Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[O:14][CH2:15][C:16]1[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:20][CH:21]=1.[CH3:27][C:28]1[N:29]=[C:30]([S:33](Cl)(=[O:35])=[O:34])[S:31][CH:32]=1.COC(C)(C)C>N1C=CC=CC=1>[CH3:27][C:28]1[N:29]=[C:30]([S:33]([NH:4][C:5]2[CH:13]=[C:12]3[C:8]([CH2:9][CH2:10][CH2:11]3)=[CH:7][C:6]=2[O:14][CH2:15][C:16]2[N:17]=[CH:18][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:20][CH:21]=2)(=[O:35])=[O:34])[S:31][CH:32]=1
Reactant: Cc1csc(S(=O)(=O)Cl)n1
Reactant: CCOC(=O)c1cnc(COc2cc3c(cc2N)CCC3)cn1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Product: CCOC(=O)c1cnc(COc2cc3c(cc2NS(=O)(=O)c2nc(C)cs2)CCC3)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 712 mg of ethyl 5-{[(6-amino-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyrazine-2-carboxylate trihydrochloride were added 35.6 mL of pyridine and 35.0 mL of a 0.21 M 4-methyl-1,3-thiazole-2-sulfonyl chloride/tert-butyl methyl ether solution, followed by stirring overnight at room temperature. The reaction liquid was concentrated under reduced pressure, and to the obtained residue was added a 5% w/v aqueous citric acid solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:1 to 95:5) to obtain 256 mg of ethyl 5-{[(6-{[(4-methyl-1,3-thiazol-2-yl)sulfonyl]amino}-2,3-dihydro-1H-inden-5-yl)oxy]methyl}pyrazine-2-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]2.[Br:14]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[Br:14][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2cc(C#N)ccc2c1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc2cc(CBr)ccc2c1
Yield: 78.6 %

Procedure:
6.11 g of 6-methyl-2-naphthalenecarbonitrile was dissolved in 100 ml of carbon tetrachloride, and the solution was mixed with 6.63 g of N-bromosuccinimide and 30 mg of 2,2-azobis-iso-butylonitrile. After refluxing under heating for 4 hours, the resulting reaction solution was mixed with chloroform, washed with water, and then dried. By distilling off the solvent, 7.07 g of colorless 6-bromomethyl-2-naphthalenecarbonitrile was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1>O1CCOCC1.CCOC(C)=O>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][C@@H:20]2[CH3:19])[N:3]=1
Reactant: C[C@H]1COCCN1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1COCCN1c1nc(Cl)cc(Cl)n1
Temperature: 130 °C
Yield: 34.2 %

Procedure:
The 2,4,6-trichloropyrimidine (100 mg, 053 mmol) was dissolved in dioxane (2 mL) with DIPEA (280 μL, 1.6 mmol) and (S)-3-methylmorpholine (54 mg, 0.53 mmol). The reaction mixture was heated at 130° C. under microwave irradiations for 15 min. It was then diluted with EtOAc and washed with brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by preparative HPLC (Waters Sun Fire C18, 30×100 mm, 5 um; 0.1% TFA-water/acetonitrile; gradient acetonitrile 5-100% in 20 min) to afford the title compound (45 mg, 34%). tR: 3.70 min (HPLC 1); ESI-MS: 248.2/250.2 [M+H]+ (LC-MS 1).
Reaction SMILES: [N+:1](=[C:3]([C:17]([CH3:19])=[O:18])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-:2].[Br-].[Li+].C(N(CC)CC)C.[CH3:29][Si:30](Cl)([CH3:32])[CH3:31]>C(#N)C>[N+:1](=[C:3]([C:17]([O:18][Si:30]([CH3:32])([CH3:31])[CH3:29])=[CH2:19])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5])=[N-:2]
Reactant: CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: C[Si](C)(C)Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(O[Si](C)(C)C)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
Into 5 ml of dry acetonitrile were suspended 263 mg (1 millimole) of p-nitrobenzyl 2-diazoacetoacetate and 122 mg (1.4 millimoles) of lithium bromide. To the mixture were added 220 μl (1.6 millimoles) of triethylamine and then 190 μl (1.5 millimoles) of trimethylsilyl chloride while agitating under an argon atmosphere at a room temperature. The resultant was heated up to 40° C. and agitated at the same temperature overnight, followed by concentration under a reduced pressure. To the residue was added 20 ml of dry hexane, and the resultant was agitated for 30 min. at a room temperature. Insoluble materials were removed by filtration and the filtrate was concentrated to dryness under a reduced pressure to give 330 mg (yield 87%) of the desired compound in a yellow solid. The physical properties of the product were in agreement with those of the product obtained in Example 1.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([I:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[C:3]=1[S:14]([CH3:17])(=[O:16])=[O:15].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[I:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([CH3:13])[C:3]([S:14]([CH3:17])(=[O:16])=[O:15])=[C:2]2[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCNCC1
Reactant: Cc1nc2ccc(I)cc2c(Cl)c1S(C)(=O)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc2ccc(I)cc2c(N2CCCCC2)c1S(C)(=O)=O
Yield: 54.4 %

Procedure:
4-Chloro-6-iodo-3-methanesulfonyl-2-methyl-quinoline (compound of example D.2) (300 mg, 0.786 mmol), piperidine (74 mg, 0.865 mmol) and N,N-diisopropyl ethyl amine (0.148 mL, 0.865 mmol) were heated in dry N,N-dimethylformamide (3 mL) for 4 h at 100° C. N,N-Dimethylformamide was evaporated at 40° C./0.1 mbar, and the residue directly purified by chromatography on silica gel in dichloromethane. One obtained 184 mg (54%) of white crystals. MS: m/z=431 (M+H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[S:20])(C(C)(C)C)(C)C.CCN(CC)CC.F>CC#N>[OH:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=1[NH:18][C:19]([NH:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[S:20]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc([N+](=O)[O-])ccc1NC(=S)Nc1ccccc1
Agent: F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NC(=S)Nc2ccccc2)c(O)c1
Yield: 76.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-phenyl-2-thiourea was prepared by treating a solution of N-(2-tert-butyldimethysilyloxy-4-nitrophenyl)-N'-phenyl-thiourea (100 mg, 0.248 mmol) in CH3CN (1 mL) with Et3N·HF (100 uL, 0.62 mmol) in acetonitrile for 10 minutes at 23° C. The solution was concentrated and flushed through a silica plug with EtOAc to afford the desired compound as an orange solid (55 mg, 77%).
Reaction SMILES: [N:1]1([NH:7][C:8](=[O:31])[CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]([C:21](=[O:29])[C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]=2[CH3:30])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:32]1(=O)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[CH:32]1([N:4]2[CH2:5][CH2:6][N:1]([NH:7][C:8](=[O:31])[CH2:9][C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]([C:21](=[O:29])[C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[C:11]=3[CH3:30])[CH2:2][CH2:3]2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C1CCCCC1
Reactant: COc1ccc2c(c1)c(CC(=O)NN1CCNCC1)c(C)n2C(=O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)c(CC(=O)NN1CCN(C3CCCCC3)CC1)c(C)n2C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 0.112 g (0.26 mmol) of N-(piperazin-1-yl)-1-(4-chlorobenzoyl)-5-methoxy-2-methylindole-3-acetamide and 0.03 mL (0.25 mmol) of cyclohexanone in 2 mL of anhydrous tetrahydrofuran was added 0.02 mL (0.32 mmol) of acetic acid then 0.078 g (0.37 mmol) of sodium triacetoxyborohydride. The reaction was stirred at room temperature for 20 hr then partitioned between ethyl acetate (20 mL) and saturated sodium bicarbonate (20 mL). The organic phase was washed with more bicarbonate (2×20 mL) then dried (MgSO4), filtered and evaporated. Preparative HPLC was used to isolate the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S:11]1[CH:15]=[C:14]([CH:16]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][CH3:36])[C:17]([O:19][C@@H:20]2[CH:25]3[CH2:26][CH2:27][N:22]([CH2:23][CH2:24]3)[CH2:21]2)=[O:18])[C:13]2[CH:37]=[CH:38][CH:39]=[CH:40][C:12]1=2>CCOC(C)=O>[Br-:1].[S:11]1[CH:15]=[C:14]([CH:16]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH2:35][CH3:36])[C:17]([O:19][C@@H:20]2[CH:25]3[CH2:26][CH2:27][N+:22]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:23][CH2:24]3)[CH2:21]2)=[O:18])[C:13]2[CH:37]=[CH:38][CH:39]=[CH:40][C:12]1=2
Reactant: CCc1ccccc1NC(C(=O)O[C@H]1CN2CCC1CC2)c1csc2ccccc12
Reactant: O=C(CBr)c1ccccc1
Solvent: CCOC(C)=O
Product: CCc1ccccc1NC(C(=O)O[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)c1csc2ccccc12
Product: [Br-]
Temperature: 100 °C
Yield: 36 %

Procedure:
A mixture of 2-bromo-1-phenylethanone (44.8 mg, 0.22 mmol) and (R)-quinuclidin-3-yl 2-(benzo[b]thiophen-3-yl)-2-(2-ethylphenylamino)acetate (C44) (86 mg, 0.20 mmol) in EtOAc (3 ml) was heated under microwave irradiation at 100° C. for 1 hour. 2-Bromo-1-phenylethanone (44.8 mg, 0.22 mmol) was added, and the mixture was heated at 100° C. under microwave irradiation for an additional hour. The solvent was evaporated, and the crude product was triturated with Et2O to collect (3R)-3-(2-(benzo[b]thiophen-3-yl)-2-(2-ethylphenylamino)acetoxy)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo[2.2.2]octane bromide (44.6 mg, 35.2% yield).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1.C([BH3-])#N.[Na+].[N:34]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O)(=O)C>CO.ClCCl>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][N:37]2[CH2:38][CH2:39][N:34]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35][CH2:36]2)=[CH:7][C:6]=1[C:13]1[C:21]2[C:16](=[C:17]([O:22][CH3:23])[N:18]=[CH:19][CH:20]=2)[N:15]([CH3:24])[CH:14]=1
Reactant: COc1nccc2c(-c3cc(C=O)ccc3Oc3ccc(F)cc3F)cn(C)c12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1nccc2c(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)ccc3Oc3ccc(F)cc3F)cn(C)c12
Temperature: 75 °C
Yield: 46.5 %

Procedure:
A suspension of Example 105B (100 mg, 0.254 mmol), sodium cyanoborohydride (47.8 mg, 0.761 mmol) and tert-butyl piperazine-1-carboxylate (94 mg, 0.51 mmol) in a mixture of methanol (3 mL), acetic acid (0.073 mL, 1.3 mmol), and dichloromethane (1 mL) was heated at 75° C. 2 hours. Upon cooling, the reaction mixture was partitioned between 50% saturated sodium bicarbonate solution (50 mL) and ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, 0-3% methanol in dichloromethane) to provide the title compound (66.7 mg, 47% yield).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]2[S:12][C:13]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=4)=[O:22])=[CH:16][C:14]=3[CH:15]=2)=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.Cl.[NH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39].CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.ClCCCl.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[O:7])=[CH:9][C:10]=1[C:11]1[S:12][C:13]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[CH:25]=3)=[O:22])=[CH:16][C:14]=2[CH:15]=1
Reactant: Cc1cccc(NC(=O)Nc2ccc3sc(-c4cc(C(=O)O)cnc4N)cc3c2)c1
Reactant: COC(=O)CCCCCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)CCCCCNC(=O)c1cnc(N)c(-c2cc3cc(NC(=O)Nc4cccc(C)c4)ccc3s2)c1
Temperature: 50 °C

Procedure:
The reaction mixture of 6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]nicotinic acid (84 mg, 0.2 mmol, 1 eq), methyl 6-aminohexanoate hydrochloride (43.7 mg, 1.2 eq), DMAP (5 mg, 0.2 eq), and EDCI (46.1 mg, 1.2 eq) in anhydrous 1,2-dichloroethane (3 mL) was stirred and heated at 50° C. for 2 hours. It was then diluted with ethyl acetate, washed sequentially with aqueous NH4Cl, saturated aqueous NaHCO3, and brine, and dried with anhydrous sodium sulfate. The upper clear solution was decanted, concentrated, and the solid residue was triturated with EtOAc-Hex (3:1) yielding methyl 6-[({6-amino-5-[5-({[(3-methylphenyl)amino]carbonyl}amino)-1-benzothien-2-yl]pyridin-3-yl}carbonyl)amino]hexanoate as a white solid in amount of 83 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=[CH:26][C:27](Cl)=[O:28])[CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([C:12]2[CH:18]=[CH:17][C:15]([NH:16][C:27](=[O:28])[CH:26]=[CH:25][C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(Cl)C=Cc1cccnc1
Reactant: COc1ccc(S(=O)(=O)c2ccc(N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)c2ccc(NC(=O)C=Cc3cccnc3)cc2)cc1
Temperature: 50 °C
Yield: 57.7 %

Procedure:
To a solution of 4-((4-methoxyphenyl)sulfonyl)aniline (76 mg, 0.29 mmol) in DMF (3 mL) is added 3-(pyridin-3-yl)acryloyl chloride (62 mg, 0.30 mmol) and K2CO3 (138 mg, 1 mmol). The mixture is heated at 50° C. for 2 h and the solvent is evaporated. The residue is partitioned between EtOAc (15 mL) and brine (10 mL) and the layers are separated. The aqueous layer is extracted with EtOAc (10 mL) and the combined extracts are dried (Na2SO4) and evaporated. Purification of the residue by preparative TLC with 100:5:0.5 CH2Cl2/MeOH/NH4OH gives the titled compounds as a white solid (66 mg, 58%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]2)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].[OH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>COCCOC.C(OCC)(=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=[CH:10]3)=[CH:32][CH:31]=1
Reactant: COC(=O)c1cccc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Reactant: OB(O)c1ccc(O)cc1
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: CCOC(C)=O
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A solution of methyl 6-{[(trifluoromethyl)sulfonyl]oxy}-1-naphthoate (271 g, 0.81 mol) (from multiple batches), tetrakis(triphenylphosphine)palladium (0) (37.4 g, 0.032 mol), 2 M sodium carbonate solution (1.3 L) and 4-hydroxyphenyl boronic acid (134 g, 0.97 mol) in ethylene glycol dimethyl ether (1.5 L) was heated at 80° C. for 1.5 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (2 L) and water (2 L). The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated to a dark semisolid residue. The crude material was purified by crystallization from dichloromethane-heptane to give 199 g of the product as a tan solid. 1H NMR (DMSO-d6): 9.64 (s, 1H), 8.76 (d, J=9 Hz, 1H), 8.21 (m, 2H), 8.07 (d, J=7 Hz, 1H), 7.93 (m, 1H), 7.66 (d, J=9 Hz, 2H), 7.58 (t, J=8 Hz, 1H), 6.89 (d, J=9 Hz, 2H), 3.93 (s, 3H).
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.[Al+3].[Cl-].[Cl-].[Cl-].ClC[CH2:16][C:17](Cl)=[O:18].Cl[CH2:21][Cl:22]>>[Cl:22][CH2:21][C:17](=[O:18])[CH2:16][C:6]1[CH:7]=[CH:8][C:3]2[O:2][CH2:1][O:9][C:4]=2[CH:5]=1
Reactant: ClCCl
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)OCO2
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCl)Cc1ccc2c(c1)OCO2
Yield: 90 %

Procedure:
To the solution of 1,2-methylenedioxybenzene (0.05 mol) dissolved in dichloromethane (30 mL), AlCl3 (0.10 mol) is added batch by batch and 3-chloropropionyl chloride (0.055 mol) is added dropwise, while the internal temperature is maintained below 5° C. Following procedures described in General Method One-Method A, 3-chloro-1-(1,2-methylenedioxybenzen-4-yl)-propanone is obtained as a white solid (9.5 g). The yield is 90.0%. MS(m/z): 213.0 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[O:10]=[C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[C:13](=O)[O:12]1.O>CN(C=O)C>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N:4]1[C:13](=[O:12])[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH:15]=2)[C:11]1=[O:10]
Reactant: Cc1cccc(C)c1N
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(C)c1N1C(=O)c2ccc(C(=O)O)cc2C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,6-dimethylaniline (1.21 g) in DMF (15 mL) was added 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (1.92 g) and the mixture was stirred at room temperature for 18 h. The mixture was poured into water and the resulting precipitate was filtered, washed with water and dried under reduced pressure. The solid was suspended in HOAc (25 mL) and the mixture was heated at 110° C. for 4 h. The resulting solution was cooled and the solvent was removed under reduced pressure to give 2-(2,6-dimethylphenyl)-1,3-dioxo-2,3-dihydro-1H-isoindole-5-carboxylic acid as an off-white solid, mp=210-213° C.; MS (m/z) 294 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C1COCC1>[N:24]1([CH2:23][CH2:22][CH2:21][NH:20][C:17](=[O:19])[C@@H:9]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1
Reactant: NCCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCCCN1CCOCC1
Yield: 91.1 %

Procedure:
To a solution in 15 ml of anhydrous THF of tert-butyloxycarbonyl-D-phenylalanine N-hydroxysuccinimmidyl ester (500 mg, 1.38 mmol), N-(3-aminopropyl)-morpholine (1.328 mmol, 0.201 ml) is added. The stirring is maintained for 90 min. The solvent is then evaporated, and the residue dissolved with AcOEt (50 ml); the organic phase is washed with NaHCO3 1M (3×50 ml), HCl 1M (3×50 ml), saturated aqueous solution of sodium chloride (3×50 ml). The solution dried on anhydrous Na2SO4. Following the evaporation of the solvent, 474 mg of (ter-butyloxycarbonyl-D-phenylalanine-N-[3(morpholin-4-yl)propyl]amide) (1.21 mmol, yield=88%) are obtained.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:30])=[CH:25][CH:24]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.CCCCCC>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([N:31]([CH3:39])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:30])=[CH:27][CH:28]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[N:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[O:10][C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2cc(-c3ccc(OC)nc3)oc2C)C2CCCCC2)cc1
Solvent: CCO
Solvent: CCCCCC
Product: COc1ccc(-c2cc(C(Nc3ccc(C(=O)N(C)CCC(=O)O)cc3)C3CCCCC3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
Ethyl 3-[{[4-({cyclohexyl[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]methyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (1388 mg) which is a synthetic intermediate in Example 13.3 was dissolved in ethanol-hexane (6:4, volume ratio), and the solution was subjected to HPLC using CHIRALPAK AD (50 mmID×500 mL, manufactured by DAICEL CHEMICAL INDUSTRIES, LTD.) and eluted with ethanol-hexane (6:4, volume ratio) as mobile phase at 30° C., a flow rate 60 mL/min. The fractions showing a peak with retention time 20 min were collected, and concentrated. The obtained amorphous compound (682 mg) was dissolved in ethanol (3 mL) and tetrahydrofuran (3 mL), 1N lithium hydroxide (2.5 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (20 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (614 mg, 96%).