Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:38]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([F:43])[CH:42]=1)[CH2:38][N:32]1[CH:31]=[CH:30][N:29]=[C:28]1[CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: Fc1cc(F)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cc(F)cc(F)c2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (40 mg, 0.085 mmol), 3,5-difluoro benzyl bromide (11.5 μL, 0.089 mmol, 1.05 equiv) and potassium carbonate (23.5 mg, 0.17 mmol) in dimethylformamide (1.0 mL) was stirred at room temperature for 16 h. The solvents were removed and the residue purified by column chromatography to afford 40.0 mg (79%). Mass spec.: 598.4 (MH)+.
Reaction SMILES: C(O[C:5]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:6])(C)C.[CH3:31][NH2:32]>>[CH3:31][NH:32][C:5]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:6]
Reactant: CN
Reactant: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Product: CNC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h

Procedure:
0.57 g of 1-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid isopropyl ester ( ) was stirred in 20 mL methyl amine (40% wt in water) at 100° C. in a sealed tube for 5 days. The methyl amine was allowed to evaporate and the residual aqueous solution was left to stand overnight uncapped. The following morning, a white precipitate was present, which was collected by vacuum filtration. The precipitate was washed with water and hexanes. The original aqueous solution was then extracted twice with ethyl, acetate. The organic layer was then dried over sodium sulfate and concentrated in vacuo to afford more product. 0.31 g of the title compound was collected as a white solid; mp 137-139° C.; 1H NMR (CDCl3) δ 1.52-1.72 (m, 5H), 1.81 (t, J=5.82 Hz, 4H), 2.15-2.20 (m, 1H), 2.86 (d, J=4.95 Hz, 3H), 3.08-3.55 (m, 1H), 3.49-3.55 (m, 4H), 4.00 (s, 4H), 6.89-6.94 (m, 2H), 6.99-7.01 (m, 1H), 7.61-7.73 (m, 2H); MS (ES) m/z 410.0 (MH+); HRMS for C19H27N3O5S: 410.1740
Reaction SMILES: C([O:4][N:5]([CH:9]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:10]1)[C:6](=[O:8])[CH3:7])(=O)C.C([O-])([O-])=O.[K+].[K+]>CO>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:11]2[CH2:10][CH:9]([N:5]([OH:4])[C:6](=[O:8])[CH3:7])[CH2:12]2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cccc(C2CC(N(OC(C)=O)C(C)=O)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cccc(C2CC(N(O)C(C)=O)C2)c1
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
To a solution of N-acetoxy-N-[3-(3-methoxyphenyl)cyclobutyl]acetamide, (34.8 mmol from above), in methanol (150 mL) was added K2CO3 (9.22 g, 69.6 mmol) and the heterogeneous mixture was stirred for 30 min. An additional portion of K2CO3 (4.50 g) was then added and the reaction was stirred an additional 30 min. It was then filtered through Celite and concentrated. The resulting residue was chromatographed (silica gel; ether) to afford 4.92 g (60% over four steps) of N-[3-(3-methoxyphenyl)cyclobutyl]-N-hydroxyacetamide as an orange oil.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH2:11][C:10]3([CH3:20])[CH3:19])=[N+]=[N-].[H][H]>CN(C)C=O.[Pd]>[NH2:1][CH2:4][CH:5]1[O:21][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[CH2:11][C:10]3([CH3:19])[CH3:20]
Reactant: [H][H]
Reactant: Cc1cc2c(c3c1NC(=O)CC3(C)C)OC(CN=[N+]=[N-])C2
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1cc2c(c3c1NC(=O)CC3(C)C)OC(CN)C2

Procedure:
The compound obtained in Example 265 (2.69 g, 9.41 mmol) was dissolved in N,N-dimethylformamide (40 ml). To the resultant solution, 10% palladium-on-carbon (1.2 g) was added, followed by stirring at room temperature for 3 hours in the atmosphere of hydrogen.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.Br[CH:16]=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O.O>[CH2:31]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:13][CH:14]=1)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16]
Reactant: CCOC(=O)C=Cc1ccc(N)cc1
Reactant: CCCCCCCCCCCCCCC=CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C=CC(=O)OCC)cc1
Temperature: 60 °C

Procedure:
A mixture of ethyl p-aminocinnamate, one equivalent of 1-bromohexadecene, one equivalent of anhydrous potassium carbonate in hexamethylphosphoramide is heated for 20 hours at 60° C. The mixture is then cooled, diluted with water and extracted with ether. The combined ether extracts are dried, filtered and evaporated to provide ethyl 4-hexadecylaminocinnamate. The ester is hydrolyzed with sodium hydroxide in a 1:1 water:ethanol solution at steam bath temperature for 10 hours. The hot solution is then acidified with acetic acid, cooled, filtered and the precipitate is washed with water. Recrystallization from chloroform yields 4-hexadecylaminocinnamic acid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[C:21]([NH:25][CH2:26][CH2:27][C:28]([NH2:30])=[O:29])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[C:21]([N:25]([CH2:26][CH2:27][C:28](=[O:29])[NH2:30])[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:24])([CH3:23])[CH3:22]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC(C)(C)NCCC(N)=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)N(CCC(N)=O)C(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with 3-(tert-butylamino)propanamide (289656-97-9) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=411.6 [MH+].
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)=[C:4]([CH3:19])[CH:3]=1.[CH3:20][S-:21].[Na+].CN(C)C(=O)C>>[CH3:19][C:4]1[CH:3]=[C:2]([S:21][CH3:20])[N:7]=[CH:6][C:5]=1[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]2)=[CH:10][CH:9]=1
Reactant: C[S-]
Reactant: Cc1cc(F)ncc1-c1ccc2cc(N)ncc2c1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CSc1cc(C)c(-c2ccc3cc(N)ncc3c2)cn1

Procedure:
A mixture of 7-(6-fluoro-4-methylpyridin-3-yl)isoquinolin-3-amine (389 mg; 1.536 mmol) and sodium thiomethoxide (344 mg; 4.66253 mmol) in N,N-dimethylacetamide (3.0 mL; 32 mmol) was subjected to microwave irradiation at 150° C. for 30 minutes to produce a mixture of the desired product and the demethylated thiol product. To the reaction mixture was added a 10 mol/L solution sodium hydroxide in water (1.5 mL; 15 mmol) followed by iodomethane (0.10 mL; 1.6 mmol). The reaction mixture was stirred at room temperature for 4 hours, and then additional iodomethane (0.05 mL; 0.8 mmol) was added. After an additional 4 hours, the reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to yield 419.9 mg of the title compound, which was carried forward without purification. LCMS (ESI): M+H=282.2; 1H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.30 (s, 1H), 7.79 (s, 1H), 7.59 (d, J=8.6 Hz, 1H), 7.47 (d, J=8.6 Hz, 1H), 7.27 (s, 1H), 6.66 (s, 1H), 5.98 (s, 2H), 2.54 (s, 3H), 2.27 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].Cl.Cl.[NH2:22][C:23]1[CH:31]=[C:30]2[C:26]([CH2:27][CH2:28][NH:29]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH:29]1[C:30]2[C:26](=[CH:25][CH:24]=[C:23]([NH:22][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:18]#[N:19])[CH:31]=2)[CH2:27][CH2:28]1
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Reactant: Nc1ccc2c(c1)NCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)NCC4)c2cc1OCC
Temperature: 100 °C
Yield: 106.3 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 258 mg (1.88 mM) of 6-Aminoindoline dihydrochloride salt in 10 ml of ethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. The solid was dissolved in 50/50 methanol/chloroform and dried onto silica gel and purified by chromatography using a gradient of 20% to 50% acetone in hexane to yield 496 mg of the title compound as a tan solid: mass spectrum (electrospray, m/e): M+H 375.1, mp=121-124° C.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br.Br.[CH2:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH2:16][CH3:17]>>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([N:21]2[CH2:22][CH2:23][N:18]([CH2:15][CH2:16][CH3:17])[CH2:19][CH2:20]2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCN1CCNCC1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Agent: Br
Product: CCCN1CCN(C(=O)[C@@H]2C[C@H]2c2ccccc2)CC1

Procedure:
This example was prepared according to Example 4 utilizing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-N-propylpiperazine dihydrobromide, which is commercially available from, for example, Sigma-Aldrich Corporation. m/z (ES+) M+1=273.2; HPLC tR=1.49 min. 1H NMR (500 MHz, CDCl3) δ 7.26 (t, J=7.6 Hz, 2H), 7.20-7.15 (m, 1H), 7.10 (d, J=7.0 Hz, 2H), 3.70-3.55 (m, 4H), 2.49-2.35 (m, 5H), 2.33-2.27 (m, 2H), 1.99-1.91 (m, 1H), 1.65 (dt, J=9.2, 4.7 Hz, 1H), 1.50 (sextet, J=7.5 Hz, 2H), 1.25 (ddd, J=8.4, 6.3, 4.3 Hz, 1H), 0.90 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.CCN(CC)CC.[N:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])=[CH:29][CH:28]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([NH:37][CH2:36][CH2:35][CH2:34][CH2:33][C:30]3[CH:29]=[CH:28][N:27]=[CH:32][CH:31]=3)=[O:12])[C:4]=2[CH:3]=1
Reactant: NCCCCc1ccncc1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCc1ccncc1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 60.9 %

Procedure:
By the method described in Example 18, the title compound of Example 2 (0.98 g, 3.3 mmol) in 30 mL of CH2Cl2 with molecular sieves #5A (3 g) and Et3N (0.47 mL, 3.36 mmol) was reacted with the title compound of Example 23 (0.5 g, 3.3 mmol) to produce 0.82 g of the title product.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([F:32])[C:30]=1[F:31])[C:25](O)=O>>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[C:29]([F:32])[C:30]=1[F:31]
Reactant: O=C(O)c1cc(F)c(F)c(Cl)c1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(F)c(F)c(Cl)c3)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-4,5-difluorobenzoic acid: MS (APCI) m/z 440 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH2:32][CH:33]1[CH2:38][CH2:37][CH:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][NH:32][C@H:33]4[CH2:38][CH2:37][C@H:36]([C:39]([OH:41])=[O:40])[CH2:35][CH2:34]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: NC1CCC(C(=O)O)CC1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: O=C(O)[C@H]1CC[C@H](NCc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and 4-aminocyclohexanecarboxylic acid (138 mg; 0.97 mmol), to give Example 168 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.95-7.88 (3H, m), 7.76-7.69 (1H, m), 7.64-7.49 (6H, m), 3.81 (2H, s), 2.58 (1H, d, J=5.6 Hz), 2.35 (1H, d, J=6.4 Hz), 1.96-1.85 (2H, m), 1.60 (2H, t, J=10.0 Hz), 1.53-1.44 (4H, m). LC/MS (Method C): 540 (M+H)+. HPLC (Method I) Rt 11.49 min (Purity: 93.8%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([OH:21])=[CH:16][N:15]=1>C(Cl)Cl>[Cl:13][C:14]1[C:19]([Cl:20])=[CH:18][C:17]([O:21][S:9]([CH3:8])(=[O:11])=[O:10])=[CH:16][N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: Oc1cnc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cnc(Cl)c(Cl)c1
Temperature: 20 °C
Reaction time: 17 h

Procedure:
At 0° C., initially 7.9 g of triethylamine and then 8.5 g of methanesulfonyl chloride were added to 11.6 g of 2,3-dichloro-5-hydroxypyridine in 150 ml of methylene chloride. The mixture was subsequently stirred at approximately 20° C. for 17 hours and then washed with 100 ml of water. The organic phase was dried over magnesium sulfate and then concentrated. The resulting crude product was purified by silica gel chromatography (mobile phase: ethyl acetate/cyclohexane (1:1)). Yield: 9.1 g.
Reaction SMILES: O[CH2:2][C:3]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]4)=[CH:12][CH:11]=2)=[C:6]([CH:30]([CH3:32])[CH3:31])[O:5][N:4]=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[NH:41][C:42](=[O:47])[C:43]([F:46])([F:45])[F:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[N:41]([CH2:2][C:3]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]=[C:21]([C:26]([O:28][CH3:29])=[O:27])[CH:20]=[CH:19]4)=[CH:12][CH:11]=2)=[C:6]([CH:30]([CH3:32])[CH3:31])[O:5][N:4]=1)[C:42](=[O:47])[C:43]([F:45])([F:46])[F:44]
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CO)noc4C(C)C)cc3)ccc2n1
Reactant: O=C(Nc1c(Cl)cccc1Cl)C(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CN(C(=O)C(F)(F)F)c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25.6 %

Procedure:
To a solution of methyl 6-[4-({[3-(hydroxymethyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (25 mg, 0.058 mmol), N-(2,6-dichlorophenyl)-2,2,2-trifluoroacetamide (15 mg, 0.058 mmol) and triphenylphosphine (30 mg, 0.12 mmol) in dichloromethane was added di-tert-butyl azodicarboxylate (27 mg, 0.12 mmol). The solution was stirred at ambient temperature for approximately 1.5 hours and then was adsorbed onto silica gel and purified by chromatography (silica gel, 0-100% ethyl acetate in hexanes gradient elution). The resulting mixture was further purified by chromatography (silica gel, 2% methanol in dichloromethane) to afford methyl 6-[4-({[3-{[(2,6-dichlorophenyl)(trifluoroacetyl)amino]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (10 mg, 26%). 1H-NMR (400 MHz, CDCl3) δ 8.36-8.33 (m, 2H), 8.22 (d, J=9 Hz, 1H), 8.06-8.01 (m, 2H), 7.71 (d, J=9 Hz, 2H), 7.42-7.29 (m, 3H), 7.11 (d, J=9 Hz, 2H), 5.05 (s, 2H), 5.04 (s, 2H), 4.05 (s, 3H), 3.27 (septet, J=7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). LRMS (APCI) m/z 672 (M+H)+.
Reaction SMILES: C1(OC(=O)[N:9]([C:19]2[CH:24]=[C:23]([O:25][C:26]3[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]4([C:38](=[O:47])[NH:39][C:40]5[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=5)[CH2:37][CH2:36]4)=[O:34])=[C:28]([F:48])[CH:27]=3)[CH:22]=[CH:21][N:20]=2)[C:10](OC2C=CC=CC=2)=[O:11])C=CC=CC=1.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>CN(C)C=O>[F:48][C:28]1[CH:27]=[C:26]([O:25][C:23]2[CH:22]=[CH:21][N:20]=[C:19]([NH:9][C:10]([N:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)=[O:11])[CH:24]=2)[CH:31]=[CH:30][C:29]=1[NH:32][C:33]([C:35]1([C:38]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[O:47])[CH2:36][CH2:37]1)=[O:34]
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)CC1
Reaction time: 8 h

Procedure:
To a solution of roughly purified [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenyl ester (200 mg) in N,N-dimethylformamide (2.0 ml) was added 1-methylpiperazine (0.170 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine in this order, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure. To the resultant residue was added diethyl ether:heptane=1:2 to precipitate a solid. The solvent was concentrated under reduced pressure, and the residue was dried under reduced pressure to provide the titled compound as white powder (27.0 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([SH:11])=[CH:7][CH:6]=1.[CH3:13][O:14][CH2:15]Cl>C(#N)C.N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:13][O:14][CH3:15])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(S)cc1
Reactant: COCCl
Solvent: c1ccncc1
Solvent: CC#N
Product: COCSc1ccc(CC(=O)OC)cc1
Yield: 78.9 %

Procedure:
A solution of (4-mercapto-phenyl)-acetic acid methyl ester (500 mg, 2.7 mmol) and chloromethyl methyl ether (331 mg, 4.1 mmol) in acetonitrile (3 mL) and pyridine (1 mL) was heated under reflux for 16 h. At this time, the reaction was concentrated in vacuo. The residue was re-dissolved in ethyl acetate (10 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×25 mL) and a saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 90/10 hexanes/ethyl acetate) afforded (4-methoxymethylsulfanyl-phenyl)-acetic acid methyl ester (482 mg, 77.6%) as a clear oil: EI-HRMS m/e calcd for C11H14O3S (M+) 226.0664, found 226.0664.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([NH:35]C(=O)C)=[CH:33][CH:32]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][C:31]2[CH:40]=[CH:39][C:34]([NH2:35])=[CH:33][CH:32]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CC(=O)Nc1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNc3ccc(N)cc3)ccc21
Yield: 95.9 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (30.0 mg, 0.0730 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with 4′-aminoacetanilide (44 mg, 0.29 mmol), acetic acid (0.084 mL, 1.5 mmol) and sodium triacetoxyborohydride (46 mg, 0.22 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(4-aminophenylaminomethyl)indol-2-yl]isoindolinone (35.2 mg, yield 88%).
Reaction SMILES: FC(F)(F)C(O)=O.[ClH:8].[Cl:9][C:10]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([F:38])[C:11]=1[O:12][C:13]1[CH:29]=[CH:28][C:16]2[N:17]([CH3:27])[C:18](=[O:26])[C:19]([C:22](=[O:25])[CH2:23]O)([CH3:21])[O:20][C:15]=2[CH:14]=1>ClCCl>[Cl:9][C:10]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([F:38])[C:11]=1[O:12][C:13]1[CH:29]=[CH:28][C:16]2[N:17]([CH3:27])[C:18](=[O:26])[C:19]([C:22](=[O:25])[CH2:23][Cl:8])([CH3:21])[O:20][C:15]=2[CH:14]=1
Reactant: CN1C(=O)C(C)(C(=O)CO)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc21
Reactant: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(C)(C(=O)CCl)Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc21

Procedure:
In Example 15, dichloromethane was used as the solvent, and trifluoroacetic acid or conc. hydrochloric acid was used in place of hydroiodic acid, and 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-2-hydroxyacetyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (Compound 95) and 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2,4-dimethyl-2-chloroacetyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazine (Compound 97) were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH3:15][O:16][C:17]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][C:18]=1[CH:19]=[CH:20][C:21](O)=O>>[CH3:15][O:16][C:17]1[C:27]([CH3:28])=[C:26]([O:29][CH3:30])[CH:25]=[CH:24][C:18]=1/[CH:19]=[CH:20]/[C:21]1[NH:1][C:2]2[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=2[N:8]=1
Reactant: COc1ccc(C=CC(=O)O)c(OC)c1C
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3ccc(OC)c(C)c3OC)nc2n(CC)c1=O
Yield: 34.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.0 g (10.1 mmol) of 5,6-diamino-1,3-diethyluracil and 2.04 g (9.19 mmol) of 2,4-dimethoxy-3-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 1.22 g (yield 32%) of Compound 76 as a yellow powder.