Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][C@@H:24]([C:26]([NH:28][CH2:29][CH2:30][C:31]([NH:33][C@H:34]([C:43]([NH:45][C@@H:46]([C:54]([O:56]CC1C=CC=CC=1)=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=1)=[O:32])=[O:27])[CH3:25])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H][H]>CO.[Pd]>[NH:1]([C:64]([O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:65])[C@H:2]([C:7]([NH:9][C@@H:10]([C:21]([NH:23][C@@H:24]([C:26]([NH:28][CH2:29][CH2:30][C:31]([NH:33][C@H:34]([C:43]([NH:45][C@@H:46]([C:54]([OH:56])=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([OH:42])=[CH:40][CH:41]=1)=[O:32])=[O:27])[CH3:25])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](C)C(=O)NCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N[C@H](C)C(=O)NCCC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)N[C@H](Cc1ccccc1)C(=O)O
Yield: 93.8 %

Procedure:
Boc-Leu-(D)Trp-(D)Ala-βAla-Tyr-(D)Phe-OBzl (0.2 g) was dissolved in methanol (50 ml) and then catalytically reduced in a hydrogen stream in the presence of palladium black catalyst. After the catalyst was filtered out and the solvent was distilled off, the residue was dissolved in a 50% aqueous solution of acetic acid (3 ml) and applied to a column (2×95 cm) of Sephadex G-25, packed with 50% aqueous acetic acid, and developed with the same solvent. The major fractions were collected and lyophilized to yield a white powder of Boc-Leu-(D)Trp-(D)Ala-βAla-Tyr-(D)Phe-OH (170 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[C:8]=1[CH3:24].ClC1C=CC=C(C(OO)=[O:33])C=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14]([C:15]2[S:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:33])[C:8]=1[CH3:24]
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3s2)c1C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCOc1ccnc(CS(=O)c2nc3ccccc3s2)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
0.6 g of 2-{4-(3-methoxypropoxy)-3-methylpyridine-2-yl}methylthiobenzothiazole was dissolved in 20 ml of dichloromethane to obtain a solution. 0.36 g of 80% m-chloroperbenzoic acid was added to the solution at -45° C. After one hour, 0.34 g of triethylamine and 30 ml of a saturated aqueous solution of sodium hydrogencarbonate were added to the obtained mixture. The resulting mixture was stirred at a room temperature for 30 minutes. The dichloromethane layer was separated, washed with a saturated aqueous solution of sodium hydrogencarbonate twice, dried over magnesium sulfate and filtered. The filtrate was concentrated to obtain a residue. This residue was purified by silica gel column chromatography to obtain 0.17 g of the title compound as a white crystal.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)[CH3:3].[C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=O)[CH3:17]>>[CH2:2]([O:4][C:5]1[CH:10]=[C:9]2[C:8](=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1)[NH:11][C:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[CH:17]2)[CH3:3]
Reactant: CCOc1ccc(NN)c([N+](=O)[O-])c1
Reactant: CC(=O)c1ccccn1
Agent: Cl
Product: CCOc1cc([N+](=O)[O-])c2[nH]c(-c3ccccn3)cc2c1
Yield: 8.4 %

Procedure:
(4-Ethoxy-2-nitrophenyl)hydrazine hydrochloride (5 g, 21 mmol) and 2-acetylpyridine (2.4 ml, 21 mmol) were reacted according to the same procedures as Preparations 4 to 5 to give the title compound (0.5 g, Yield 8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)=[O:8].[NH:22]1[CH2:25][CH:24]([NH:26][C:27](=[O:44])[CH2:28][NH:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:43])([F:42])[F:41])[CH:38]=3)[N:33]=[CH:32][N:31]=2)[CH2:23]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][NH:6][C:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:22]2[CH2:23][CH:24]([NH:26][C:27](=[O:44])[CH2:28][NH:29][C:30]3[C:39]4[C:34](=[CH:35][CH:36]=[C:37]([C:40]([F:41])([F:43])[F:42])[CH:38]=4)[N:33]=[CH:32][N:31]=3)[CH2:25]2)[CH2:11][CH2:10]1)=[O:8]
Reactant: COc1ccc(CNC(=O)C2CCC(=O)CC2)c(OC)c1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: COc1ccc(CNC(=O)C2CCC(N3CC(NC(=O)CNc4ncnc5ccc(C(F)(F)F)cc45)C3)CC2)c(OC)c1

Procedure:
Reaction of N-(2,4-dimethoxybenzyl)-4-oxocyclohexanecarboxamide with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH2:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:17])[F:18])[CH2:11][CH2:10][N:9]1[C:32](=[O:42])[C@@H:33]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[NH:34][C:43](=[O:45])[CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
200 mg 0.348 mmol) of the mixture of (2R*,4S*)-2-benzyl-1-((R)-phenylalanyl)-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine diastereomers are reacted with 39 μl (0.417 mmol) of acetic anhydride in analogy to Example 31. The title compound is obtained as mixture of diastereomers (white foam). TLC: methylene chloride/methanol/conc. ammonia (1000:50:1) Rf =0.28, FD-MS: M+ =616.
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[N:8]=[C:9]([CH2:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:6].[Li+].[OH-].CC(=O)OCC>O1CCOCC1>[C:23]([O:22][C:20]([NH:19][CH2:18][C:9]1[O:10][C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:5]([OH:6])=[O:4])[N:8]=1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1nc(CNC(=O)OC(C)(C)C)oc1-c1ccccc1
Agent: N#N
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1nc(C(=O)O)c(-c2ccccc2)o1
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(tert-butoxycarbonylamino-methyl)-5-phenyl-oxazole-4-carboxylic acid methyl ester (200 mg, 0.60 mmol) in dioxane (2.0 mL) was treated with 1N LiOH (2.0 mL). The resulting mixture was stirred for 1 h. EA (10 mL) was added and the organic phase was washed with 1N HCl (3 mL), dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=0.89 min, [M+H]+=319.17.
Reaction SMILES: C(S)=C.[C:4]1(=[O:10])[O:9][C:7](=[O:8])[CH:6]=[CH:5]1.[NH2:11][C:12]1[CH:20]=[CH:19][C:15](C(O)=O)=[CH:14][CH:13]=1>>[C:4]([OH:9])(=[O:10])[CH2:5][CH2:6][C:7]([NH:11][C:12]1[CH:20]=[CH:19][CH:15]=[CH:14][CH:13]=1)=[O:8]
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=C1C=CC(=O)O1
Agent: C=CS
Product: O=C(O)CCC(=O)Nc1ccccc1

Procedure:
The copolymer of vinyl mercaptan and maleic anhydride which is further reacted with p-amino benzoic acid to form polymeric succinanilic acid,
Reaction SMILES: [NH2:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1.C(Cl)(Cl)Cl.[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26](Cl)=[O:27].Cl>O.C(N(CC)CC)C>[Cl:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:25]=1[C:26]([NH:1][C:2]1[N:7]2[O:8][C:9](=[O:11])[N:10]=[C:6]2[N:5]=[C:4]([N:12]([CH2:16][CH:17]=[CH2:18])[CH2:13][CH:14]=[CH2:15])[N:3]=1)=[O:27]
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C=CCN(CC=C)c1nc(NC(=O)c2c(Cl)cccc2Cl)n2oc(=O)nc2n1

Procedure:
5.0 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one are mixed with 150 ml. of chloroform, 10 ml. of triethylamine and 4.5 ml. of 2,6-dichlorobenzoyl chloride and heated to reflux for 7 hours. The mixture is then cooled, diluted with water, adjusted to pH 4 with hydrochloric acid and extracted with chloroform. The combined organic extracts are dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is chromatographed over silica gel using a mixture of methylene chloride and methanol (99:1) for the elution. Recrystallization from diisopropyl ether and methylene chloride yields pure 2,6-dichloro-N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}benzamide having a melting point of 133°-135° C.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.C(N(CC)CC)C.[C:18](Cl)(=[O:21])[CH:19]=[CH2:20]>ClCCl.O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:18](=[O:21])[CH:19]=[CH2:20]
Reactant: c1ccc2c(c1)CCNC2
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCc2ccccc2C1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 56817.1 %

Procedure:
To a stirred solution of 1,2,3,4-tetrahydroisoquinoline (1 g, 7.52 mmol) in anhydrous dichloromethane (10 ml) was added triethylamine (4.17 ml, 30.00 mmol) and acryloyl chloride (0.73 ml, 9.02 mmol) at 0° C. The reaction mixture was stirred at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the reaction mixture was diluted with water (50 ml) and extracted with dichloromethane (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 40% ethyl acetate/pet ether as an eluent to get the desired compound as a pale brown liquid (800 g, 57%). 1H NMR (400 MHz, DMSO-d6) δ 7.24-7.06 (m, 4H), 6.70-6.60 (m, 1H), 6.33 (dd, J=16.6, 1.5 Hz, 1H), 5.73 (dd, J=10.5, 1.7 Hz, 1H), 4.80 (s, 1H), 4.73 (s, 1H), 3.89 (t, J=5.8 Hz, 2H), 3.78 (t, J=5.8 Hz, 2H).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][NH:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=[CH:2]1.[Cl:12][C:13]1[CH:14]=[C:15](F)[CH:16]=[CH:17][C:18]=1[Cl:19]>>[ClH:12].[Cl:12][C:13]1[CH:14]=[C:15]([O:11][CH:10]2[CH2:9][NH:8][CH2:7][CH2:6][C:5]3[S:1][CH:2]=[CH:3][C:4]2=3)[CH:16]=[CH:17][C:18]=1[Cl:19]
Reactant: Fc1ccc(Cl)c(Cl)c1
Reactant: OC1CNCCc2sccc21
Product: Cl
Product: Clc1ccc(OC2CNCCc3sccc32)cc1Cl

Procedure:
The same method as in Example 3 was conducted using 5,6,7,8-tetrahydro-4H-thieno[2,3-d]azepin-4-ol (Reference Example 29) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dichloro-1-fluorobenzene instead of 1,3-difluorobenzene to give the objective compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9]O)=[CH:7][CH:6]=[CH:5][N:4]=1.C1(P([N:25]=[N+:26]=[N-:27])(C2C=CC=CC=2)=O)C=CC=CC=1.C12CCCCC1CCCNN=2.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:25]=[N+:26]=[N-:27])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ncccc1CO
Agent: C1CCC2CCCNN=C2C1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ncccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.4 g of 2-methoxy-3-hydroxymethylpyridine was dissolved in 100 ml toluene, and 13.8 ml diphenyl phosphoryl azide and 9.5 ml diazabicyclo[5.4.0]undecene were added, and the mixture was stirred overnight at room temperature. Water was added to the reaction product which was then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 9.5 g of [(2-methoxy-3-pyridyl)methyl]azide.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl.[N:30]1([CH2:37][CH2:38][O:39][C:40]2[CH:48]=[CH:47][C:43]([C:44](O)=O)=[CH:42][N:41]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:37][CH2:38][O:39][C:40]2[N:41]=[CH:42][C:43]([CH2:44][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:47][CH:48]=2)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: O=C(O)c1ccc(OCCN2CCCCCC2)nc1
Reactant: CCNc1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Agent: Cl
Product: CCN(Cc1ccc(OCCN2CCCCCC2)nc1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 81.6 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 6-(2-azepan-1-ylethoxy)nicotinic acid hydrochloride (60 mg) according to an analogous synthetic method to Example 337 described below and purified by LC-MS, the title compound (34 mg) was obtained.
Reaction SMILES: N#N.[C:3]1([C:9]2[O:13][CH:12]=[N:11][C:10]=2[C:14]([OH:16])=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH2:40]([O:42][CH2:43][C:44]1[N:45]=[C:46]([CH2:49][N:50]2[N:54]=[C:53]([NH2:55])[CH:52]=[N:51]2)[O:47][CH:48]=1)[CH3:41]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:40]([O:42][CH2:43][C:44]1[N:45]=[C:46]([CH2:49][N:50]2[N:54]=[C:53]([NH:55][C:14]([C:10]3[N:11]=[CH:12][O:13][C:9]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[O:16])[CH:52]=[N:51]2)[O:47][CH:48]=1)[CH3:41]
Reactant: O=C(O)c1ncoc1-c1ccccc1
Reactant: CCOCc1coc(Cn2ncc(N)n2)n1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCc1coc(Cn2ncc(NC(=O)c3ncoc3-c3ccccc3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of commercially available 5-phenyloxazole-4-carboxylic acid (36 mg, 0.19 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (5.8 mg, 0.05 mmol), HOBt (31 mg, 0.23 mmol), EDC (91 mg, 0.48 mmol) and DIPEA (0.13 mL, 0.76 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(ethoxymethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (43 mg, 0.19 mmol) in CH2Cl2 (0.9 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (10 mL) and the org. phase was washed with water (10 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (3:7 hept-EA) gave the title compound as a yellow oil: TLC: rf (7:3 hept-EA)=0.34. LC-MS-conditions 07: tR=0.84 min, [M+H]+=395.08.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:10][CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:29][O:28][C:22]1[CH:23]=[C:24]([O:26][CH3:27])[N:25]=[C:20]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][C:8]3[CH:9]=[CH:10][C:11]([CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:12][CH:13]=3)[CH2:2][CH2:3]2)[N:21]=1
Reactant: COc1cc(OC)nc(Cl)n1
Reactant: CC(=O)NCc1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OC)nc(N2CCN(Cc3ccc(CNC(C)=O)cc3)CC2)n1
Temperature: 0 °C
Yield: 64.2 %

Procedure:
A solution of N-(4-((piperazin-1-yl)methyl)phenylmethyl)acetamide (5.0 g) obtained in Example 88(2), 2-chloro-4,6-dimethoxypyrimidine (3.9 g) and potassium carbonate (4.2 g) in acetonitrile (50 ml) was refluxed under heating for 5 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-brown solid. The obtained pale-brown solid was purified by silica gel column chromatography (developing solvent; chloroform:methanol=9:1) and crystallized from diisopropyl ether to give the title compound (5.0 g) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([C:24]1([CH2:27][CH3:28])[CH2:26][O:25]1)[CH3:23]>>[CH2:22]([C:24]([OH:25])([CH2:27][CH3:28])[CH2:26][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[CH3:23]
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: CCC1(CC)CO1
Product: CCC(O)(CC)COc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1

Procedure:
Reaction of 2-(3-(3-hydroxyphenyl)propyl)isoindoline-1,3-dione with 2,2-diethyloxirane following method described in Example 18 gave 2-(3-(3-(2-ethyl-2-hydroxybutoxy)phenyl)propyl)isoindoline-1,3-dione. 1H NMR (400 MHz, CDCl3) δ 7.75-7.88 (m, 4H), 7.06 (t, J=6.8 Hz, 1H), 6.72-6.76 (m, 2H), 6.61 (d, J=8.4 Hz, 1H), 3.74 (s, 2H), 3.69 (t, J=6.4 Hz, 2H), 2.63 (t, J=7.2 Hz, 2H), 1.95-2.05 (m, 2H), 1.61-1.66 (m, 4H), 0.91 (t, J=7.6 Hz, 6H).
Reaction SMILES: [C:1]1([CH:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]#[N:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:27]([O:30][C@H:31]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34](OC(=O)C)[O:33][C@@H:32]1[CH2:44][O:45][C:46](=[O:48])[CH3:47])(=[O:29])[CH3:28].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(OCC)(=O)C>ClC(Cl)(Cl)C>[C:27]([O:30][C@H:31]1[C@@H:35]([O:36][C:37](=[O:39])[CH3:38])[C@H:34]([N:14]2[CH:13]=[N:12][C:11]3[C:15]2=[N:16][C:17]([C:19]#[N:20])=[N:18][C:10]=3[NH:9][CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:33][C@@H:32]1[CH2:44][O:45][C:46](=[O:48])[CH3:47])(=[O:29])[CH3:28]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#Cc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C#N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 47.3 %

Procedure:
N,O-Bistrimethylsilylacetamide (44 ml, 0.18 mol) was added to a suspension of 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carbonitrile (10.0 g, 0.03 mol) (Preparation 24) in 1,1,1-trichloroethane (250 ml). The suspension was heated under reflux. When all suspended solid had dissolved the reaction mixture was allowed to cool to room temperature and the solvent was removed under reduced pressure. The residue was twice dissolved in toluene (50 ml) and the solvent was removed under reduced pressure. The residue was then dissolved in toluene (100 ml) and (2R,3R,4R,5S)-4,5-bis(acetyloxy)-2-[(acetyloxy)methyl]tetrahydro-3-furanyl acetate (10.3 g, 0.032 mol) was added. The solution was stirred at room temperature and trimethylsilyltrifluoromethanesulphonate (16 ml, 0.088 mol) was carefully added. The resulting solution was heated under reflux for 2 hours and then allowed to cool to room temperature. The reaction mixture was diluted by the addition of ethyl acetate (100 ml) and then washed with saturated aqueous sodium hydrogen carbonate solution (ten portions of 100 ml) and saturated aqueous sodium chloride solution (100 ml). The aqueous extracts were combined and washed with ethyl acetate (three portions of 100 ml). The combined organic layers were dried (anhydrous magnesium sulphate) and the solvent was removed under reduced pressure to give a solid that was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 concentrated aqueous ammonia (97:3:0.5 by volume increasing to 80:20:3 by volume). This gave the title compound as a foam (8.5 g).
Reaction SMILES: [O:1]1[C:5](B(O)O)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Br[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[N:16][CH:15]=1.[ClH:24].[CH2:25](OCC)C>>[O:1]1[C:5]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][N:16]([CH3:25])[CH2:15]2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[ClH:24].[O:1]1[C:5]([CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][N:16]([CH3:25])[CH2:15]2)=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: CCOCC
Reactant: OB(O)c1cc2ccccc2o1
Reactant: Brc1cncc2ccccc12
Agent: Cl
Product: CN1Cc2ccccc2C(c2cc3ccccc3o2)C1

Procedure:
Racemic 4-(benzo[b]furan-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline was prepared from 2-benzo[b]furanboronic acid and 4-bromoisoquinoline as described in Example 36 (Steps D to F). This racemic compound (120 mg) was separated on semi-prep chiral HPLC (chiralcel OD-H, 1×25 cm, eluent: 3% isopropanol in heptane, flow: 3.1 ml/minute, 500 μl injections, 20 mg/injections). The resulting free bases were dissolved in ethyl acetate and treated with a 2 M solution of HCl in diethyl ether (2 equiv) to give (+)-4-(benzo[b]furan-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline, hydrochloride salt (13 mg, 99.6% AUC HPLC, 100% AUC chiral HPLC): 1H NMR (300 MHz, Acetone-d6) 7.71-7.80 (m, 1H), 7.50-7.58 (m, 1H), 7.31-7.45 (m, 2H), 7.01-7.23 (m, 5H); 5.35-5.50 (m, 1H), 4.47-4.70 (m, 2H), 3.70-4.00 (m, 2H), 3.11 (s, 3H), 2.43 (s, 3H); EI MS m/z=263 [C18H17NO]+; [α]25D +37° (c 0.5, MeOH, free base) and (−)-4-(benzo[b]furan-2-yl)-2-methyl-1,2,3,4-tetrahydroisoquinoline, hydrochloride salt (49 mg, 99.7% AUC HPLC, 100% chiral HPLC): 1H NMR (300 MHz, Acetone-d6) 7.64-7.71 (m, 1H), 7.42-7.49 (m, 1H), 7.25-7.36 (m, 2H), 6.93-7.15 (m, 4H), 5.22-4.40 (m, 1H), 3.40-4.60 (m, 2H), 3.60-3.90 (m, 2H), 3.02 (s, 3H), 2.35 (s, 3H); EI MS m/z=263 [C18H17NO]+; [α]25D −40° (c 0.5, MeOH, free base).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:34][CH:35]([F:37])[F:36])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[CH:22][C:21]=1[Cl:33])[C:10]([CH2:17][CH3:18])=[N:11]2.O1CCCC1.[OH-].[Li+]>O>[Cl:33][C:21]1[CH:22]=[C:23]([C:26]([N:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:27])[CH:24]=[CH:25][C:20]=1[CH2:19][C:9]1[C:10]([CH2:17][CH3:18])=[N:11][C:12]2[C:7]([C:8]=1[O:34][CH:35]([F:37])[F:36])=[C:6]([O:5][CH2:4][C:3]([OH:38])=[O:2])[CH:15]=[CH:14][C:13]=2[F:16]
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)N2CCCC2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(C(=O)N2CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of {3-[2-chloro-4-(pyrrolidine-1-carbonyl)benzyl]-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy}acetic acid methyl ester (0.26 g), tetrahydrofuran (5.0 mL), water (5.0 mL) and lithium hydroxide (0.040 g) was stirred at room temperature for 20 minutes. The mixture was washed with ethyl acetate and the aqueous phase acidified by the addition of 1.0 M aqueous hydrochloric acid and then extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and the solvent removed under reduced pressure. Purification of the residue by preparative reverse-phase HPLC, using a gradient of acetonitrile in water gave title compound as an off-white solid, 0.13 g.