(2H)-one 114a (338 mg, 0.729 mmol), Pd(PPh3)4 (38.3 mg, 0.033 mmol), Na2CO3 aqueous solution (1.0 N, 2.19 mL, 2.19 mmol), DME (2 mL) were added. The mixture was reacted in microwave at 135° C. for 15 min. CH2Cl2 (200 mL) was added and the resulting mixture was washed with water (30 mL×3), brine (30 mL×1), dried over MgSO4, filtered, and removed solvent in vacuo. Silica gel column chromatography (MeOH:DCM=5:95) gave 130d.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([NH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:12][C:11]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[N:10]2)=[CH:4][CH:3]=1.CI.[C:34](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[C:14](=[O:15])[C:13]([N:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:34])=[CH:12][C:11]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)=[N:10]2)=[CH:30][CH:31]=1
Reactant: CCOC(=O)Nc1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)N(C)c1cc(-c2ccc(OC)cc2)nn(CC=Cc2ccc(Cl)cc2)c1=O
Yield: 89.2 %

Procedure:
In N,N-dimethylformamide, 2-(4-chlorocinnamyl)-4-ethoxycarbonylamino-6-(4-methoxyphenyl)-2H-pyridazin-3-one (100 mg) was stirred at 80° C. for 1 hour in the presence of methyl iodide and potassium carbonate. The procedures of Example 1 were then repeated likewise, whereby the title compound (92 mg, 89.2%) was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15](F)[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:29][NH:30][CH3:31].CS(C)=O>O>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([OH:28])[CH2:14][CH2:13][N:12]([CH:15]([N:30]([CH3:31])[CH3:29])[CH2:16][CH:17]([F:26])[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:19])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CNC
Reactant: O=C(c1ccccc1)C(F)CC(F)N1CCC(O)(c2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: CN(C)C(CC(F)C(=O)c1ccccc1)N1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of γ-[4-(p-chlorophenyl)-4-hydroxypiperidin-1-yl]-2,4-difluorobutyrophenone hydrochloride (2.0 g), 40 % aqueous solution of dimethylamine (10.0 g) and dimethylsulfoxide (30 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into cold water (200 ml). The precipitate was filtered and recrystallized from aqueous ethanol to yield γ-[4-(p-chlorophenyl)-4-hydroxypiperidin-1-yl]-4-dimethylamino-2-fluorobutyrophenone. M.P. 160° to 163°C.
Reaction SMILES: Cl.[C:2]([O:5][C@H:6]1[C@H:11]([NH2:12])[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3].Cl.CN(C)CCCN=C=NCC.[C:38]1([CH2:44][C:45](O)=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:2]([O:5][C@H:6]1[C@H:11]([NH:12][C:45](=[O:46])[CH2:44][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@@H:10]([O:13][C:14](=[O:16])[CH3:15])[C@H:9]([O:17][C:18](=[O:20])[CH3:19])[C@@H:8]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[O:7]1)(=[O:4])[CH3:3]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](N)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(O)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](NC(=O)Cc2ccccc2)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 12 h
Yield: 68.6 %

Procedure:
To a suspension of (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-amino-tetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (0.500 g, 1.31 mmol) in CH2Cl2 (20 mL) was added 4-(dimethylamino)pyridine (0.478 g, 3.91 mmol) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.300 g, 1.57 mmol) and 2-phenylacetic acid (0.2132 g, 1.57 mmol). The reaction was stirred for 12 h. Additional CH2Cl2 (80 mL) was added and the organic layer was washed once with saturated aqueous NaHCO3 (10 mL). The organic layer was then dried (MgSO4) and concentrated in vacuo. Flash chromatography of the crude material on silica gel (3:2 EtOAc:hexanes) followed by crystallization (EtOAc/hexanes) afforded (2S,3R,4R,5S,6R)-6-(acetoxymethyl)-3-(2-phenylacetamido)-tetrahydro-2H-pyran-2,4,5-triyl triacetate as a white solid (0.418 g, 69% yield).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][NH:4]1.[C:8](Cl)(=[O:10])[CH3:9].[OH-].[K+]>ClCCl>[OH:1][CH2:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8](=[O:10])[CH3:9]
Reactant: OCC1CCCN1
Reactant: CC(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(=O)N1CCCC1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
2-(Hydroxymethyl)pyrrolidine (500 mg) was mixed with dichloromethane (5 ml), and TEA (0.9 ml) and acetyl chloride (407 mg) were added thereto at 0° C., followed by stirring at room temperature overnight. 8 M Potassium hydroxide was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The reaction mixture was extracted by the addition of water and CHCl3/MeOH (4:1), the organic layer was washed with water and saturated brine, and dried over anhydrous Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (MeOH/CHCl3) to obtain 1-[2-(hydroxymethyl)pyrrolidin-1-yl]ethanone (442 mg).
Reaction SMILES: [N:1]([CH:4]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]1=[O:23])=[N+]=[N-]>C(O)C.[Pd]>[NH2:1][CH:4]1[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=2[N:6]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]1=[O:23]
Reactant: CCOC(=O)CN1C(=O)C(N=[N+]=[N-])CCCCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN1C(=O)C(N)CCCCc2ccccc21

Procedure:
A solution of 3-azido-1-ethoxycarbonylmethyl-1,3,4,5,6,7-hexahydro-1-benzazonin-2one (5.0 g) in ethanol (500 ml) is hydrogenated at atmospheric pressure using 10% palladium on charcoal (0.7 g) as catalyst. The catalyst is filered off and the solvent removed under reduced pressure to give 3-amino-1-ethoxycarbonylmethyl-1,3,4,5,6,7-hexahydro-1-benzazonin-2-one.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH3:25])[CH2:21][CH2:20]1)=[O:18])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(C)(C)C.[NH:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([S:36](Cl)(=[O:38])=[O:37])[C:30]=2[CH:29]=[CH:28]1>>[CH3:25][CH:22]1[CH2:21][CH2:20][N:19]([C:17]([CH:8]([NH:7][S:36]([C:31]2[C:30]3[CH:29]=[CH:28][NH:27][C:35]=3[CH:34]=[CH:33][CH:32]=2)(=[O:37])=[O:38])[CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[O:18])[CH2:24][CH2:23]1
Reactant: O=S(=O)(Cl)c1cccc2[nH]ccc12
Reactant: CC1CCN(C(=O)C(CCc2ccncc2)NC(=O)OC(C)(C)C)CC1
Product: CC1CCN(C(=O)C(CCc2ccncc2)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
Example 53 is prepared from 70 mg (0.19 mmol) of tert-butyl{1-[(4-methylpiperidin-1-yl)carbonyl]-3-pyridin-4-ylpropyl}carbamate and indole-4-sulfonyl chloride in the same manner as Example 49 (51 mg, 60% yield). ESI MS Calc. 440.2; Found: 441.3 (M+H)+.
Reaction SMILES: [C:1]([NH2:5])(=[O:4])[C:2]#[CH:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[NH:17][C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:3]#[C:2][C:1]([NH2:5])=[O:4])=[CH:23][CH:22]=1)=[O:19]
Reactant: O=C(Nc1ccc(I)cc1)Nc1cc(C(F)(F)F)ccc1F
Reactant: C#CC(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NC(=O)C#Cc1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.1 %

Procedure:
To a mixture of propynoic acid amide (41.4 mg, 0.60 mmol), 1-[2-fluoro-5-(trifluoromethyl)phenyl]-3-(4-iodophenyl)urea (169.7 mg, 0.40 mmol), triethylamine (0.167 mL, 1.2 mmol), dichlorobis(triphenylphosphine)palladium(II) (22.5 mg, 0.032 mmol), and triphenylphosphine (5.2 mg, 0.020 mmol) in 3.0 mL DMF (degassed) was added copper(I)iodide (7.6 mg, 0.04 mmol) and the reaction stirred at rt for 17 hours. The reaction was combined with a prior test reaction (36.5 mg theoretical yield) and partitioned between EtOAc and H2O/brine mixture. The EtOAc layer was washed 3 times with H2O/brine mixture, then brine, dried with anhydrous Na2SO4 and rotary evaporated to a solid. The solid was chromatographed eluting with EtOAc/CHCl3 and then triturated with EtOAc/hexane to give the title compound as a light tan solid (118.5 mg, 65%). 1H NMR (DSMO-d6) δ: 9.45 (s, 1H), 8.98 (d, J=2.9 Hz, 1H), 8.59 (dd, J=7.3, 2.1 Hz, 1H), 8.07 (br. s, 1H), 7.59 (br. s., 1H), 7.47-7.58 (m, 5H), 7.38-7.45 (m, 1H).
Reaction SMILES: OC1C(=O)N(C)C2C([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=CC=CC=2.[CH:19]([N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[C:23]1=[O:32])([CH3:21])[CH3:20]>>[OH:31][C:24]1[C:23](=[O:32])[N:22]([CH:19]([CH3:20])[CH3:21])[C:30]2[C:25]([C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:26][CH:27]=[CH:28][CH:29]=2
Reactant: CC(C)N1C(=O)C(=O)c2ccccc21
Reactant: CCOC(=O)c1c(O)c(=O)n(C)c2ccccc12
Product: CCOC(=O)c1c(O)c(=O)n(C(C)C)c2ccccc12

Procedure:
Intermediate 19 was prepared as a white powder following the procedure described for Intermediate 16 by replacing indoline-2,3-dione with 1-isopropylindoline-2,3-dione. 1H NMR (400 MHz, chloroform-d) δ ppm 8.10 (1 H, br. s.), 7.77 (1 H, d, J=7.8 Hz), 7.60 (1 H, d, J=8.3 Hz), 7.42 (1 H, t, J=7.7 Hz), 7.27 (1 H, t, J=7.5 Hz), 4.53 (2 H, q, J=7.1 Hz), 1.45 (3 H, t, J=7.1 Hz). LC-MS (ESI) m/z 276.0 (M+H), RT=1.93 min (Method B)