Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.C1COCC1.C[O:32][CH2:33][C:34]([CH3:39])([CH3:38])[C:35](O)=[O:36].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:33](=[O:32])[C:34]([CH3:39])([CH3:38])[CH2:35][OH:36])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: COCC(C)(C)C(=O)O
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(CO)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 9.4 %

Procedure:
The title compound was prepared according to the procedure described in Example-107 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.100 g, 0.271 mmol), THF:DMF (5 mL:1 mL), 3-methoxy-2,2-dimethylpropanoic acid (0.053 g, 0.407 mmol), TBTU (0.261 g, 0.813 mmol), TEA (2.0 mL). The obtained crude was purified by column chromatography using basic alumina as stationary phase and eluting with the solution of 2% ammonia in 10.0% MeOH:DCM to afford 0.012 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.05 (s, 6H), 3.30 (s, 211), 4.30 (d, J=4.5 Hz, 1H), 4.36 (s, 1H), 7.53 (d, J=6.3 Hz, 1H), 7.75 (s, 1H), 8.08 (t, J=4.5 Hz, 1H), 8.21 (d, J=6.3 Hz, 2H); MS (m/z): 469.04 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH3:13])=[C:7]2[C:3]=1[CH:4](SC)[C:5](=[O:14])[NH:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.O>ClCCl>[CH3:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH3:13])=[C:7]2[C:3]=1[CH2:4][C:5](=[O:14])[NH:6]2
Reactant: COc1cc(C)c2c(c1C)C(SC)C(=O)N2
Agent: Cc1ccccc1S(=O)(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: COc1cc(C)c2c(c1C)CC(=O)N2
Reaction time: 3 h
Yield: 86.5 %

Procedure:
To a solution of 4,7-dimethyl-5-methoxy-3-(methylthio)-1,3-dihydro-2H-indol-2-one (17.8 g, 75 mmol) in dichloromethane (350 ml) were added triphenylphosphine (23.6 g, 90 mmol) and toluenesulfonic acid monohydrate (17.1 g, 90 mmol) at room temperature and stirred for 3 hours. The reaction mixture was poured into a cold water, and the precipitated crystals were collected by filtration. After washing with dichloromethane and water, 12.4 g of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.CN(C=O)C.Cl[CH2:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([Cl:15])=[CH:11][C:12]([O:14][CH2:23][C:24]3[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[CH:25]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: Cc1cc(CCl)n(C)n1
Reactant: COC(=O)Cc1csc2cc(O)cc(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1csc2cc(OCc3cc(C)nn3C)cc(Cl)c12
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a mixture of methyl(4-chloro-6-hydroxy-1-benzothiophen-3-yl)acetate (125 mg) and DMF (dry) (2 mL) were added 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole (84 mg) and K2CO3 (101 mg) at room temperature, and the mixture was stirred at 60° C. for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (172 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH2:6]
Reactant: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CN)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-({3-ethyl-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.076 g, 0.14 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature 1 h and evaporated to give crude product which was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=2)=[CH:10][O:9][N:8]=1.[NH2:23][CH2:24][CH:25]1[CH2:27][CH2:26]1>>[CH:25]1([CH2:24][NH:23][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:14]([O:13][CH2:12][C:11]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][O:9][CH:10]=3)=[N:15][CH:16]=2)[CH2:27][CH2:26]1
Reactant: O=C(O)c1ccc(OCc2conc2-c2ccccn2)nc1
Reactant: NCC1CC1
Product: O=C(NCC1CC1)c1ccc(OCc2conc2-c2ccccn2)nc1
Yield: 97 %

Procedure:
As described for example 358 g, 6-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.24 mmol) was converted using aminomethylcyclopropane instead of 4-aminotetrahydropyran to the title compound (80 mg, 97%) which was obtained as a white solid. MS: m/e=351.4 [M+H]+.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:19][C:20]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][N:24]2[Si](C(C)C)(C(C)C)C(C)C>C1COCC1.CCOC(C)=O>[F:19][C:20]1[C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2
Reactant: COC(=O)c1ccc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2[nH]ccc2c1F
Reaction time: 0.17 h

Procedure:
TBAF (1M solution in THF, 15.8 mmol, 15.8 mL) was added to a solution of compound 70b (7.9 mmol, 2.76 g) in THF at 0° C. After 10 min at room temperature, the reaction was diluted with EtOAc and washed with brine, saturated NaHCO3, and water. The organic layer was concentrated and purified by flash column chromatography (silica gel, 35% EtOAc/hexanes) to afford compound 70c.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]#[N:21])[CH2:15][CH2:14]3)(=[O:12])=[O:11])[S:7][C:6]=2[CH:22]=1.C(N(C(C)C)CC)(C)C.[SH2:32]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([S:10]([N:13]3[CH2:14][CH2:15][N:16]([CH2:19][C:20]([NH2:21])=[S:32])[CH2:17][CH2:18]3)(=[O:11])=[O:12])[S:7][C:6]=2[CH:22]=1
Reactant: N#CCN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1
Reactant: S
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=S)CN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1

Procedure:
A suspension of [4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-acetonitrile (1.2 g, 3.2 mmol) is heated with diisopropylethylamine (0.65 g, 5.0 mmol) in a solution of ethanol saturated with hydrogen sulfide gas for 4 hours. The reaction is cooled, filtered and washed with cold ethanol to provide 2-[4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-piperazin-1-yl]-thioacetamide. 1H NMR (300 MHz, DMSO-d6) δ9.71 (bs, 1H), 9.01 (bs, 1H), 8.35 (d, 1H), 8.21 (s, 1H), 8.08 (d, 1H), 7.59 (dd, 1H), 4.15 (s, 2H), 3.73 (s, 2H), 3.43 (s, 4H).
Reaction SMILES: [C:1]1([CH:7]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:19]3[C:20](O)=[CH:21][C:22]4[O:26][CH2:25][C:24]([CH3:28])([CH3:27])[C:23]=4[CH:29]=3)([CH2:17][OH:18])[C:9]2=[O:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(CCN2C3C(=CC=CC=3)C(C3C(O)=CC4OCOC=4C=3)(CO)C2=O)CC1>>[C:32]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:17][O:18][C:20]4[CH:21]=[C:22]5[C:23](=[CH:29][C:19]3=4)[C:24]([CH3:27])([CH3:28])[CH2:25][O:26]5)[C:9]2=[O:31])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1(C)COc2cc(O)c(C3(CO)C(=O)N(C(c4ccccc4)c4ccccc4)c4ccccc43)cc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Product: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 1-(diphenylmethyl)-3-(6-hydroxy-3,3-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained: mp 190-192° C.; 1H NMR (300 MHz, CDCl3) δ 7.40-7.26 (m, 10H), 7.19-7.15 (m, 1H), 7.07-6.93 (m, 3H), 6.55-6.51 (m, 1H), 6.38 (s, 1H), 6.20 (s, 1H), 4.98 (d, 1H), 4.71 (d, 1H), 4.17 (s, 2H), 1.17 (s, 3H), 1.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 178.1, 161.1, 161.0, 141.8, 137.9, 137.2, 132.8, 130.0, 128.6, 128.5, 128.4, 128.2, 128.0, 127.8, 123.9, 123.1, 120.8, 116.1, 112.1, 93.4, 85.4, 80.4, 58.7, 57.4, 41.3, 27.7, 27.6; MS (ES+) m/z 474.5 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH:15]=[C:14]([CH3:17])[C@:13]([CH2:19][CH2:20][C:21](NC4SC=NN=4)=[O:22])([CH3:18])[CH2:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:29][C:30]1[N:31]=[C:32]([NH2:36])[S:33][C:34]=1[CH3:35]>>[CH3:29][C:30]1[N:31]=[C:32]([NH:36][C:21](=[O:22])[CH2:20][CH2:19][C@:13]2([CH3:18])[C:14]([CH3:17])=[CH:15][C:16]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[N:9]=[CH:10][C:11]=3[CH2:12]2)[S:33][C:34]=1[CH3:35]
Reactant: Cc1nc(N)sc1C
Reactant: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CCC(=O)Nc1nncs1
Product: CC1=Cc2c(cnn2-c2ccc(F)cc2)C[C@]1(C)CCC(=O)Nc1nc(C)c(C)s1

Procedure:
The title compound was prepared in a manner analogous to the preparation of the title compound of Example 171, replacing 2-amino-1,3,4-thiadiazole with 4,5-dimethyl-2-aminothiazole. MS found: (M+H)+=425. 1H NMR (400 MHz, chloroform-D) δ ppm 1.20 (s, 3 H) 1.75-1.86 (m, J=8.65, 6.10 Hz, 1 H) 1.87-1.97 (m, 1 H) 1.91 (s, 3 H) 2.29 (s, 6 H) 2.50-2.57 (m, 2 H) 2.62 (d, J=16.28 Hz, 1 H) 2.80 (d, J=16.00 Hz, 1 H) 6.20 (s, 1 H) 7.19 (t, J=8.65 Hz, 2 H) 7.44 (dd, J=9.16, 4.58 Hz, 1 H) 7.51 (s, 1 H).
Reaction SMILES: [CH2:1]([N:5]([CH2:37][CH2:38][CH2:39][CH3:40])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:16]=2[C:23]([N:25]2[C@H:34]([CH2:35][OH:36])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:9]=1)=[O:7])[CH2:2][CH2:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].C(S)C.ClCCl>O>[CH2:37]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:8]1[C:12]([Cl:13])=[C:11]([CH3:14])[N:10]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[C:23]([N:25]2[C@H:34]([CH2:35][OH:36])[CH2:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:26]2)=[O:24])[N:9]=1)=[O:7])[CH2:38][CH2:39][CH3:40]
Reactant: CCCCN(CCCC)C(=O)c1nn(-c2ccc(OC)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCS
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(O)cc2C(=O)N2Cc3ccccc3C[C@H]2CO)c(C)c1Cl
Yield: 22.9 %

Procedure:
A mixture of 4-chloro-1-[2-((S)-3-hydroxymethyl-3,4-dihydro-1H-isoquinoline-2-carbonyl)-4-methoxy-phenyl]-5-methyl-1H-pyrazole-3-carboxylic acid dibutylamide (40 mg, 0.071 mmol) and aluminium chloride (75 mg, 0.56 mmol) was stirred in ethanethiol (0.052 mL, 0.71 mmol) and dichloromethane (0.5 mL) for 12 hours at ambient temperature under a nitrogen atmosphere. The mixture was added with water and extracted with 1:4 methanol:methylene chloride. The organic layer was removed in vacuo. After eluting through a short pad of silica gel column and C18 column, the crude material was purified by HPLC to afford the title compound (9 mg, 33% yield). MS (ESI) [m/e, (M+H)+]=553.5. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.66-7.50 (m, 7H), 2.03-5.08 (m, 14H), 0.53-1.62 (m, 14H).
Reaction SMILES: C([O:3][C:4](=[O:41])[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([NH:29][CH2:30][CH2:31][NH:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][N:34]=4)=[N:16][C:17]([C:21]4[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=4[Cl:28])=[CH:18]3)[N:13]=2)[CH2:8][CH2:7]1)C.O.[OH-].[Na+]>COCCOC>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([NH:32][CH2:31][CH2:30][NH:29][C:15]2[N:14]3[N:13]=[C:12]([CH:9]4[CH2:10][CH2:11][N:6]([CH2:5][C:4]([OH:41])=[O:3])[CH2:7][CH2:8]4)[N:20]=[C:19]3[CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:16]=2)=[N:34][CH:35]=1)#[N:40]
Reactant: CCOC(=O)CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(C4CCN(CC(=O)O)CC4)nn23)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
105 mg (0.18 mmol) of ethyl-{4-[5-({2-[(5-cyanopyridin-2-yl)amino]ethyl}amino)-7-(2,4-dichlorophenyl)[1,2,4]triazolo[1,5-c]pyrimidin-2-yl]piperidin-1-yl}acetate (Example 57A) were dissolved in 1,2-dimethoxyethane (7.5 ml), water (5 ml) and 31 mg (0.76 mmol) of sodium hydroxide were added and the reaction mixture was stirred at RT for 16 h. The mixture was then concentrated by lyophilization. This gave, after purification of the residue by preparative HPLC (Method 11), 65 mg (65% of theory) of the product as a solid.
Reaction SMILES: O.[OH-].[Li+].OO.C([C@H]1COC(=O)N1[C:19]([C@H:21]1[CH2:25][C:24](=[O:26])[N:23]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[O:36][CH3:37])[CH2:22]1)=[O:20])C1C=CC=CC=1.S([O-])(O)=[O:39].[Na+]>O.O1CCCC1>[CH3:37][O:36][C:29]1[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:28]=1[CH2:27][N:23]1[C:24](=[O:26])[CH2:25][C@H:21]([C:19]([OH:20])=[O:39])[CH2:22]1
Reactant: O=S([O-])O
Reactant: COc1ccc(CN2C[C@@H](C(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)CC2=O)c(OC)c1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C[C@@H](C(=O)O)CC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of lithium hydroxide monohydrate (2.0 g) in water (45 ml) was added dropwise 30 wt % aqueous solution of hydrogen peroxide solution (11 ml)) in an ice-sodium chloride cooling bath, and the mixture was stirred for 15 minutes. To this reaction solution was added tetrahydrofuran (36 ml), and then a solution of (S)-4-benzyl-3-[(S)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone (17.2 g) in tetrahydrofuran (144 ml) was added dropwise thereto, and the mixture was stirred for additional 20 minutes. To this reaction solution was slowly added a 10 wt % aqueous solution of sodium hydrogen sulfite (131 ml), and the mixture was stirred at room temperature for 1 hour after removing the bath, and then extracted with ethyl acetate (180 ml). The resulting organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate to chloroform/methanol=9/1). To the resulting product (6.7 g) was added diisopropyl ether (13.4 ml), the mixture was stirred at 70° C., and then cooled to 0° C. with stirring. A solid was collected from this suspension by filtration, dried under reduced pressure to give the titled compound (5.5 g). An analysis of this solid by HPLC analysis condition 1 showed that an isomer with longer retention time was a main product.
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH3:27][CH2:28][CH2:29]Br>>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH2:28][CH3:29])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCCBr
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2Cl)c1OC
Agent: [H-]
Agent: [Na+]
Product: CCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2Cl)c1OC
Yield: 104 %

Procedure:
Sodium hydride (50%, 920 mg), ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]acetate (6 g) and n-propyl bromide (3.2 g) were treated in a similar manner to that of Example 10-(5) to give oily ethyl 2-cyano-2-[2-methoxy-3-(2-chlorophenoxy)phenyl]valerate (7 g).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]34[CH2:21][CH2:20][C:17]([CH:22]=[N:23]O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].O=P(Cl)(Cl)Cl.O>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[NH:8][C:7]([C:14]34[CH2:19][CH2:18][C:17]([C:22]#[N:23])([CH2:20][CH2:21]3)[CH2:16][CH2:15]4)=[N:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2nc(C34CCC(C=NO)(CC3)CC4)[nH]c2n(CCC)c1=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c2nc(C34CCC(C#N)(CC3)CC4)[nH]c2n(CCC)c1=O
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a stirred suspension of 4-(2,6-dioxo-1,3-dipropyl-2,3,6,9-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carbaldehyde oxime (400 mg, 1.03 mmol) in CHCl3 (20 ml), cooled with the aid of an ice bath, was added POCl3 (neat, 1.5 eq, 237 mg) and the resulting mixture was allowed to reach ambient temperature overnight (17 h). The reaction mixture was poured into water, the phases were separated and the organic phase was washed with saturated aqueous solution of NaHCO3, dried over Na2SO4, filtered and concentrated in vacuo to give a white, brittle foam (360 mg, 95%). MS: 370 (MH+).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:13]1([SH:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>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].C(OCC)(=O)C>[CH:13]1([S:19][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)c1cccc(I)c1
Reactant: SC1CCCCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc(SC2CCCCC2)c1
Temperature: 100 °C
Reaction time: 7 h

Procedure:
Ethyl 3-iodobenzoate (5.00 g) was dissolve din dioxane (100 mL), and cyclohexanethiol (2.32 mL), N,N-diisopropylethylamine (6.29 mL), Xantphos (2.09 g) and Pd2(dba)3 (1.66 g) were added thereto in that order, and stirred in a nitrogen atmosphere at 100° C. for 7 hours. After left cooled, ethyl acetate was added to it, then washed with water ad saturated brine in that order, and dried with sodium sulfate. The drying agent was removed through filtration, the solvent was evaporated off under reduced pressure, and the residue was purified through silica gel column chromatography (ethyl acetate/hexane=from 0% to 25%, gradient) to give the intended compound (5.11 g) as an orange oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])#[N:2].C1C(=O)N([Br:21])C(=O)C1>ClC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:21][CH2:13][C:4]1[C:3]([C:1]#[N:2])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cccc(C#N)c1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(C#N)c1CBr
Yield: 98.2 %

Procedure:
A suspension of methyl 3-cyano-2-methylbenzoate (10.6 g, 60.5 mmol), NBS (16.2 g, 90.7 mmol) and azobisisobutyronitrile (AIBN) (100 mg) in tetrachloromethane (200 mL) was refluxed under nitrogen atmosphere for 6 hours. TLC analysis indicated the complete consumption of methyl 3-cyano-2-methylbenzoate (TLC solvent: 10% ethyl acetate in hexane). The reaction mixture was filtered and washed with chloroform (3×20 mL). The combined filtrate and washings were concentrated under reduced pressure. The residue was washed through a short column of silica gel using 10% ethyl acetate in hexanes as an eluent. The eluent was concentrated and the resultant product dried under vacuum overnight to provide 15.1 g of methyl 2-bromomethyl-3-cyanobenzoate (98% yield). 1H NMR spectrum (in DMSO-d6): δ 8.15 (d, J=8.0 Hz, 1H); 8.12 (d, J=7.9 Hz, 1H); 7.67 (t, 1H); 5.04 (s, 2H); 3.89 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]1[CH2:22][O:21]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:7]>O1CCCC1>[C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:19][CH:20]([OH:21])[CH2:22][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:14]=[CH:13][CH:12]=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][C:34]2[S:35][CH:36]=[CH:37][N:38]=2)=[O:32])=[C:26]([F:39])[CH:25]=1)#[N:7]
Reactant: C1CCNC1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCC1CO1
Solvent: C1CCOC1
Product: N#Cc1cc2c(Oc3ccc(NC(=O)Nc4nccs4)c(F)c3)ccnc2cc1OCC(O)CN1CCCC1
Temperature: 50 °C

Procedure:
After adding tetrahydrofuran (1 ml) and pyrrolidine (0.1 ml) to N-[4-(6-cyano-7-oxiranylmethoxy-quinolin-4-yloxy)-2-fluorophenyl]-N′-(thiazol-2-yl)urea (120 mg), the mixture was heated at 50° C. for 40 minutes. The reaction solution was purified by NH silica gel column chromatography (ethyl acetate-methanol system) to obtain the title compound (70 mg) as light yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[NH:12][S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[Br:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>CCOCC>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[Br:25])[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: BrCc1ccccc1Br
Reactant: COC(=O)c1cc(C)cc(C)c1NS(=O)(=O)c1ccc(OC)cc1
Solvent: CCOCC
Product: COC(=O)c1cc(C)cc(C)c1N(Cc1ccccc1Br)S(=O)(=O)c1ccc(OC)cc1
Yield: 73.4 %

Procedure:
In the same manner as described in Example 9, 0.699 g (2.0 mmol) of the product of Example 62 and 0.6 g (2.4 mmol) of 2-bromobenzyl bromide provided 0.761 g (73%) of the desired product as a white solid after trituration with ether. Electrospray Mass Spec 518.1(M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10]N1C(=O)CCC1=O>CN(C=O)C>[Cl:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Clc1c[nH]c2ccccc12
Reaction time: 4 h
Yield: 69.8 %

Procedure:
To a solution of indole (2.0 g, 17.0 mmol) in DMF (12 mL) at 10° C. under a nitrogen atmosphere was added N-chlorosuccinimide (2.49 g, 18.7 mmol). The reaction was stirred for 4 h then quenched with 10% sodium bisulfite solution. After stirring for 15 min the precipitated solid was collected by vacuum filtration. The filtered solid was washed with water then dissolved in dichloromethane. The solution was washed with water, brine and dried over sodium sulfate then concentrated in vacuo to give 3-chloroindole (1.8 g, 70%) as a yellow-brown solid: 1H NMR (CDCl3, 300 MHz) δ 8.06 (s, 1H), 7.64 (d, J=7.8 Hz, 1H), 7.34-7.37 (m, 1H), 7.16-7.22 (m, 2H).