Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[O:14]=[C:6]1[C:5]2[CH:15]=[CH:16][C:2]([NH:1][CH2:25][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][C:4]=2[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7]1
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: CCOC(=O)CC(C)Br
Product: CCOC(=O)CCCNc1ccc2c(=O)[nH]c3ncccc3c2c1
Yield: 12.9 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 458 using 70 (160 mg, 0.76 mmol) and ethyl 3-bromobutanoate (0.01 mL, 0.91 mmol) to provide 460 (32 mg, 13% yield) as a white powder. LC-MS (M+H=326, obsd.=326). 1H NMR (400 MHz, DMSO-D6) δ 8.53 (ddd, J=1.7, 6.4, 9.7, 2H), 8.03 (d, J=8.6, 1H), 7.27 (m, 2H), 6.88 (dd, J=2.1, 8.7, 1H), 6.14 (s, 2H), 4.47 (t, J=6.9, 2H), 3.97 (q, J=7.1, 2H), 2.33 (t, J=7.4, 2H), 1.95 (p, J=7.3, 2H), 1.12 (t, J=7.1, 3H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:19][C:20]([CH2:23][NH2:24])=[N:21][N:22]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+].Cl>O1CCCC1.O>[NH2:24][CH2:23][C:20]1[S:19][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:25])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:22][N:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(CN)s3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2nnc(CN)s2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 7.5 %

Procedure:
To a solution of [6-(5-aminomethyl-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.22 g, 0.6 mmol) in tetrahydrofuran (10 mL) at 0° C. was added lithium hydroxide (0.06 g, 2.42 mmol) in water (5 mL). The mixture was stirred at 0° C. for 1.5 hours then acidified to pH=2 with 2N HCl. The mixture was concentrated in vacuo and the residue purified by preparative HPLC to give [6-(5-aminomethyl-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.015 g, 7%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.37 (s, 1H), 8.58 (br. s., 3H), 7.48 (s, 1H), 7.33 (d, J=1.62 Hz, 1H), 5.56 (dd, J=9.23, 2.52 Hz, 1H), 4.43 (s, 2H), 3.10 (dd, J=15.63, 2.71 Hz, 1H), 2.34 (s, 3H), 2.18 (dd, J=15.44, 9.21 Hz, 1H); MS (ESI) m/z: 336 [M+1]+; HPLC purity: 94.12% (MaxPlot), 96.99% (220 nm).
Reaction SMILES: [CH2:1]([N:8]1[CH:17]=[C:16](I)[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[C:25](B(O)O)=[C:24]([CH3:29])[O:23][N:22]=1.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:1]([N:8]1[CH:17]=[C:16]([C:25]2[C:21]([CH3:20])=[N:22][O:23][C:24]=2[CH3:29])[C:15]2[C:10](=[CH:11][N:12]=[CH:13][CH:14]=2)[C:9]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: O=c1c2cnccc2c(I)cn1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1noc(C)c1-c1cn(Cc2ccccc2)c(=O)c2cnccc12
Temperature: 95 °C
Yield: 52.7 %

Procedure:
A mixture of 2-benzyl-4-iodo-2,7-naphthyridin-1(2H)-one (0.540 g, 1.49 mmol), (3,5-dimethylisoxazol-4-yl)boronic acid (0.315 g, 2.24 mmol) and Na2SO4 (0.474 g, 4.47 mmol) in toluene (25 mL), ethanol (25 mL) and water (4 mL) was degassed. Pd(PPh3)4 (0.172 g, 0.15 mmol) was then added and the reaction mixture was heated at 95° C. for 6 h. After that time the reaction was cooled to rt, concentrated under reduced pressure and diluted with ethyl acetate (100 mL). The organic phase was washed with water then brine, dried over Na2SO4, and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, dichloromethane to 99:1 ethyl acetate/methanol) to give 2-benzyl-4-(3,5-dimethylisoxazol-4-yl)-2,7-naphthyridin-1(2H)-one (0.260 g, 54%) as an off-white solid: mp 174-177° C.; 1H NMR (400 MHz, CDCl3) δ 9.73 (s, 1H), 8.75 (d, J=5.4 Hz, 1H), 7.31-7.41 (m, 5H), 7.16 (s, 1H), 7.02 (d, J=5.4 Hz, 1H), 5.26 (s, 2H), 2.23 (s, 3H), 2.06 (s, 3H); ESI MS m/z 332 [M+H]+.
Reaction SMILES: [CH:1]([C:5]1[CH2:6][C@@H:7]2[C@H:10]([CH:11]=1)[C:9](=[CH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)([CH2:3][CH3:4])[CH3:2].N12CCCN=C1CCCCC2.P([O-])(O)(O)=O.[K+].[N+:37]([CH3:40])([O-:39])=[O:38]>>[N+:37]([CH2:40][C@@:9]1([CH2:12][C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:8][C@H:7]2[C@@H:10]1[CH:11]=[C:5]([CH:1]([CH2:3][CH3:4])[CH3:2])[CH2:6]2)([O-:39])=[O:38]
Reactant: CCC(C)C1=C[C@@H]2C(=CC(=O)OC(C)(C)C)C[C@@H]2C1
Reactant: C[N+](=O)[O-]
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCC2=NCCCN2CC1
Product: CCC(C)C1=C[C@H]2[C@@H](C1)C[C@]2(CC(=O)OC(C)(C)C)C[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 5 h

Procedure:
Tert-butyl(±)-[(1S,5R)-3-sec-butylbicyclo[3.2.0]hept-3-en-6-ylidene]acetate (3.10 g, 11.8 mmol) was dissolved in nitromethane (30 mL). To the solution, 1,8-diazabicyclo[5.4.0]undec-7-ene (2.20 g, 14.5 mmol) was added, and the mixture was stirred at 60° C. for 5 hours. The mixture was allowed to cool, and a saturated aqueous solution of potassium dihydrogen phosphate was then added thereto, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain the compound of interest as a yellow oil substance (3.28 g, 86%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:5]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:7]([CH2:8][C@@H:9]([C:22]([O:24]C)=[O:23])[NH:10][C:11](=[O:21])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:6]1)[CH3:4]>CO>[CH2:3]([N:5]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:7]([CH2:8][C@@H:9]([C:22]([OH:24])=[O:23])[NH:10][C:11](=[O:21])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])=[CH:6]1)[CH3:4]
Reactant: CCn1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)OC)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCn1cc(C[C@H](NC(=O)C=Cc2ccccc2F)C(=O)O)c2ccccc21
Reaction time: 23 h
Yield: 91.7 %

Procedure:
One mol/L of an aqueous sodium hydroxide solution (9.9 mL) was added dropwise to methanol (100 mL) solution of the compound obtained in Example 146 (2.6 g) at room temperature. The mixture was allowed to stir for 23 hours. The reaction mixture was concentrated to a ⅕ volume, added with water, and made acidic with dilute hydrochloric acid. The crystals precipitated were filtered, and washed with water, to give the captioned compound (2.3 g, 93%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][C:8]1[C:12]2[C:13](=[O:27])[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]=2[NH:10][N:9]=1)([O-])=O>CN(C=O)C.CO.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:28]=[CH:29][CH:30]=1)[CH2:7][C:8]1[C:12]2[C:13](=[O:27])[N:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:20]=3[C:11]=2[NH:10][N:9]=1
Reactant: O=c1c2c(Cc3cccc([N+](=O)[O-])c3)n[nH]c2c2cccnc2n1-c1ccccc1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1cccc(Cc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution of 3-(3-nitrobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (273 mg, 0.69 mmol, prepared in Example 25) in DMF (14 ml) and methanol (14 ml) was added activated carbon-palladium (27 mg), the mixture was stirred under hydrogen atmosphere overnight, and filtered. After methanol was distilled off, the resultant solution was admixed with water, and filtered to give precipitates which were dried to afford 3-(3-aminobenzyl)-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (220 mg, 87%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1(O)[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([BH3-])#N.[Na+].O>ClCCCl.[I-].[Zn+2].[I-]>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH2:29][O:30][CH3:31])=[CH:25][CH:26]=2)[O:21][CH2:20][C:19]1([C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][O:41][CH3:42])=[CH:35][CH:34]=1)[CH3:32])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2(O)C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Agent: [BH3-]C#N
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2C#CCCCCCCCO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of 4-[9-(t-butyldimethylsilyloxy)-1-nonynyl]-4-hydroxy-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (3.10 g, 5.06 mmol) in 1,2-dichloroethane (200 ml) were added zinc iodide (2.42 g, 7.59 mmol) and sodium cyanoborohydride (2.23 g, 35.42 mmol), which was then stirred at room temperature for 8 hours. After the reaction was completed, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=9:1) to give the title compound (1.50 g, yield 50%, 3RS/4RS:3RS14SR=6:1) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([NH:28][S:29]([CH:32]=[CH2:33])(=[O:31])=[O:30])([CH3:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24].Br[C:35]1[S:36][CH:37]=[CH:38][CH:39]=1.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:27][C:21]([NH:28][S:29](/[CH:32]=[CH:33]/[C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)(=[O:31])=[O:30])([CH3:20])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26]
Reactant: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Reactant: Brc1cccs1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC(C)(C)NS(=O)(=O)/C=C/c1cccs1
Temperature: 140 °C
Yield: 21.2 %

Procedure:
Palladium acetate (169 mg, 0.75 mmol) and triphenylphosphine (420 mg, 1.6 mmol) were added to a solution of ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (10 g, 45.7 mmol) and 2-bromo-thiophene (3.74 mL, 39.1 mmol) in N,N-dimethylformamide (75 mL). Triethylamine (14.7 mL, 105.5 mmol) was added and the mixture was flushed with nitrogen and heated at 140° C. for 16 hours. The mixture was cooled to room temperature and 1N HCl (250 mL) was added in one portion. The mixture was extracted with ethyl acetate (3×200 mL) and the combined organics were dried over MgSO4, filtered and concentrated in vacuo to afford a solid. The solid was purified by dry flash chromatography (SiO2, heptane to 1:1 heptane: ethyl acetate). The fractions were combined to afford (E)-2-thiophen-2-yl-ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide (2.5g, 21% yield).
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]1([CH3:10])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>>[C:4]1([CH3:10])[C:9]([CH2:1][OH:2])=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccccc1
Reactant: C[O-]
Agent: [Na+]
Product: Cc1ccccc1CO

Procedure:
The preferred conditions are to dissolve 1 mole of alcohol (II) and 1.25 to 1.75 mole of ester (V) in which R4 is methyl in 25 to 35 parts by weight of toluene, referred to the quantity of (II) used. The solution is heated to 65°-75° C., 0.025 to 0.05 mole of sodium methylate is added, and the toluene-methanol azeotrope formed is distilled slowly for 1 to 2 hours. A further 0.0125 to 0.025 mole of sodium methylate is added and the solution is distilled for 30 minutes to 1 hour; this last operation is repeated once more. The products of the reaction are then isolated and purified by the aforesaid techniques.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[S:21][C:20]([S:22][CH3:23])=[C:19]([C:24]#[N:25])[C:18]=3[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:14]([CH3:32])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.CCOC(C)=O>[Pd].CO>[NH2:1][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[S:21][C:20]([S:22][CH3:23])=[C:19]([C:24]#[N:25])[C:18]=3[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:14]([CH3:32])=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CSc1sc(-c2nc(Nc3cccc([N+](=O)[O-])c3)ncc2C)c(C2CCCCC2)c1C#N
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CSc1sc(-c2nc(Nc3cccc(N)c3)ncc2C)c(C2CCCCC2)c1C#N
Reaction time: 8 h

Procedure:
A suspension of 5-[2-(3-Nitrophenylamino)-5-methyl-pyrimidin-4-yl]-4-cyclohexyl-2-methylsulfanyl-thiophene-3-carbonitrile (0.187 g, 402 umol) and 10% palladium on carbon in methanol was stirred under a hydrogen atmosphere overnight resulting in complete conversion to product as determined by TLC (40% EtOAc:hexanes). The reaction was filtered through celite and concentrated in vacuo to afford the desired amine V-8 (0.186 g, 426 umol) in quantitative yield. 1NMR (CDCl3) δ1.0-1.1(m, 10H), 2.1 (s, 3H), 2.6 (s, 3H), 6.2 (d, 1H), 6.8 (d, 1H), 6.9-7.0 (m, 3H) , 8.2 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20]CC3C=CC=CC=3)[CH:15]=2)[CH:10]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)[CH:10]([O:28][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COc2cccc(C3CCN(Cc4ccccc4)CC3OCc3ccc4ccccc4c3)c2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: Oc1cccc(C2CCN(Cc3ccccc3)CC2OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 31.5 %

Procedure:
A solution of 250 mg (0.487 mmol) of (3RS,4RS)-1-benzyl-4-(3-benzyloxy-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine in 1.1 ml of methylene chloride was treated at room temperature with 247 μl (236 mg, 1.946 mmol, 4 eq.) of N,N-dimethylaniline and 195 mg (1.46 mmol, 3.0 eq.) of aluminium trichloride and stirred at room temperature for 2.5 hours. Subsequently, the mixture was partitioned between methylene chloride and 5% sodium hydrogen carbonate solution, the organic phase was dried over magnesium sulphate and finally the solvent was removed under reduced pressure. The crude product was purified by chromatography on silica gel with a 4:1 mixture of methylene chloride and hexane as the eluent. There were obtained 65 mg (32% of theory) of (3RS,4RS)-1-benzyl-4-(3-hydroxyphenyl)-3-(naphthalen-2-ylmethoxy)-piperidine as a beige coloured solid; MS: 423 (M)+.
Reaction SMILES: [CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])[CH2:5][CH2:4][CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl.O>[CH:1]1([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH:8][C:20](=[O:21])[CH2:19][Cl:18])[CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1C1C=CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=C(CCl)Nc1ccccc1C1C=CCC1
Temperature: 0 °C
Yield: 77 %

Procedure:
A solution of 10.00 g (62.8 mmol) of 2-(cyclopent-2-enyl)aniline from Example 1 in 150 mL of methylene chloride and 5.28 g (62.8 mmol) of sodium bicarbonate in 15 mL of water were combined with rapid stirring and cooled 0° C. with the aid of an ice bath. A solution of 7.099 (62.8 mmol) of chloroacetyl chloride in 25 mL of methylene chloride was then added dropwise through the course of 20 min. After an additional hour of vigorous stirring. the layers were separated and the organic layer was dried over anhydrous magnesium sulfate. Evaporation of the solvent in the organic layer and recrystallization of the precipitate with ether afforded 11.41 g (77% yield) of N-[2-(cyclopent-2-enyl)phenyl]-2-chloroacetamide: mp 101°-102° C.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]([C:16]#[N:17])[C:14]#[N:15].O.[NH2:19][NH2:20]>C(O)C>[CH3:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]1[C:16]([NH2:17])=[N:19][NH:20][C:14]=1[NH2:15]
Reactant: NN
Reactant: Cc1c(CC(C#N)C#N)cccc1C(F)(F)F
Solvent: O
Solvent: CCO
Product: Cc1c(Cc2c(N)n[nH]c2N)cccc1C(F)(F)F
Yield: 47.4 %

Procedure:
To a mixture of malononitrile (2.352 g, 35.6 mmol) in 95% Ethanol (50 mL) was added 2-methyl-3-(trifluoromethyl)benzaldehyde (6.7 g, 35.6 mmol). The reaction was stirred at rt for 18 h. Additional EtOH (20 mL) was added and the mixture was stirred for 20 minutes and cooled to 0° C. in an ice bath. Sodium borohydride (0.364 g, 9.61 mmol) was introduced to the vigorously stirred mixture and the reduction was complete in about 10 min. To the reaction mixture was added water (40 mL). 1N HCl was added in to quench the excess hydride. More water was added in until precipitation was complete. Filtration gave {[2-methyl-3-(trifluoromethyl)phenyl]methyl}propanedinitrile (6.5 g, 77%). To a mixture of {[2-methyl-3-(trifluoromethyl)phenyl]methyl}propanedinitrile (6.5 g, 27.3 mmol) in Ethanol (80 mL) was added hydrazine hydrate (2.68 mL, 54.6 mmol). The reaction mixture was heated at reflux temperature for 8 h. The reaction mixture was concentrated. The crude material was purified on a silica column (eluting with MeOH/DCM: 0˜10%) to give the product (3.5 g, 47%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.47 (s, 3H) 3.69 (s, 2H) 7.11-7.37 (m, 2H) 7.51 (d, 1H); LC/MS: MS (ES+) m/e 271.2 [M+H]+.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([N:73]3[CH2:78][CH2:77][C:76]([F:80])([F:79])[CH2:75][CH2:74]3)=[CH:71][CH:72]=2)[C:56]=1[CH3:81].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:80][C:76]1([F:79])[CH2:75][CH2:74][N:73]([C:70]2[N:69]=[CH:68][C:67]([C:57]3[C:56]([CH3:81])=[C:55]([NH:47][C:46]4[C:41]([N:38]5[CH2:39][CH2:40][O:35][CH2:36][CH2:37]5)=[N:42][CH:43]=[C:44]([N:48]5[CH2:49][CH2:50][O:51][CH2:52][CH2:53]5)[CH:45]=4)[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=3)=[CH:72][CH:71]=2)[CH2:78][CH2:77]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(-c2ccc(N3CCC(F)(F)CC3)nc2)nc2cc(F)cc(F)c2c1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCC(F)(F)CC3)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.015 g, 0.031 mmol), 2,5-dimorpholinopyridin-3-amine (0.062 g, 0.23 mmol), 4-chloro-2-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-5,7-difluoro-3-methylquinoline (0.08 g, 0.20 mmol) and Pd2dba3 (0.007 g, 0.008 mmol) and sodium tert-butoxide (0.047 g, 0.49 mmol) in toluene (2.0 mL) at 100° C. for 73 h. The crude product was purified by column chromatography on silica gel (0 to 100% DCM/methanol/ammonium hydroxide (90/9/1)) to give the desired product 2-(6-(4,4-difluoropiperidin-1-yl)pyridin-3-yl)-N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methylquinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.47 (1H, d, J=2.2 Hz), 7.90 (1H, dd, J=8.9, 2.4 Hz), 7.76 (1H, d, J=5.9 Hz), 7.57-7.63 (1H, m), 7.55 (1H, d, J=2.7 Hz), 7.38-7.46 (1H, m), 7.10 (1H, d, J=8.8 Hz), 6.41 (1H, d, J=2.3 Hz), 3.80 (4H, m), 3.60-3.77 (8H, m), 3.13 (2H, br. s.), 2.94-3.04 (4H, m), 2.82 (2H, br. s.), 2.13 (3H, s), 2.03 (4H, m). Mass Spectrum (ESI) m/e=638.2 (M+1).
Reaction SMILES: CN(C)C=O.S([O:16][CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(C1C=CC(C)=CC=1)(=O)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C.O>[F:28][C:29]1[CH:34]=[CH:33][C:32]([O:16][CH:17]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:20]2)=[CH:31][CH:30]=1
Reactant: Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC2CN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)cc2)C1
Yield: 72.9 %

Procedure:
An N,N-dimethylformamide solution (1.5 mL) of tert-butyl 3-(tosyloxy)azetidine-1-carboxylate (164 mg, 0.50 mmol), 4-fluorophenol (67.3 mg, 0.60 mmol), and cesium carbonate (116 mg, 0.60 mmol) was stirred at 80° C. for 16 hours. After completion of the reaction, water was added to the reaction solution and extraction with ethyl acetate from the resultant mixture was performed three times. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (97.4 mg, yield 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([O:13][CH3:14])[C:11]=1[OH:12])[C:6]([OH:8])=[O:7].[C:15](OC(=O)C)(=[O:17])[CH3:16].N1C=CC=CC=1>O>[C:15]([O:12][C:11]1[C:10]([O:13][CH3:14])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C(=O)O)cc(OC)c1OC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3,5-dimethoxy-4-hydroxybenzoic acid (3.00 g) and acetic anhydride (30 ml) was dropwise added pyridine (15 ml) with ice-cooling over a 5 minutes period. After stirring at room temperature for 30 minutes, the reaction mixture was poured into water and stirred at room temperature for 30 minutes followed by extracting thrice with ethyl acetate. The combined extract was washed with 10% hydrochloric acid, dried and concentrated. The residue was recrystallized from a mixture of methylene chloride and hexane to afford the title compound (3.13 g), melting at 192°-194° C.
Reaction SMILES: [C:1](O)(=O)C.C=O.C([BH3-])#N.[Na+].[Cl:11][C:12]1[CH:52]=[CH:51][C:15]([CH2:16][CH:17]2[N:22]3[C:23](=[O:46])[CH:24]([NH:38][C:39]([CH:41]4[CH2:45][CH2:44][CH2:43][NH:42]4)=[O:40])[CH2:25][N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])(=[O:29])=[O:28])[CH:21]3[CH2:20][N:19]([CH:47]([CH3:49])[CH3:48])[C:18]2=[O:50])=[CH:14][CH:13]=1>CO>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]2[N:22]3[C:23](=[O:46])[CH:24]([NH:38][C:39]([CH:41]4[CH2:45][CH2:44][CH2:43][N:42]4[CH3:1])=[O:40])[CH2:25][N:26]([S:27]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])(=[O:29])=[O:28])[CH:21]3[CH2:20][N:19]([CH:47]([CH3:49])[CH3:48])[C:18]2=[O:50])=[CH:51][CH:52]=1
Reactant: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCN3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCCN3C)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
0.3 ml (5.2 mmol) of acetic acid, 0.25 ml (3.33 mmol) of formaldehyde (37% in water) and 1.5 ml (1.5 mmol) of sodium cyanoborohydride (1M in THF) were added to a solution of 93 mg (0.142 mmol) of the amine from Example 40 in 7.5 ml of methanol. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was diluted with 10 ml of DCM, basified with 7N—NH3 in methanol, filtered and concentrated. This residue was purified by preparative RP-HPLC. 50 mg of the desired compound were obtained. LC/MS (calculated, monoisotopic MW=669; measured value (M+H)=670)