Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:31][C:32](=[O:38])[C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:5]=[C:6]([CH3:30])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14](C(OC(C)(C)C)=O)[N:13]=[C:12]2[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:36]([O:35][C:33](=[O:34])[C:32]([NH:31][C:4]1[CH:5]=[C:6]([CH3:30])[C:7]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[C:12]3[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[C:2]([CH3:1])[CH:3]=1)=[O:38])[CH3:37]
Reactant: CCCCCc1nn(C(=O)OC(C)(C)C)c2ccc(Oc3c(C)cc(NC(=O)C(=O)OCC)cc3C)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCc1n[nH]c2ccc(Oc3c(C)cc(NC(=O)C(=O)OCC)cc3C)cc12
Yield: 99 %

Procedure:
A solution of 474 mg (0.905 mmol) of ethyl ({3,5-dimethyl-4-[(1-tert-butoxycarbonyl-3-pentylindazol-5-yl)oxy]phenyl]}amino)(oxo) acetate (Example 13) and 2.58 g (22.63 mmol) of trifluoroacetic acid in 30 ml of methylene chloride is stirred at room temperature overnight. The mixture is subsequently concentrated in vacuo and the residue obtained is purified on silica gel using cyclohexane/ethyl acetate 3:2. 391 mg (99% of theory) of ethyl-({3,5-dimethyl-4-[(3-pentyl-1H-indazol-5-yl)oxy]phenyl}amino)(oxo)acetate are obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][S:7][C:6]1=[N:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1.[Cl:31]C1C=CC(CBr)=CC=1.Cl>>[NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:31])=[CH:17][CH:18]=2)=[CH:8][S:7][C:6]1=[N:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][C:27]([F:29])([F:30])[F:28])=[CH:24][CH:25]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: NCCCn1c(COCc2ccccc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: NCCCn1c(COCc2ccc(Cl)cc2)csc1=Nc1ccc(OC(F)(F)F)cc1
Yield: 45 %

Procedure:
The compound (313 mg) obtained in Example 208 (2) and 4-chlorobenzyl bromide (216 mg) were treated in a similar manner to in Example 208 (3), (4) to give the title compound (152 mg) as hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH2:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[NH:12]1[CH:16]=[CH:15][N:14]=[C:13]1[CH:17]=O.C(O)(=O)C>C(O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][N:11]=[CH:17][C:13]2[NH:12][CH:16]=[CH:15][N:14]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1ncc[nH]1
Reactant: NNc1ccc([N+](=O)[O-])cn1
Solvent: CC(=O)O
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NN=Cc2ncc[nH]2)nc1
Reaction time: 8 h

Procedure:
3.10 g (20.1 mmol) of 5-nitro-2-pyridylhydrazine and 2.00 g (20.8 mmol) of 2-imidazolecarbaldehyde were dissolved in 50 ml of ethanol. To this mixture, 1 ml of acetic acid was added and heated under reflux for 2 hours while being stirred. After the resultant reaction mixture was allowed to stand still overnight, coarse crystals precipitated were filtrated by the suction-filtration. The obtained coarse crystals were recrystallized from a hot ethanol solution to obtain a desired product.
Reaction SMILES: [F:1][C:2]1[C:7]2[NH:8][C:9](=S)[CH2:10][CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:14]([NH:17][NH2:18])(=O)[CH3:15]>C(O)CCC>[F:1][C:2]1[C:7]2[N:8]3[C:14]([CH3:15])=[N:17][N:18]=[C:9]3[CH2:10][CH2:11][NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)NN
Reactant: Fc1cccc2c1NC(=S)CCN2
Solvent: CCCCO
Product: Cc1nnc2n1-c1c(F)cccc1NCC2
Temperature: 130 °C
Reaction time: 8 h
Yield: 49.5 %

Procedure:
A disposable tube was charged with 9-fluoro-4,5-dihydro-1H-benzo[b][1,4]diazepine-2(3H)-thione (40 mg, 0.204 mmol) and a stirbar. nBuOH (5 mL) was added, followed by acetohydrazide (30.2 mg, 0.408 mmol), and the solution was stirred at 130° C. overnight. The solution was concentrated with celite and purified by silica gel chromatography (eluting with methylene chloride/methanol/1% ammonium hydroxide) to yield 10-fluoro-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine as an off-white amorphous solid (0.022 g, 0.101 mmol, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([CH:16]([NH:18][OH:19])[CH3:17])=[CH:9][CH:10]=3)[S:5][C:4]=2[CH:3]=1.C[Si]([N:24]=[C:25]=[O:26])(C)C.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13]([O:12][C:11]3[CH:10]=[CH:9][C:8]([CH:16]([N:18]([OH:19])[C:25]([NH2:24])=[O:26])[CH3:17])=[CH:7][C:6]=3[S:5]2)=[CH:14][CH:15]=1
Reactant: CC(NO)c1ccc2c(c1)Sc1cc(Cl)ccc1O2
Reactant: C[Si](C)(C)N=C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc2c(c1)Sc1cc(Cl)ccc1O2)N(O)C(N)=O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the product from Step 1 (320 mg, 1.09 mmol) in THF (15 mL) there was added 85% trimethylsilyl isocyanate (295 mg, 2.18 mmol) and the mixture was stirred at room temperature for 45 minutes. After addition of water (5 mL) the mixture was stirred a further 10 minutes, then the THF was evaporated, the residual aqueous suspension diluted with water and filtered to afford the title compound as a white solid, m.p.: dec 173° C. (gassing).
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[NH:20][C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>COCCOC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][N:13]3[C:17]4[N:18]=[C:19]([S:23][CH3:24])[N:20]([CH3:32])[C:21](=[O:22])[C:16]=4[C:15]([CH3:25])=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CSc1nc2c(c(C)cn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(=O)n1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.1 %

Procedure:
Under argon gas, 7-[4-(4-chlorobenzoyl)benzyl]-5-methyl-2-methylthio-7H-pyrrolo[2, 3-d]pyrimidin-4(3H)-one (254 mg) was dissolved in anhydrous DME (10 ml)-anhydrous DMF (6 ml). Then, 60% sodium hydride-oil (26.4 mg) was added with ice-cooling and, after 30 minutes of agitation, methyl iodide (98 mg) was added. Then, at room temperature, the mixture was stirred for 2.5 hours. This reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (chloroform) to provide the title compound (176 mg). 1H-NMR (CDCl3) δ: 2.39(3H,s), 2.56(3H,s), 3.56(3H,s), 5.29(2H,s), 6.47(1H,d,J=l.OHz), 7.29(2H,d,J=8.4Hz), 7.45(2H,d,J=8.4Hz), 7.73(4H,d,J=8.4Hz).
Reaction SMILES: ClC1C(F)=CC(F)=C(C=1)C(NS(C)(=O)=O)=O.[Cl:17][C:18]1[C:19](F)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24].[C:35]12([CH2:45][OH:46])[CH2:44][CH:39]3C[CH:41]([CH2:43][CH:37](C3)C1)[CH2:42]2.C1(CO)CCCCCC1>>[Cl:17][C:18]1[C:19]([O:46][CH2:45][CH:35]2[CH2:42][CH2:41][CH2:43][CH2:37][CH2:39][CH2:44]2)=[CH:20][C:21]([F:33])=[C:22]([CH:32]=1)[C:23]([NH:25][S:26](=[O:31])(=[O:30])[N:27]([CH3:29])[CH3:28])=[O:24]
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: CS(=O)(=O)NC(=O)c1cc(Cl)c(F)cc1F
Agent: OCC1CCCCCC1
Product: CN(C)S(=O)(=O)NC(=O)c1cc(Cl)c(OCC2CCCCCC2)cc1F

Procedure:
Following the procedure as described in Example 8 and making variations as required to replace 5-chloro-2,4-difluoro-N-(methylsulfonyl)benzamide with 5-chloro-N—(N,N-dimethylsulfamoyl)-2,4-difluorobenzamide and adamantan-1-ylmethanol with cycloheptylmethanol, the title compound was obtained as a colorless solid (0.08 g, 20%): 1H NMR (300 MHz, DMSO-d6) δ 11.77 (s, 1H), 7.72 (d, J=7.4 Hz, 1H), 7.24 (d, J=12.3 Hz, 1H), 3.94 (d, J=6.6 Hz, 2H), 2.87 (s, 6H), 2.00-1.25 (m, 13H); MS (ES−) m/z 405.1, 407.1 (M−1).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:33](I)[CH3:34]>C(#N)C>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:26]#[N:27])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:33][CH3:34])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:28]=[C:29]([Br:32])[CH:30]=[N:31][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1OC1CCNCC1)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Reactant: CCI
Solvent: CC#N
Product: CCN1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Temperature: 50 °C
Yield: 66.6 %

Procedure:
A solution of 9-benzenesulfonyl-3-bromo-5-(piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (102 mg, 0.2 mmol) in acetonitrile (10 mL) was treated with ethyl iodide (34 mg, 17.4 μL, 0.2 mmol). The reaction mixture was heated for 24 h at 50° C., until analysis (TLC/LCMS) showed complete consumption of starting material. The reaction mixture was allowed to cool to ambient temperature and was then concentrated in vacuo. The resultant residue was partitioned between ethyl acetate (10 mL) and 1M sodium carbonate solution (5 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by chromatography (silica, Si-SPE, EtOAc) to afford the title compound as a white solid (72 mg, 60%). 1H NMR (CDCl3, 400 MHz): 9.56 (s, 1H), 8.76 (d, J=2.3 Hz, 1H), 8.65 (s, 1H), 8.25-8.22 (m, 2H), 7.67-7.62 (m, 1H), 7.54-7.49 (m, 2H), 5.15 (s, 1H), 2.96 (s, 2H), 2.48 (s, 2H), 2.23 (s, 4H), 2.02 (d, J=16.9 Hz, 2H), 1.18-1.04 (m, 3H). LCMS (Method G): RT=3.5 min, M+H+=541.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[C:16]([C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)#[CH:17].C(N(CC)CC)C>[Cu](I)I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1>[CH3:10][O:9][C:7]([C:6]1[CH:11]=[C:2]([C:17]#[C:16][C:18]23[CH2:27][CH:22]4[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]4)[CH2:19]2)[CH2:25]3)[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=1)=[O:8]
Reactant: C#CC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1cc(Br)cc(C(=O)OC)c1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)c1cc(C#CC23CC4CC(CC(C4)C2)C3)cc(C(=O)OC)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Next, 125 g of dimethyl 5-bromoisophthalate (458 mmol), 1.1 g of triphenylphosphine (4.19 mmol), 0.275 g of copper iodide (1.44 mmol), 64.26 g of 1-ethynyladamantane (401 mmol), 375 mL of dehydrated triethylamine, 200 mL of dehydrated pyridine, 0.3 g of dichlorobis (triphenylphosphine) palladium (0.427 mmol) and a stirrer were charged in a 1 L recovery flask and agitated at 100° C. for one hour. After reaction solution was filtered, solvent was removed from the reaction solution under reduced pressure. Solid thus obtained was washed with 1 L of ion-exchange water and then with 1 L of 2 mol/L hydrochloric acid aqueous solution, followed by drying under reduced pressure, thus obtaining 121.5 g of 1-(3,5-bis(methoxycarbonyl)phenyl)-2-(1-adamantyl)ethyne (344.9 mmol; yield: 86.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=1F)=O.O.[NH2:25][NH2:26]>CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:13]2[C:14](=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=2)[NH:26][N:25]=1
Reactant: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2F)c(OC)c1
Reactant: NN
Agent: CN(C)c1ccncc1
Solvent: O
Product: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)c(OC)c1
Yield: 37.2 %

Procedure:
Prepared according to Method D Step A from (2,4-dimethoxyphenyl)[2-fluoro-3-(trifluoromethyl)phenyl]methanone (1.50 g, 5.17 mmol), hydrazine hydrate (1.61 mL, 51.7 mmol) and DMAP (0.632 g, 5.17 mmol) to give the product (0.619 g) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:21])=[N:15][CH:16]=[C:17]([C:19]#[CH:20])[CH:18]=1)[CH3:11].C(N(C(C)C)CC)(C)C.[C:31]1([CH:37]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:38]2[CH2:41][CH:40]([N:42]=[N+:43]=[N-:44])[CH2:39]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO.[Cu](I)I>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:21])=[N:15][CH:16]=[C:17]([C:19]2[N:44]=[N:43][N:42]([CH:40]3[CH2:41][N:38]([CH:37]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[CH2:39]3)[CH:20]=2)[CH:18]=1)[CH3:11]
Reactant: C#Cc1cnc(N)c(OC(C)c2c(Cl)ccc(F)c2Cl)c1
Reactant: [N-]=[N+]=NC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(Oc1cc(-c2cn(C3CN(C(c4ccccc4)c4ccccc4)C3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-ethynyl-2-aminopyridine (4.2 g, 12.62 mmol) was dissolved in methanol (40 mL), and diisopropylethylamine (8.36 g, 64.78 mmol), copper iodide (62 mg, 0.33 mmol) and 1-(diphenylmethyl)-3-azidoazetidine (3.34 g, 12.62 mmol) were added successively. The reaction was stirred overnight at room temperature. TLC test showed that the raw materials were completely reacted. The resultant mixture was concentrated under reduced pressure;
Reaction SMILES: [CH:1]1([CH:7]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([O:38]CC)=[O:37])=[O:32])=[CH:27][CH:26]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([NH:33][CH2:34][CH2:35][C:36]([OH:38])=[O:37])=[O:32])=[CH:29][CH:30]=2)[C:8]2[O:9][C:10]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:11]=3[C:12]=2[CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2COCCOC)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOCc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.9 %

Procedure:
To a mixture of ethyl 3-[({4-[(cyclohexyl{5-fluoro-3-[(2-methoxyethoxy)methyl]-1-benzofuran-2-yl}methyl)amino]phenyl}carbonyl)amino]propanoate (216 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (69.6 mg, 34%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[CH:19][CH:18]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2.[OH-].[Na+]>CO.O1CCCC1>[F:34][C:2]([F:1])([F:33])[CH2:3][CH2:4][CH:5]([C:17]1[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=1)[NH:6][C:7]1[CH:8]=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: CCOC(=O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1ccc(C(CCC(F)(F)F)Nc2cnc3ccccc3c2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of ethyl(+/−)-3-(4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzamido)propanoate (74 mg, 0.16 mmol) in methanol (0.78 mL) and tetrahydrofuran (0.78 mL) was added 1 N aq sodium hydroxide (0.78 mL, 0.78 mmol). After 10 minutes, the solution was concentrated under reduced pressure to remove methanol and tetrahydrofuran. The mixture was then acidified to pH 4 with 1 N aq hydrochloric acid and diluted with sat. aq sodium chloride (10 mL). The aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure to give (+/−)-3-(4-(4,4,4-trifluoro-1-(quinolin-3-ylamino)butyl)benzamido)propanoic acid. 1HNMR (400 MHz, DMSO-d6) δ 12.18 (br. s., 1H), 8.56 (d, J=2.7 Hz, 1H), 8.44 (t, J=5.6 Hz, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.76-7.72 (m, 1H), 7.54 (d, J=8.2 Hz, 2H), 7.52-7.48 (m, 1H), 7.37-7.27 (m, 2H), 7.03 (d, J=7.8 Hz, 1H), 6.86 (d, J=2.5 Hz, 1H), 4.73-4.61 (m, 1H), 3.46-3.37 (m, 2H), 2.47 (t, J=7.0 Hz, 2H), 2.39-2.23 (m, 1H), 2.14-1.92 (m, 2H), 1.20-1.13 (m, 1H); (M+1): 446.2.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[N:28][C:5]2S[CH2:7][CH2:8][N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[F:20])[N:13]=[C:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:11]=3[CH3:27])[C:4]=2[CH:3]=1.O.OO.[OH:33][S:34]([O-:36])=O.[Na+]>CCOC(C)=O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:29]=[N:28][C:5]2[S:34](=[O:36])(=[O:33])[CH2:7][CH2:8][N:9]([C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]=4[F:20])[N:13]=[C:12]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:11]=3[CH3:27])[C:4]=2[CH:3]=1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CCSc2ncc(Cl)cc21
Reactant: O=S([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1N1CCS(=O)(=O)c2ncc(Cl)cc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7-chloro-1-(5-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine (30 mg, 0.071 mmol) in EtOAc (2.5 mL) was added disodium tungstate (2.08 mg, 7.09 μmol) and water (0.2 mL). The reaction was cooled at 0° C. and then H2O2 (36.2 μL, 0.355 mmol, 30%) was added. The reaction was allowed to warm to rt for 1 h. After this time more disodium tungstate (5 mg) was added followed by H2O2 (0.3 mL) and the reaction was stirred at rt overnight. After this time the reaction was diluted with EtOAc (50 mL) and treated with a saturated aqueous solution of NaHSO3 (10 mL). The separated organic layer was washed with brine (10 mL), dried over MgSO4, filtered and evaporated in vacuo to give 7-chloro-1-(5-fluoro-3-methyl-2-pyridin-2-ylquinolin-4-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazine 4,4-dioxide. Mass Spectrum (ESI) m/e=455.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:21][CH:20]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:18][C:19]2[CH:31]=[CH:30][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)[CH:5]=[N:6][C:7]=1[O:8][CH:9]([C:10]([F:12])([F:13])[F:11])[C:14]([F:16])([F:17])[F:15]
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(Nc2cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c2)cc1
Reaction time: 18 h
Yield: 59.5 %

Procedure:
To a dichloromethane (10 mL) solution of tert-butyl 4-(5-chloro-6-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)pyridin-3-ylamino)benzoate (Preparation 258, 220 mg, 0.47 mmol) was added trifluoroacetic acid (2 mL) at room temperature, and the reaction stirred for 18 hours. The reaction mixture was concentrated in vacuo and the residue was purified by reverse phase chromatography eluting with acetonitrile:water (5:95 to 95:5) to yield the title compound as a pale yellow solid (116 mg, 60%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[N:7]2.[O:33]1[C:37]([C:38](O)=[O:39])=[CH:36][N:35]=[CH:34]1>>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[C:4]([NH:20][C:21]1[CH:22]=[N:23][CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:26]=1)=[C:5]([CH3:19])[C:6]([N:13]1[CH2:14][CH2:15][N:16]([C:38]([C:37]3[O:33][CH:34]=[N:35][CH:36]=3)=[O:39])[CH2:17][CH2:18]1)=[N:7]2
Reactant: O=C(O)c1cnco1
Reactant: Cc1c(N2CCNCC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1
Product: Cc1c(N2CCN(C(=O)c3cnco3)CC2)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Q using 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(piperazin-1-yl)quinolin-4-amine (40.0 mg, 0.09 mmol) and oxazole-5-carboxylic acid to give (4-(5,7-difluoro-3-methyl-4-(5-morpholinopyridin-3-ylamino)quinolin-2-yl)piperazin-1-yl)(oxazol-5-yl)methanone. 1H NMR (DMSO-d6) δ ppm 2.11 (s, 3H), 3.06 (br s, 4H), 3.33-3.39 (m, 4H), 3.69 (br s, 4H), 3.86 (br s, 4H), 6.52 (s, 1H), 7.15-7.20 (m, 1H), 7.28-7.30 (m, 1H), 7.53 (s, 1H), 7.78 (br s, 2H), 8.38 (s, 1H), 8.59 (s, 1H). Mass Spectrum (ESI) m/e=535.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=O.O.[NH4+:11].[Cl-]>[Zn].CC(=O)OCC>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[N:11][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[O-:3]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: O
Product: [O-][N+](=Nc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
0.204 mL (2.0 mmol) of nitrobenzene and either of 17.2 mg (the amount required for swelling of the reactant, nitrobenzene, in 100%) of Polymer supported reagent-1 synthesized in Example 3 or 14 mg (the amount required for swelling of the reactant, nitrobenzene, in 100%) of Polymer supported reagent-2 synthesized in Example 4 were put into a 50 mL, two-neck flask equipped with a water cooler, and the resulting mixture was stirred at a nitrogen atmosphere for 20 minutes to swell the the polymer supported reagent with the reactant. To this were added 0.262 g (4.0 mmol) of Zn powders, 0.214 g (4.0 mmol) of NH4Cl, and 15 mL of distilled water, and then the reduction reaction was conducted at 80° C. for 200 minutes. After the completion of the reaction, 30 mL of an organic solvent, EA was added thereto and stirred at room temperature for 30 minutes. The resulting mixture was then filtered to separate firstly the solid mixture and the liquid mixture solution. The liquid mixture solution as obtained was put into a separating funnel to separate a water layer and an EA layer. To the separated water layer was added 20 mL of EA and stirred to extract the product remained in the water layer. This procedure was repeated 3 times. To the EA solution as combined was added 1.0 g of anhydrous magnesium sulfate and the resulting mixture was stirred for 30 minutes and then filtered. From the filtered EA solution, an excessive amount of EA was evaporated by using an evaporator to obtain azoxybenzene as a main product.