Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[CH:15]3[CH2:16][CH2:17][O:18][CH:14]3[O:13][N:12]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].C(Cl)(=O)C(Cl)=O.[C:29]1(=O)[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH2:30]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[C:10]([C:11]2[CH:15]3[CH2:16][CH2:17][O:18][CH:14]3[O:13][N:12]=2)=[C:9]([S:19]([CH3:22])(=[O:21])=[O:20])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:29]1[CH2:34][CH2:33][CH2:32][C:31](=[O:35])[CH:30]=1)=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: CS(=O)(=O)c1ccc(C(=O)[O-])c(Cl)c1C1=NOC2OCCC12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c(Cl)c1C1=NOC2OCCC12
Reaction time: 2 h

Procedure:
58.0 g (167.8 mmol) of 2-chloro-4-methylsulfonyl-3-(3a,4,5,6a-tetrahydrofuro[3,2-d]isoxazol-3-yl)-benzoate are dissolved in 600 ml of dichloromethane, and 31.94 g (251.6 mmol) of oxalyl chloride and three drops of dimethylformamide are added at room temperature. After the evolution of gas has ceased (approx. 2 hours), the mixture is refluxed for a further hour. It is subsequently concentrated, and redissolved in 300 ml of dichloromethane. At 0-5° C., a mixture of 19.5 g (173.9 mmol) of 1,3-cyclohexanedione and 17.6 g (173.9 mmol) of triethylamine in 200 ml of dichlormethane is added dropwise. The mixture is stirred for 2 hours and then washed in succession with sodium carbonate solution and sodium chloride solution, and the organic phase is then dried over magnesium sulfate. After removal of the solvent, 64.5 g (87% of theory) of crude 3-oxocyclohex-1-enyl 2-chloro-4-methyl-sulfonyl-3-(3a,4,5,6a-tetrahydrofuro[3,2-d]isoxazol-3-yl)benzoate are obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=1>ClCCl>[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:21])=[C:18]([C:25]([F:26])([F:27])[F:28])[CH:17]=1
Reactant: Cc1ccc(C(=O)Cl)c(C(F)(F)F)c1
Reactant: O=C1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N2CCNC(=O)C2)c(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
2-piperazinone (0.400 g, 4 mmol, commercially available from e.g. Sigma-Aldrich) was dissolved in dichloromethane (DCM) (20 mL), and to this was added triethylamine (0.669 mL, 4.80 mmol). The solution was then cooled to 0° C. before 4-methyl-2-(trifluoromethyl)benzoyl chloride (I62) (0.979 g, 4.40 mmol) in dichloromethane (DCM) (5 mL) was added dropwise. The solution was stirred, under argon, for 30 minutes before the solvent was evaporated in vacuo. The remaining residue was then re-dissolved in DCM (40 mL) and washed with water (20 mL), a saturated solution of sodium bicarbonate (20 mL) and brine (20 mL), before being dried over anhydrous sodium sulphate. The sodium sulphate was then removed by filtration and the solvent was evaporated in vacuo. The remaining solid was then stirred in hexane (40 mL) at 55° C. for 30 minutes. The solid was then removed by filtration to yield the product in 1.110 g.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[N:24][C:23]([NH2:26])=[N:22]1>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[CH2:20][N:21]1[CH:25]=[N:24][C:23]([NH:26][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:22]1
Reactant: Nc1ncn(Cc2cccc(Cl)c2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3ncn(Cc4cccc(Cl)c4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 1-(3-chloro-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a yellowish solid (Yield=64%). MS ISP (m/e): 390.1 (100) [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[I:13]Cl.Cl>CO>[I:13][C:8]1[C:9]([O:11][CH3:12])=[CH:10][C:3]([O:2][CH3:1])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: ClI
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Solvent: CO
Product: COc1cc(OC)c(C=O)cc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
To a solution of 2,4-dimethoxy-benzaldehyde (20.0 g, 120.4 mmol) in methanol (550 mL) was added a solution of iodine monochloride (23.25 g, 144.9 mmol) in methanol (60 mL) dropwise over 20 min. The solution was allowed to stir at ambient temperature for 3 hours and then poured into a solution of hydrochloric acid (0.5 M, 600 mL). The resulting precipitate was collected by filtration, washed with water, and dried in vacuo. The crude product was further recrystallized from a mixture of tetrahydrofuran and heptane (1:1, v/v) to give the title compound as a white solid (30.62 g, 87.5%), m.p. 170–172° C. 1H NMR (CDCl3) δ 10.19 (s, 1H), 8.22 (s, 1H), 6.39 (s, 1H), 3.97 (s, 3H), 3.95 (s, 3H).
Reaction SMILES: [NH2:1][C@@:2]1([N:24]2[CH2:32][C:30](CO[Si](C(C)(C)C)(C)C)([CH3:31])[C:28](=[O:29])[NH:27][C:25]2=[O:26])[O:16][C@H:6]([CH:7]([Si](C(C)(C)C)(C)C)[OH:8])[C@@:4]([Si](C(C)(C)C)(C)C)([OH:5])[CH2:3]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:1][C@@:2]1([N:24]2[CH:32]=[C:30]([CH3:31])[C:28](=[O:29])[NH:27][C:25]2=[O:26])[O:16][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)CN([C@@]2(N)C[C@@](O)([Si](C)(C)C(C)(C)C)[C@@H](C(O)[Si](C)(C)C(C)(C)C)O2)C(=O)NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cn([C@@]2(N)C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reaction time: 1 h

Procedure:
A suspension of 1'-amino-3',5'-bis(t-butyldimethylsilyl)-5-t-butyldimethylsiloxymethyl thymidine and tetrabutylammonium fluoride in THF stands at room temperature for one hour. The solvent is evaporated and the residue chromatographically separated on silica.
Reaction SMILES: [Na].[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5](Br)[N:4]=1.[CH3:10][OH:11]>>[Br:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:11][CH3:10])[N:4]=1
Reactant: CO
Reactant: Brc1cccc(Br)n1
Agent: [Na]
Product: COc1cccc(Br)n1

Procedure:
Dried sodium (970 mg, 42.2 mmol) was added portionwise to cooled methanol (50 ml) under nitrogen, and once addition was complete, 2,6-dibromopyridine (10 g, 42.2 mmol) was added portionwise. The resulting suspension was heated under reflux for 24 hours. The cooled reaction was concentrated under reduced pressure, the residue diluted with water (100 ml), and extracted with ethyl acetate (2×75 ml). The organic extracts were dried (MgSO4), and evaporated under reduced pressure to give a pale yellow oil. The crude product was purified by column chromatography on silica gel using an elution gradient of pentane:ethyl acetate (100:0 to 98:2) to give the title compound as a clear oil, 4.23 g.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:26][CH2:27][C:28]([NH:32][S:33]([C:36]1[S:37][C:38]([Cl:42])=[C:39]([NH2:41])[CH:40]=1)(=[O:35])=[O:34])([CH2:30][OH:31])[CH3:29]>>[Cl:42][C:38]1[S:37][C:36]([S:33](=[O:35])(=[O:34])[NH:32][C:28]([CH2:27][OH:26])([CH3:29])[CH2:30][OH:31])=[CH:40][C:39]=1[NH:41][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=3)=[N:6][C:7]=12)=[O:14]
Reactant: CC(CO)(CO)NS(=O)(=O)c1cc(N)c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CC(CO)(CO)NS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide (example B.7) according to general procedure II. Light yellow solid. MS (ISP) 638.0 [(M−H)−]; mp 237° C.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:14](O)[CH3:15]>>[Br:1][C:2]1[O:6][C:5]([C:7]([O:9][CH2:14][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(Br)o1

Procedure:
10 g of 5-bromo-2-furancarboxylic acid were refluxed for 24 hours in 200 ml of ethanol in the presence of 2 ml of thionyl chloride. The solvent was evaporated and the residue was poured into an aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate and the extract was dried. The solvent was evaporated to obtain 8.5 g of the expected product.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=C)=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:30])([F:29])[F:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[N+]1([O-])CC[O:35]CC1.I([O-])(=O)(=O)=O.[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]3[O:16][N:15]=[C:14]4[C:17]5[C:22]([CH2:23][CH2:24][C:13]=34)=[CH:21][C:20]([CH:25]=[O:35])=[CH:19][CH:18]=5)[C:8]=2[C:27]([F:28])([F:30])[F:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a clear solution of 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6A, 1.6 g, 3.92 mmol) in THF (15 mL) were sequentially added NMO (50% in water, 1.219 mL, 5.88 mmol) and osmium tetroxide (4% in water, 0.958 mL, 0.157 mmol) at room temperature. The solution was vigorously stirred at room temperature overnight. A cloudy solution of sodium periodate (1.425 g, 6.66 mmol) in water (14 mL) was added. The mixture was stirred at room temperature under nitrogen for 0.5 hr. Water (20 mL) was then added and the mixture was stirred at room temperature for 30 min. The solid was filtered, washed with water (2×2 mL) and methanol (2 mL) and dried to give 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole-7-carbaldehyde (1.6 g, 3.90 mmol, 100% yield) as a white solid. The compound had an HPLC retention time=4.02 min. (condition C); LC/MS M+1=410.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21]>>[Cl:17][C:18]1[CH:19]=[C:20]([NH:21][C:14](=[O:16])[C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cccc(Cl)c1

Procedure:
Coupling of N-tert-butoxycarbonyl-L-methionine (1a) and 3-chloroaniline (2c) according to General Procedure A, gave after purification on a SILICA GEL column hexane-acetone (3:1) an oily liquid of (3c) (C16H23N2O3S1Cl1, 94%), Rf=0.40 (hexane-acetone 3:1), [α]D23 =-36.8° (c 1.44, CHCl3), IR (KBr) ν: 440, 461, 519, 548, 606, 681, 739, 777, 864, 880, 903, 963, 999, 1026, 1049, 1076, 1099, 1165, 1252, 1267, 1300, 1368, 1393, 1427, 1456, 1483, 1506, 1522, 1539, 1595, 1670, 1684, 1697, 2336, 2361, 2868, 2918, 2978, 3061, 3086, 3131, 3198, 3291, 3522, 3545 cm-1, 1H NMR (CDCl3) δ: 8.472 (br s, 1H, Ar--NH), 7.616-7.629 (m, 1H, ArH), 7.240-7.283 (m, 1H, ArH), 7.153 (dd, 1H, J 7.8 Hz and 8.1 Hz, ArH), 7.023 (d, 1H, J 7.8 Hz, ArH), 5.377 (br s, 1H, NH), 4.407-4.427 (m, 1H, Hα), 2.566-2.618 (m, 2H, CH2γ), 2.116-2.184 (m, 1H, Hβ), 2.084 (s, 3H, CH3ε), 1.940-2.070 (m, 1H, Hβ), 1.425 (s, 9H, t-Bu); EIMS (70 eV) m/z (%): 358 (M+, 2).
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][N:9]1[CH:13]([C:14]([OH:16])=O)[CH2:12][N:11]([C:17]2[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:10]1=[O:24].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N1CCOCC1)C.[Cl:56][C:57]1[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=1[CH2:64][NH2:65]>ClCCl>[Cl:56][C:57]1[CH:62]=[C:61]([Cl:63])[CH:60]=[CH:59][C:58]=1[CH2:64][NH:65][C:14]([CH:13]1[CH2:12][N:11]([C:17]2[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[C:10](=[O:24])[N:9]1[CH3:8])=[O:16]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: Cc1ncccc1N1CC(C(=O)O)N(C)C1=O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1N1CC(C(=O)NCc2ccc(Cl)cc2Cl)N(C)C1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A mixture of 3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxylic acid TFA salt (279 mg, 0.8 mmol), 1-hydroxybenzotriazole hydrate (147 mg, 0.96 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (184 mg, 0.96 mmol) and N-ethyl morpholine (0.613 ml, 4.8 mmol) in dichloromethane (18 ml) was stirred at room temperature for 10 minutes. A solution of [1-(2,4-dichlorophenyl)methyl]amine (141 mg, 0.8 mmol) in dichloromethane (2 ml) was added and the reaction stirred at room temperature for 4 hours. The mixture was partitioned between dichloromethane and saturated sodium hydrogen carbonate solution. The organic phase was separated, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give N-[(2,4-dichlorophenyl)methyl]-3-methyl-1-(2-methyl-3-pyridinyl)-2-oxo-4-imidazolidinecarboxamide (147 mg, 47%). LC/MS [M+H]+=393, retention time=1.76 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[NH:16][C:17](=[O:30])[C:18]3[C:23]([CH3:24])=[C:22]([C:25]([O:27]CC)=[O:26])[S:21][C:19]=3[N:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl>[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[NH:16][C:17](=[O:30])[C:18]3[C:23]([CH3:24])=[C:22]([C:25]([OH:27])=[O:26])[S:21][C:19]=3[N:20]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1sc2nc(CN3CCN(C(=O)OC(C)(C)C)CC3)[nH]c(=O)c2c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(C(=O)O)sc2nc(CN3CCN(C(=O)OC(C)(C)C)CC3)[nH]c(=O)c12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
436 Milligrams of ethyl 2-(4-tert-butoxycarbonylpiperazin-1-ylmethyl)-5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-carboxylate as synthesized in Production Example 21 was suspended in 4 mL of 0.5N sodium hydroxide and stirred at 100° C. for 2 hours. After cooling off, the reaction liquid was neutralized with 1N hydrochloric acid, and the precipitate was recovered by filtration. Drying the same, 377 mg (92%) of the title compound was obtained.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([CH3:12])=[CH:11][C:4]=2[CH:3]=1.[CH3:13]CCCCCC>>[CH3:12][C:10]1[CH:9]=[CH:8][C:5]2[CH:6]=[C:7]([CH3:13])[CH:2]=[CH:3][C:4]=2[CH:11]=1
Reactant: Cc1ccc2ccc(C)cc2c1
Reactant: CCCCCCC
Product: Cc1ccc2cc(C)ccc2c1
Temperature: 80 °C

Procedure:
A mixture of DMN isomers containing 2% by weight of 2,7-DMN, etc. as shown in Table 3 as the starting raw material was isomerized under liquid-phase flow system and atmospheric pressure at a reaction temperature of 220° C. at a WHSV of 1.0 hr-1 in the presence of a catalyst (alumina content of 20% by weight) prepared by molding with alumina, mordenite type H (silica/alumina molar ratio of 203, produced by Tosoh Corporation). The resultant isoiverization reaction product shown in Table 3 as reaction product (1) was incorporated with the same amount of n-heptane, heated to 80° C. to dissolve the reaction product and then cooled to 20° C. to precipitate crystal. The slurry containing the crystal was filtered by suction with a G2 glass filter, and the crystal thus obtained was rinsed with n-heptane cooled to 20° C. in an amount by weight half the reaction product. As a result, there was obtained 2,6-DMN crystal having the chemical composition given in Table 3 as "Crystal (1)" in a recovery rate of 64.2%. Here, the recovery rate is the percentage of the amount of 2,6-DMN in the resultant crystal based on the amount thereof in the starting raw material for crystallization.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:31]=[CH:30][C:18]2[C:19]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:20]([CH2:22]O)[O:21][C:17]=2[CH:16]=1.S(Cl)([Cl:34])=O.C(=O)([O-])O.[Na+]>>[Cl:34][CH2:22][C:20]1[O:21][C:17]2[CH:16]=[C:15]([O:14][CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[O:6][C:2]=3[CH3:1])[CH:31]=[CH:30][C:18]=2[C:19]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(CO)oc2c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1COc1ccc2c(-c3ccccc3)c(CCl)oc2c1
Reaction time: 1 h
Yield: 92 %

Procedure:
{6-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-yl}methanol (1.50 g) was added to thionyl chloride (5 mL) at 0° C., and the mixture was stirred for 1 hr. After concentration of the reaction mixture, saturated aqueous sodium hydrogen carbonate was added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give 4-{[(2-chloromethyl-3-phenyl-1-benzofuran-6-yl)oxy]methyl}-5-methyl-2-phenyl-1,3-oxazole as colorless crystals (1.43 g, yield 92%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(N=C=NC(C)C)(C)C.[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][N:27]2[CH2:31][CH2:30][C@@H:29]([NH:32][C:33](=[O:36])[CH2:34][NH2:35])[CH2:28]2)=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][N:27]2[CH2:31][CH2:30][C@@H:29]([NH:32][C:33](=[O:36])[CH2:34][NH:35][C:4](=[O:6])[C:3]3[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=3[NH2:1])[CH2:28]2)=[CH:24][CH:23]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Agent: CC(C)N=C=NC(C)C
Solvent: ClC(Cl)Cl
Product: Nc1ccc(Cl)cc1C(=O)NCC(=O)N[C@@H]1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2-Amino-5-chlorobenzoic acid (0.060 mL) and diisopropylcarbodiimide (0.060 mol) were added to a chloroform (2 mL) solution of (R)-1-(4-chlorobenzyl)-3-(glycylamino)pyrrolidine (0.050 mmol). The resulting reaction solution was stirred at room temperature for 15 hours. The mixture solution was loaded onto a Varian™ SCX column and washed with methanol (15 mL). The obtained crude product was eluted with a solution of 2 M NH3 in methanol (5 mL) and concentrated to thereby afford (R)-1-(4-chlorobenzyl)-3-[N-[2-amino-5-chlorobenzoyl]glycyl]amino]pyrrolidine (Compd. No. 1084) (12.7 mg, 60%). The purity was determined by RPLC/MS (87%). ESI/MS m/e 421.0 (M++H, C20H22Cl2N4O2).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([C:11]([OH:13])=O)[CH:8]=[C:7]([C:14]2[N:15]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:16]([CH3:23])=[C:17]([S:19](=[O:22])(=[O:21])[NH2:20])[CH:18]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:31]([NH:35][C:11](=[O:13])[C:9]1[CH:8]=[C:7]([C:14]2[N:15]([CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:16]([CH3:23])=[C:17]([S:19](=[O:21])(=[O:22])[NH2:20])[CH:18]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[N:10]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)O)nc(C(C)(C)C)c2)n1CC1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(=O)NC(C)(C)C)nc(C(C)(C)C)c2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27.7 %

Procedure:
A mixture of compound 19 (150 mg, 0.34 mmol), tert-butylamine (36 mg, 0.48 mmol), HATU (207 mg, 0.54 mmol) and DIPEA (146 mg, 1.14 mmol) in DMF (5 mL) was stirred at rt for 20 min, diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4, concentrated and purified by CC (PE/EA=2/1) to give compound 20 (46 mg, 30%) as a white powder. 1H-NMR (300 MHz, CDCl3) δ: 8.17 (s, 1H), 7.93 (d, 1H, J=1.5 Hz), 7.40 (d, 1H, J=1.5 Hz), 6.61 (s, 1H), 4.70 (d, 2H, J=5.4 Hz), 3.84 (d, 2H, J=6.9 Hz), 2.55 (s, 3H), 1.61 (m, 3H), 1.50 (s, 9H), 1.42 (s, 9H), 1.30-1.38 (m, 3H), 0.97-1.03 (m, 3H), 0.63 (m, 2H). MS Calcd.: 488; MS Found: 489 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:39])[C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[NH:17][C:18](=[O:38])[C:19]2[CH:24]=[CH:23][C:22](F)=[CH:21][C:20]=2[O:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[N:6][CH:7]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1>>[C:34]([O:33][C:31]([NH:30][CH2:29][CH2:28][CH2:27][O:26][C:20]1[CH:21]=[C:22]([N:40]2[CH2:44][CH2:43][CH2:42][CH2:41]2)[CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C:11]1[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:39])=[O:38])=[O:32])([CH3:36])([CH3:37])[CH3:35]
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)NCCCOc1cc(F)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Product: CC(C)(C)OC(=O)NCCCOc1cc(N2CCCC2)ccc1C(=O)Nc1ccc(F)cc1C(=O)Nc1ccc(Cl)cn1
Yield: 79 %

Procedure:
A solution of N-(5-chloropyridin-2-yl)-5-fluoro-2-[4-fluoro-2-(3-tert-butoxycarbonylaminopropoxy)benzoylamino]benzamide (0.4 g, 0.71 mmol) in pyrrolidine (10 mL) was heated at 80° C. for 6 hr. The reaction was concentrated in vacuo and the residue was purified by RPLC (ethyl acetate/hexane 1:4) to give pure product (0.345 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[N:19])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][NH2:19])[CH2:15][CH2:16]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: N#CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 90.5 %

Procedure:
To a solution of [4-(6-fluoro-1 H-indazol-3-yl)-1-piperdinyl]-acetonitrile (6.1 g, 23.6 mmol) in dry THF (235 ml) was added (dropwise) lithium aluminum hydride (LAH) (28.4 mmol, 1.0M in THF) at room temperature, under nitrogen. Upon complete addition, the reaction mixture was warmed to reflux for 3 hours. After cooling to 0 C. in an ice bath, the reaction was carefully quenched with water (4.0 ml). The solids were removed via filtration and washed with THF. The combined filtrates were concentrated to give 5.6 g of the desired product. This material was suspended in DCM and filtered to give the product as an off-white solid, m.p. 125°-128° C.