Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:24])[CH2:18][C:19]([O:21]CC)=[O:20])=[C:11]([F:25])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(OC1C=CC(NC2N=CN=C(OC3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1)C1C=CC=CC=1>>[NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17](=[O:24])[CH2:18][C:19]([OH:21])=[O:20])=[C:11]([F:25])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)CC(=O)Nc1cc(F)c(Oc2ccnc(N)c2)cc1F
Agent: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Product: Nc1cc(Oc2cc(F)c(NC(=O)CC(=O)O)cc2F)ccn1
Yield: 0 %

Procedure:
Ethyl 3-(4-(2-aminopyridin-4-yloxy)-2,5-difluorophenylamino)-3-oxopropanoate (0.24 g, 0.68 mmol) was converted to the title compound (0.039 mg, 18%) in a manner similar to the preparation of Compound B of Example 116. HRMS(ESI+), Calcd.: 324.0796 (M+H)+, found: 324.0795 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: BrCc1ccc2ccccc2c1
Product: COC(=O)c1cccc(Sc2c(C)n(Cc3ccc4ccccc4c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 4, Step 1, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester and 2-(bromomethyl)naphthalene.
Reaction SMILES: C[Al](C)C.C1(O)CCCC1.[CH3:11][C:12]1[C:17]2[CH2:18][CH2:19][CH2:20][C:16]=2[N:15]=[C:14]([NH:21][C:22]([NH:24][S:25]([C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([O:32]C)=[O:31])(=[O:27])=[O:26])=[O:23])[N:13]=1.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:11][C:12]1[C:17]2[CH2:18][CH2:19][CH2:20][C:16]=2[N:15]=[C:14]([NH:21][C:22]([NH:24][S:25]([C:28]2[CH:37]=[CH:36][CH:35]=[CH:34][C:29]=2[C:30]([OH:32])=[O:31])(=[O:27])=[O:26])=[O:23])[N:13]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2c(n1)CCC2
Agent: C[Al](C)C
Agent: Cl
Agent: OC1CCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)nc2c1CCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.7 %

Procedure:
To 20 ml of dry toluene was added 2.4 ml of 2 M trimethylaluminum in toluene under a nitrogen atmosphere. Subsequently, 0.82 g cyclopentanol in 1 ml toluene was added via syringe and the mixture stirred at ambient temperature for 15 minutes. After addition of 1.56 g of methyl 2-[[(6,7-dihydro-4-methyl-5H-cyclopentapyrimidin-2-yl)aminocarbonyl]aminosulfonyl]benzoate to the mixture, the reaction was heated to 80° for 3.5 hours. The mixture was then cooled in ice while B 40 ml of 5% aqueous hydrochloric acid was added. Ethyl acetate was then added and shaking of the two phase mixture resulted in the crystallization of the product which was collected and dried to yield 1.5 g of 2-[[(6,7-dihydro-4-methyl-5H-cyclopentapyrimidin-2-yl)aminocarbonyl]aminosulfonyl]benzoic acid, cyclopentyl, ester, m.p. 183°-184°. The product showed characteristic absorptions at 3120, 1725, 1720 cm-1 in the infrared spectrum and at 1.7-2.35, 2.50, 2.95, 5.4, 7.6, 8.4, 8.5 and 13.0 ppm in the nuclear magnetic resonance spectrum (60 MHz), indicating the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][C@H:49]([CH3:52])[C@H:48]([C:53](O)=[O:54])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]>ClCCl>[CH3:52][C@H:49]1[CH2:50][CH2:51][N:46]([C:44]([O:43][C:39]([CH3:41])([CH3:40])[CH3:42])=[O:45])[CH2:47][C@H:48]1[C:53]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:54]
Reactant: C1CCNC1
Reactant: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (4.12 g, 10.85 mmol), diisopropylethylamine (2.33 g, 18.08 mmol) and pyrrolidine (782 mg, 10.85 mmol) were added to a solution of cis-1-(tert-butoxycarbonyl)-4-methylpiperidine-3-carboxylic acid (2.2 g, 9.04 mmol) in anhydrous dichloromethane (30 mL) at room temperature. The reaction mixture was stirred at room temperature for 4 h. The mixture was quenched with water and was extracted with dichloromethane. The organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford cis-tert-butyl 4-methyl-3-(pyrrolidine-1-carbonyl)piperidine-1-carboxylate (2.6 g).
Reaction SMILES: O.C([O-])(=O)C.[Ca+2].C([O-])(=O)C.C([O-])(=O)C.[Na+].[CH2:16]([O:23][C:24]([NH:26][C@H:27]([C:32]([OH:34])=O)[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:35][O:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH2:39].COC(=O)C(CC1C=CC=CC=1)N>O>[CH3:35][O:36][C:37](=[O:47])[C@H:38]([CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[NH:39][C:32](=[O:34])[C@H:27]([CH2:28][C:29](=[O:30])[OH:31])[NH:26][C:24]([O:23][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:25]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(=O)[O-]
Agent: COC(=O)C(N)Cc1ccccc1
Agent: [Ca+2]
Solvent: O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)OCc1ccccc1
Yield: 79.8 %

Procedure:
The preparation of the immobilized enzyme and the reaction were conducted in the same manner as in Example 1 with the exception that: The quantity of Thermoase and that of the calcium acetate monohydrate were 9.0 g and 0.45 g respectively, the quantity of the 0.05 M sodium acetate buffer solution of pH 7.5 was 90 ml; the acrylic ester matrix carrier (Amberlite XAD-7, Trademark) was replaced with 16.6 g of another carrier of the similar class (Amberlite XAD-8, Trademark, containing about 150 wt.% of water on a dry basis; the quantity of N-benzyloxycarbonyl-L-aspartic acid was 2.14 g (8 m mol): L-phenylalanine methyl ester was replaced with 2.87 g (16 m mol) of DL-phenylalanine methyl ester; the quantity of the water saturated ethyl acetate solution was changed to 26 ml; and the reaction time was five fours. N-Benzyloxycarbonyl-L-aspartyl-L-phenylalanine methyl ester was obtained in the yield of 79.8%.
Reaction SMILES: C(OC([N:8]([CH2:14][CH2:15][CH2:16][N:17]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[CH:20][S:19][C:18]1=[N:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[O:37][CH3:38])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=O)(C)(C)C.Cl>>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([N:29]=[C:18]2[N:17]([CH2:16][CH2:15][CH2:14][NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:21]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)=[CH:20][S:19]2)=[C:31]([O:37][CH3:38])[CH:32]=1
Reactant: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: Cl
Product: COc1cc(Cl)ccc1N=c1scc(-c2ccc(F)cc2)n1CCCNCCC(=O)O

Procedure:
The compound (700 mg) obtained in the above (1) was treated in a similar manner to in Example 9 (2) to give the title compound (588 mg) as hydrochloride.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:8][CH:7]2[CH:5]([O:6]2)[CH2:4][O:3]1.[C:9]1([C@H:15]([NH2:17])[CH3:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)(C)C>[CH3:1][C@@H:2]1[O:3][CH2:4][C@H:5]([OH:6])[C@@H:7]([NH:17][C@H:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:16])[CH2:8]1
Reactant: C[C@H]1CC2OC2CO1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CC(C)O
Product: C[C@H](N[C@H]1C[C@H](C)OC[C@@H]1O)c1ccccc1
Temperature: 85 °C

Procedure:
A mixture of (4S)-4-methyl-3,7-dioxabicyclo[4.1.0]heptane (˜3 mL dichloromethane solution, 10 mmol) and (R)-1-phenylethanamine (2.4 g, 20 mmol) in isopropyl alcohol (20 mL) was stirred at 85° C. for 1 week. After that, the solution was cooled to room temperature and purified by prep-HPLC to get the title compound (more polar, 120 mg, 10% for 2 steps) as a yellow solid and a side product (less polar, 400 mg, 32% for 2 steps) as a white solid. MS (ES+) C14H21NO2 requires: 235, found: 236 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[C:7]1=[O:20].Cl.C(N(CC)CC)C.[CH3:32][CH:33]([CH3:37])[C:34](Cl)=[O:35]>C(Cl)Cl>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][N:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[C:7]1=[O:20])(=[O:35])[CH:33]([CH3:37])[CH3:32]
Reactant: CC(C)C(=O)Cl
Reactant: COC(=O)c1ccc2ccn(Cc3cccc(N)c3)c(=O)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2ccn(Cc3cccc(NC(=O)C(C)C)c3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of methyl 2-(3-aminobenzyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate.HCl (0.15 g, 0.44 mmol) dissolved in methylene chloride (5 mL) was added triethylamine (0.30 mL, 2.2 mmol) and 2-methylpropanoyl chloride (0.09 mL, 0.87 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was then concentrated to dryness and the residue was purified by flash silica gel chromatography (0% to 5% EtOAc/DCM) to afford methyl 2-[3-(isobutyrylamino)benzyl]-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.15 g, 88%). LC-MS: (FA) ES+ 379.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].[C:7]([C:9]1[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=1)#[N:8].C([O-])([O-])=O.[K+].[K+].O>CS(C)=O.CN(C)C=O>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][N:13]1[CH:14]=[C:9]([C:7]#[N:8])[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: ClCCCCBr
Reactant: N#Cc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cn(CCCCCl)c(=O)[nH]c1=O
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
2.6 g (15.0 mmol) of 1-bromo-4-chlorobutane were added dropwise to a solution of 2.06 g (15.0 mmol) of 5-cyanouracil in 50 ml of dimethyl sulfoxide (DMSO) and 20.0 ml of N,N-dimethylformamide (DMF) at 0° C., and 2.07 g (15.0 mmol) of K2CO3 were added in portions over the course of 1 hour. The mixture was then stirred at 20° C. for 10 minutes (dialkylated product already identifiable). Water was added to the reaction mixture, and then the aqueous mixture was extracted twice with diethyl ether and twice with methylene chloride. The aqueous phase was adjusted to pH 3-4 and then extracted with methylene chloride. The methylene chloride phase was then dried, the desiccant was removed by filtration, and the solvent was evaporated to dryness in vacuo; yield: 0.6 g. 1-(4-Chlorobutyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile was employed without further purification in the next step.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([OH:23])=O)[CH2:9]1.[C:34]1([CH3:46])[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:35]=1>>[F:30][C:28]([F:31])([F:29])[C:26]1[CH:25]=[C:5]([CH:4]=[C:3]([C:2]([F:32])([F:33])[F:1])[CH:27]=1)[CH2:6][N:7]([CH3:24])[C@@H:8]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C@H:10]([C:21]([N:43]2[CH2:44][CH2:45][N:40]([C:36]3[CH:35]=[C:34]([CH3:46])[CH:39]=[CH:38][CH:37]=3)[CH2:41][CH2:42]2)=[O:23])[CH2:9]1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@H]1C[C@@H](C(=O)O)N(Cc2cccc(Cl)c2)C1
Reactant: Cc1cccc(N2CCNCC2)c1
Product: Cc1cccc(N2CCN(C(=O)[C@@H]3C[C@H](N(C)Cc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CN3Cc3cccc(Cl)c3)CC2)c1
Yield: 8 %

Procedure:
As described for Example 64e, (2S,4S)-4-[(3,5-bis-trifluoromethyl-benzyl)-methyl-amino]-1-(3-chloro-benzyl)-pyrrolidine-2-carboxylic acid (1 mmol) was converted, using 4-m-tolyl-piperazine instead of 2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one, to the title compound (52.3 mg) in 8% yield as colorless oil. MS m/e=654.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8](O)[CH3:9])=[CH:6][CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[N:3]=1.O=S(Cl)[Cl:23]>C(Cl)Cl>[Cl:23][CH:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[CH:5][CH:6]=1)[CH3:9]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)O
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1C(C)Cl

Procedure:
0.472 g (1.68 mmol) of the above prepared [rac]-1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-ethanol was dissolved in 8 ml of CH2Cl2 and treated dropwise at 0° C. with 0.399 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° for 5 Min. and at RT for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents yielded 0.488 g of pure title compound as light yellow oil.
Reaction SMILES: P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.CCCCCC.O(C(C)(C)C)[Na].[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[CH2:32][C@H:33]3[NH:44][CH2:43][CH2:42][C@@:39]4([C:40]=2[CH:41]=1)[C@H:34]3[CH2:35][CH2:36][CH2:37][CH2:38]4.[N+:45]([C:48]1[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=1)([O-:47])=[O:46]>C1(C)C=CC=CC=1.C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]2[CH2:32][C@H:33]3[N:44]([C:51]4[CH:52]=[CH:53][C:48]([N+:45]([O-:47])=[O:46])=[CH:49][CH:50]=4)[CH2:43][CH2:42][C@@:39]4([C:40]=2[CH:41]=1)[C@H:34]3[CH2:35][CH2:36][CH2:37][CH2:38]4
Reactant: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)NCC3
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)O[Na]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@@]13CCCC[C@H]1[C@@H](C2)N(c1ccc([N+](=O)[O-])cc1)CC3
Temperature: 80 °C
Yield: 30 %

Procedure:
Pd(OAc)2 (1.34 mg, 0.006 mmol) and 10% solution of P(t-Bu)3 in hexane (0.015 ml, 0.0048 mmol) were added to the suspension of NaO-t-Bu (86.4 g, 0.9 mmol), (+)-3-methoxy-morphinan (0.1645 g, 0.5 mmol) and 4-(nitro) -bromobenzene (0.1212 g, 0.6 mmol) in toluene (˜12 mL) in the presence of nitrogen. The resulting mixture was heated at 80° C. for 6 h. The reaction mixture was allowed to cool to room temperature, diluted with methylene chloride (50 mL), and washed with water. Concentration of the organic layer and flash chromatography on silica gel was carried out eluting with hexane first and then with a 5% to 20% ethyl acetate solution in hexane to provide a yellow liquid, 56.4 mg (30% yield); ms (EI): m/z 378 (M).
Reaction SMILES: [CH3:1][C:2]1[CH:38]=[CH:37][C:5]([S:6][CH:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:26][CH:25]=3)=[CH:15][CH:14]=2)[C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:6][CH:7]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][NH:22][C:23](=[O:36])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:26][CH:25]=3)=[CH:17][CH:18]=2)[C:8]([OH:10])=[O:9])=[CH:37][CH:38]=1
Reactant: COC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)Sc1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(SC(Cc2ccc(OCCNC(=O)c3ccc(-c4ccccn4)cc3)cc2)C(=O)O)cc1
Yield: 77.4 %

Procedure:
In a similar manner to that described in Example 2, methyl 2-(4-methylthiophenoxy)-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (203 mg), which is the product of Example 130, was reacted with aqueous sodium hydroxide solution (1N, 0.74 ml) and the reaction mixture was treated to give the title compound (153 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])[C:8](OS(C(F)(F)F)(=O)=O)=[CH:7]2.[O:30]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.CCOCC.O.[Pd](Cl)Cl.C(#N)C.C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[CH3:21])[C:8]([C:40]1[CH:41]=[CH:42][C:37]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:38][CH:39]=1)=[CH:7]2
Reactant: Cc1ccc(Cn2c(OS(=O)(=O)C(F)(F)F)cc3cccc(Cl)c3c2=O)c(C)c1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(Cn2c(-c3ccc(Oc4ccccc4)cc3)cc3cccc(Cl)c3c2=O)c(C)c1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
A mixture of trifluoromethanesulfonic acid 8-chloro-2-(2,4-dimethylbenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl ester (61.9 mg, 0.14 mmol), 4-phenoxyphenylboronic acid (45.9 mg, 0.21 mmol), and triphenylarsine (17.6 mg, 57.5 μmol) in THF (0.7 mL) under a nitrogen atmosphere was treated with bis-(acetonitrile) palladium (II) chloride (4.6 mg, 17.7 μmol) and aqueous sodium carbonate solution (0.7 mL of a 2 M solution) with vigorous stirring at ambient temperature. After 90 minutes stirring at ambient temperature, TLC analysis showed only a trace of starting trifluoromethanesulfonic acid 8-chloro-2-(2,4-dimethylbenzyl)-1-oxo-1,2-dihydroisoquinolin-3-yl ester remaining. The reaction was diluted with ether (20 mL), and water (10 mL). The basic aqueous layer was extracted with ether (3×10 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and conc. to afford a yellow semi-solid. The material was purified by silica gel column chromatography eluting with a gradient from 0% to 10% ethyl acetate/hexane. The main peak was collected to afford 8-chloro-2-(2,4-dimethylbenzyl)-3-(4-phenoxyphenyl)-2H-isoquinolin-1-one (41 mg, 63% yield) as a brittle white foam contaminated with a small amount (<10%) of an impurity: 1H-NMR (400 MHz, CDCl3): δ 7.51-7.49 (2H, m), 7.41-7.34 (3H, m), 7.18-7.11 (3H, m),7.04-7.00 (2H, m), 6.94-6.84 (5H, m), 6.68 (1H, d, J=7.8 Hz), 6.42 (1H, s), 5.09 (2H, s), 2.24 (3H, s), 2.00 (3H, s) ppm.
Reaction SMILES: Br[C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=1.B([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([F:27])[CH:19]=1)(O)O.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[NH2:14][C:3]1[C:2]([C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([F:27])[CH:19]=2)=[CH:7][C:6]([CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:5][N:4]=1
Reactant: O=C(O)c1ccc(B(O)O)cc1F
Reactant: Nc1ncc(C2CCOCC2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1ncc(C2CCOCC2)cc1-c1ccc(C(=O)O)c(F)c1
Temperature: 125 °C
Reaction time: 0.67 h
Yield: 136.9 %

Procedure:
To a microwave vial were charged with 3-bromo-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine (500 mg, 1.95 mmol), 4-borono-2-fluorobenzoic acid (1.07 g, 5.83 mmol), aqueous Na2CO3 (2 M, 4.86 mL) and DME (10 mL). The mixture was purged with argon, then followed by addition of Pd(PPh3)4 (225 mg, 0.194 mmol). The mixture was purged with argon, sealed and heated via microwave reactor at 125° C. for 20 min, and then at 130° C. for another 40 min. The DME layer of the reaction mixture was collected, and the solid precipitates were triturated with methanol (2×10 mL). Methanol supernatants were combined with DME layer, and concentrated. The obtained residue was stirred with Et2O (2×60 mL), and the Et2O supernatants were discarded. The solid residue was partitioned between EtOAc (20 mL) and aq. HCl (1 N, 20 mL). The EtOAc layer was stripped with 1N HCl (2×5 mL), and the aqueous layers were combined. The aqueous layer was concentrated under reduced pressure, and the obtained light yellow solid was triturated with methanol (8 mL). The supernant was isolated via filtration and concentrated. 4-(2-Amino-5-(tetrahydro-2H-pyran-4-yl)pyridin-3-yl)-2-fluorobenzoic acid (0.844 g, 2.67 mmol, 137% yield) was obtained as light yellow foam. LCMS (m/z) 317.2 (MH+) 0.46 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[N:15]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:14]=[C:13]2[C:24]([OH:26])=O.[NH3:27].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Cl:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:16]=1[N:15]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH:14]=[C:13]2[C:24]([NH2:27])=[O:26]
Reactant: N
Reactant: O=C(O)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: NC(=O)c1cn(CC2CCCCC2)c2c(Cl)cccc12
Reaction time: 20 h

Procedure:
Oxalyl chloride (4.95 g, 39.0 mmol) was added dropwise to a mixture of 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carboxylic acid (6.4 g, 21.9 mmol) and dichloromethane (150 ml) under ice-water cooling and the resulting mixture was stirred at room temperate for 20 h. Dichloromethane and excess oxalyl chloride were removed by evaporation and the obtained residue was mixed with dichloromethane (100 ml). Aqueous ammonia (33%, 50 ml) and potassium carbonate (6.05 g, 43.8 mmol) was added into the mixture under ice-water bath cooling. After stirring at room temperature for 2 h, the reaction mixture was concentrated in vacuo, then the obtained solid was washed with water, then n-heptane, and dried under reduced pressure to afford 7-chloro-1-(cyclohexyl)methyl-1H-indole-3-carboxylic acid amide (6.4 g, 22.0 mmol).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1.C(OC(C)C)(C)C>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([NH:21][C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])=[CH:17][CH:16]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)cn1
Solvent: CC(C)OC(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C2CC2)cn1
Yield: 71 %

Procedure:
As described for example 179b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridin-3-ylamine (150 mg, 0.53 mmol) was converted, using cyclopropanecarbonylchloride instead of acetyl chloride, to the title compound (132 mg, 71%) which was obtained as a white solid after trituration with diisopropylether. MS: m/e=350.0 [M+H]+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[NH2:7][S:8]([C:11]1[C:12]([Cl:35])=[CH:13][C:14]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[C:15]([CH:27]=1)[C:16]([O:18][CH2:19][CH2:20]CC(OCC)=O)=[O:17])(=[O:10])=[O:9]>ClCCl>[NH2:7][S:8]([C:11]1[C:12]([Cl:35])=[CH:13][C:14]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[C:15]([CH:27]=1)[C:16]([O:18][CH2:19][CH2:20][CH2:1][C:2]([Cl:4])=[O:3])=[O:17])(=[O:9])=[O:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)CCCOC(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1
Solvent: ClCCl
Product: NS(=O)(=O)c1cc(C(=O)OCCCC(=O)Cl)c(NCc2ccco2)cc1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of oxalyl chloride (0.040 mole) in dichloromethane (20 mL) is added dropwise to an ice bath cooled solution of 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoic acid (300) (0.040 mole) in dichloromethane (50 mL). The reaction is stirred at ambient temperature for 5 hours. The reaction solution is washed with 5% aqueous sodium bicarbonate, with water, and then with a saturated sodium chloride solution. The organic layer is dried over sodium sulfate, filtered and concentrated in vacuo to give 4-(5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoyloxy)butanoyl chloride (313). See eg., D. L. Musso, et. al., J. Med. Chem., (2003) 46: 409.