Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH2:36])[CH:33]=[CH:32][C:30]=2[N:31]=1>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[NH:26][C:27]1[S:28][C:29]2[CH:35]=[C:34]([NH:36][C:1](=[O:10])[C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=3)[CH:33]=[CH:32][C:30]=2[N:31]=1
Reactant: COc1cc2ncnc(Nc3nc4ccc(N)cc4s3)c2cc1OC
Reactant: COc1cccc(C(=O)Cl)c1
Product: COc1cccc(C(=O)Nc2ccc3nc(Nc4ncnc5cc(OC)c(OC)cc45)sc3c2)c1

Procedure:
N-[2-(6,7-Dimethoxyquinazolin-4-ylamino)benzothiazol-6-yl]-3-methoxybenzamide was prepared from m-anisoyl chloride (17 μL, 0.113 mmol) and N2-(6,7-dimethoxyquinazolin-4-yl)benzothiazole-2,6-diamine (40 mg, 0.113 mmol) according to GP 2 (yellowish solid, 41 mg, 84 μmol, 74%). LC/ESI-MS: m/z=488 [M+H]+; m/z=486 [M−H]−; Rt=3.17 min.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH2:23][NH2:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][CH2:32][CH2:33]Br)C.C(N(CC)CC)C>CC(C)CCO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH2:23][N:24]4[CH2:33][CH2:32][CH2:31][C:30]4=[O:29])=[CH:22][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCCBr
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(CN)cc(OC)c21
Solvent: CC(C)CCO
Solvent: CCN(CC)CC
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(CN3CCCC3=O)cc(OC)c21
Yield: 33.2 %

Procedure:
A solution of 50 mg (0.143 mmol) C-[2-(4-Isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-methylamine, 28 mg (0.143 mmol) ethyl-4-bromobutyrate and 28 μl (0.2 mmol) triethylamine in 4 ml 3-methyl-1-butanol is stirred at reflux temperature for 8 h. Then the reaction mixture is poured on water and extracted (3×) with EtOAc. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (EtOAc:MeOH=98:2) to afford 20 mg of the title compound as a colorless oil.
Reaction SMILES: [C:1]([OH:12])(=O)[C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[CH:3]=1.[NH2:13][CH:14]([CH3:17])[CH2:15]O>>[CH3:15][CH:14]1[CH2:17][O:7][C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([C:1]3[O:12][CH2:15][CH:14]([CH3:17])[N:13]=3)[CH:3]=2)=[N:13]1
Reactant: O=C(O)c1cccc(C(=O)O)c1
Reactant: CC(N)CO
Product: CC1COC(c2cccc(C3=NC(C)CO3)c2)=N1
Temperature: 78.88888888888889 °C

Procedure:
50 g of isophthalic acid is refluxed at 165° C. (329° F.) for 18 hr in 150 mL of 2-amino-1-propanol. The bulk of the excess amino alcohol is then distilled off and the remaining viscous liquid dissolved in 200 mL of 2% NaOH. The resulting bis-N-(1-methyl-2-hydroxyethyl)isophthalamide is then precipitated in acetone, filtered and dried. To 10 g of the aforementioned diamide is slowly added 300 mL of thionyl chloride with stirring. The mixture is then heated to reflux (79° C., 174° F.) for approximately 1 hour, after which time the homogenous yellow solution is cooled and poured into diethylether to precipitate the 4,4'-dimethyl-2,2'-(1,3-phenylene)bis(oxazoline) hydrochloride salt. The salt is neutralized using 20% NaOH and the free base extracted into ether. The organic phase is then dried and evaporated to give 4,4'-dimethyl-2,2'-(1,3-phenylene)bis(oxazoline).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[C:10]([CH2:12]O)[CH:9]=[CH:8][N:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.P(Br)(Br)[Br:15].C1COCC1.C([O-])(O)=O.[Na+]>C(OCC)C.C(OCC)(=O)C>[Br:15][CH2:12][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:11]=1
Reactant: OCc1ccnc(-n2cccn2)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: BrCc1ccnc(-n2cccn2)c1
Temperature: 65 °C
Yield: 69.3 %

Procedure:
To a stirred solution of (2-(1H-pyrazol-1-yl)pyridin-4-yl)methanol (175 mg, 1.00 mmol) in diethyl ether (5 mL), PBr3 (0.11 mL, 1.00 mmol) was added dropwise at 0° C. Then THF (5 mL) was added to the resulting white precipitate and the mixture was heated at 65° C. for 1 h. The mixture was cooled to rt, diluted with ethyl acetate (5 mL) and poured into saturated aqueous NaHCO3 solution (5 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to yield the title compound (165 mg, 70%). [LCMS RtE=1.33 min, [M+H]+=237.9/239.9].
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Li])CCC.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[Cl:22])C(Cl)=O>C1COCC1.CCCCCC.Cl>[Cl:12][C:13]1[CH:14]=[C:15]([C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: N#CCC(=O)O
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 76.2 %

Procedure:
To a solution of cyanoacetic acid (4.07 g, 47.8 mmol) in THF (240 mL) cooled to −78° C. under an atmosphere of argon was added 1.6 M n-butyllithium in hexane (59.8 mL). The reaction mixture was stirred for 10 min at −78° C. and was then allowed to warm to 0° C. The reaction mixture was recooled to −78° C. To the mixture was added dropwise 3,4-dichlorobenzoyl chloride (5.01 g, 23.9 mmol) in THF (30 mL). The reaction mixture was allowed to warm to rt. The reaction mixture was diluted with 1N HCl and extracted with EtOAc. The organic solutions were combined, washed with sat NaHCO3, brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 3-(3,4-dichlorophenyl)-3-oxopropanenitrile (3.9 g, 76%). LCMS: (FA) ES− 212.0. 1H NMR (400 MHz, CDCl3) δ: 8.01 (d, 1H), 7.75 (dd, 1H), 7.63 (d, 1H) and 4.05 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][CH:32]([OH:34])[CH3:33].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][CH:32]([OH:34])[CH3:33])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: CC(O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)CNCc1ccc2c(c1)cc(-c1ccc(Cl)c3c1C(=O)NC3)n2C(=O)OC(C)(C)C

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-amino-2-propanol (0.015 mL, 0.19 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-[1-(tert-butoxycarbonyl)-5-(2-hydroxypropylaminomethyl)indol-2-yl]isoindolinone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH:15]1[CH2:17][CH2:16]1.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:23](Cl)=[O:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH:15]1[CH2:17][CH2:16]1)[C:23](=[O:24])[C:22]1[CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=[C:20]([C:19]([F:18])([F:33])[F:34])[CH:21]=1
Reactant: Clc1ccccc1-c1ccncc1NC1CC1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N(c1cnccc1-c1ccccc1Cl)C1CC1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(2-chloro-phenyl)-pyridin-3-yl]-cyclopropyl-amine and 3,5-bis(trifluoromethyl)benzoyl chloride (CAS RN 1271-19-8). The compound was purified by two subsequent silica gel chromatographies using a MPLC system (10 g column, gradient of n-heptane:EtOAc (100:0 to 50:50) and n-heptane:EtOAc (100:0 to 60:40)) and by preparative HPLC (phenomenex gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2). Colorless solid (24%). MS (ESI): m/z=485.08 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9](O)=[O:10])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1.C([N:20](CC)CC)C.C(Cl)(=O)OCC.N>O.O1CCCC1>[CH3:1][C:2]1[C:6]([CH2:7][CH2:8][C:9]([NH2:20])=[O:10])=[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:4][N:3]=1
Reactant: Cc1noc(-c2ccccc2)c1CCC(=O)O
Reactant: CCN(CC)CC
Agent: CCOC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(-c2ccccc2)c1CCC(N)=O
Temperature: -20 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a mixture of 3-(3-methyl-5-phenyl-4-isoxazolyl)propionic acid (0.95 g), triethylamine (1.0 ml) and tetrahydrofuran (50 ml) was added ethyl chlorocarbonate (0.5 ml) at −30° C. and the mixture was stirred at −20° C. for 1 hr. To the obtained mixture was added aqueous ammonia (5 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated to give 3-(3-methyl-5-phenyl-4-isoxazolyl)propionamide (0.86 g, yield 91%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 149–151° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16](Cl)(=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>N1C=CC=CC=1>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:16](=[O:24])[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(C(=O)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ccc(C(=O)c2ccccc2)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 110.8 %

Procedure:
To 4-aminobenzophenone (1.97 g) dissolved in pyridine (50 mL), phenyl chlorocarbonate (1.38 g) was added at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1 to 1/2) to give the subject compound (3.1 g).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]([C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)([CH3:21])[CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1.[CH2:30](I)[CH3:31].C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>O.CN(C)C=O>[CH2:30]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:3]([CH3:21])([CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[C:9]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:8]=2)[CH:2]([F:1])[F:29])=[CH:27][CH:26]=1)[CH3:31]
Reactant: CCI
Reactant: CC(CCCc1ccc(F)c(Oc2ccccc2)c1)(c1ccc(O)cc1)C(F)F
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(C)(CCCc2ccc(F)c(Oc3ccccc3)c2)C(F)F)cc1

Procedure:
1.5 g (3.75 mmol) 1,1-difluoro-5-(4-fluoro-3-phenoxyphenyl)-2-(4-hydroxyphenyl)-2-methylpentane, 10 ml dimethylformamide, 700 mg (4.5 mmol) ethyl iodide and 725 mg (5.25 mmol) K2CO3 were heated at 80° C. for 8 hours with a catalytic amount of sodium iodide. It was then added to water, extracted with ethyl acetate, dried over Na2SO4 and evaporated. After chromatography on silica gel, using hexane/toluene, 1.4 g of the desired product remained i.e. 87.4% of theory. The physical data are identical for the product of Example 1. The starting material was obtained as follows
Reaction SMILES: Cl.[NH2:2][OH:3].[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH2:14][CH:15]=[CH2:16])=[C:9]([CH:12]=1)[CH:10]=O.O1CCOCC1>>[Br:4][C:5]1[CH:6]=[CH:7][C:8]([O:13][CH2:14][CH:15]=[CH2:16])=[C:9]([CH:12]=1)[CH:10]=[N:2][OH:3]
Reactant: C=CCOc1ccc(Br)cc1C=O
Reactant: NO
Agent: Cl
Solvent: C1COCCO1
Product: C=CCOc1ccc(Br)cc1C=NO

Procedure:
A 0.16 mol/L hydroxylamine hydrochloride/1 N sodium hydroxide solution was sent as a first fluid from the center at a ratio of supply pressure/back pressure of 0.15 MPa/0.07 MPa, a rotation speed of 500 rpm, and a sending temperature of 15° C., and a 0.12 mol/L 5-bromo-2-allyloxybenzaldehyde/dioxane solution was introduced as a second fluid into a space between the processing surfaces at 15 mL/min. The first fluid and the second fluid were mixed in a thin film fluid, and then a solution obtained after processing was discharged from the space between the processing surfaces at 30 mL/min. As a result of HPLC analysis, substantially complete conversion to 5-bromo-2-allyloxybenzaldoxime was observed.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][C:14]([OH:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][CH2:12]2)[CH2:7]1)=[O:4].CCN(CC)CC.Cl[C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>C(O)(C)C>[S:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:1][CH2:2][C:3]([NH:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:12][CH2:13][C:14]([OH:23])([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:15][CH2:16]2)[CH2:7]1)=[O:4]
Reactant: NCC(=O)N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Reactant: Clc1nc2ccccc2s1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: O=C(CNc1nc2ccccc2s1)N[C@@H]1CCN(C2CCC(O)(c3ccccn3)CC2)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
The mixture of 2-amino-N-[(3R)-1-(4-hydroxy-4-pyridin-2-ylcyclohexyl)pyrrolidin-3-yl]acetamide (0.080 g, 0.25 mmol), Et3N (0.35 mL, 2.5 mmol) and 2-chloro-benzothiazole (0.424 g, 2.5 mmol) in isopropanol was stirred overnight at 90° C. The reaction mixture was concentrated and chromatographed to provide 55 mg of the title compound in 49% yield. MS (EI) calculated: (M+H)+=452.2; found: 452.2.
Reaction SMILES: [SH:1][CH2:2][C@H:3]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:4]([OH:6])=[O:5].[BH4-].[Na+].[OH-].[Na+].COC1C=CC(C2NC(C(O)=O)CS2)=CC=1>C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>[SH:1][CH2:2][CH:3]([NH:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=1)[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(CN[C@@H](CS)C(=O)O)cc1
Agent: COc1ccc(C2NC(C(=O)O)CS2)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Solvent: CC(=O)O
Product: COc1ccc(CNC(CS)C(=O)O)cc1
Temperature: 2.5 °C
Yield: 68 %

Procedure:
Preparation of (R)-3-mercapto-2-(4-methoxy-benzylamino)-propionic acid (A compound of Formula IIa): A 22 L three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with sodium borohydride (221.3 g, 5.85 mol). A 1.75 L portion of 0.25 M sodium hydroxide was added and the mixture was stirred until homogeneous. The solution was cooled to 0-5° C. 2-(4-methoxy-phenyl)-thiazolidine-4-carboxylic acid (350.0 g, 1.46 mol) was dissolved in 2.1 L of a 0.62 M K2CO3 aqueous solution. The resulting solution was added to the solution of sodium borohydride while maintaining an internal temperature of below 30° C. The reaction was stirred until HPLC analysis showed no remaining starting material (approximately 1 hour). The reaction was cooled to 0° C. and 700 mL of glacial acetic acid was added with stirring. The final pH of the reaction mixture was approximately 5. The resulting white solid was filtered, washed with 3 L of water and 2.5 L of ethanol, and dried in a vacuum oven at 50° C. for 12 hours. Approximately 240 g of 3-mercapto-2-(4-methoxy-benzylamino)-propionic acid was obtained (68% yield). 1H NMR (300 MHz, DMSO) δ 7.32 (d, 8.9 Hz, 2H), 6.91 (d, 8.9 Hz, 2H), 3.87 (AB, JAB=13.1 Hz, ΔνAB=18.5 Hz, 2H), 3.72 (s, 3H), 3.24 (dd, J=5.3, 5.3 Hz, 1H), 2.76 (d, J=5.7 Hz, 2H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][C:7]2[NH:12][C:11](=S)[NH:10][C:9](=[O:14])[CH:8]=2)[CH2:3][CH2:2]1.BrCC(O)=[O:18].[OH-].[Na+]>CCO.O>[CH:1]1([CH2:4][O:5][CH2:6][C:7]2[NH:12][C:11](=[O:18])[NH:10][C:9](=[O:14])[CH:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(O)CBr
Reactant: O=c1cc(COCC2CC2)[nH]c(=S)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1cc(COCC2CC2)[nH]c(=O)[nH]1
Temperature: 0 °C
Yield: 36.8 %

Procedure:
6-[(Cyclopropylmethoxy)methyl]-2-sulfanylidene-1,2,3,4-tetrahydropyrimidin-4-one (10.3 g, 48.5 mmol) was added to bromoacetic acid (21.5 g, 155 mmol, 3.2 eq) in EtOH (108 mL) and H2O (441 mL). The reaction mixture was refluxed for 16 h then cooled down to rt and basified to pH˜10 with sodium hydroxide (3 M, aq). The mixture was concentrated in vacuo and hydrochloric acid (aq, 10%) was added. The mixture was cooled to 0° C. The precipitate was isolated by filtration and dried to give the title compound as a solid (3.5 g, 37%).
Reaction SMILES: [CH3:1][C:2]1=[CH:3][CH2:4][CH2:5][C:6]([C@@H:8]2[C@@H:11]([CH2:12][CH2:13]1)[C:10]([CH3:15])([CH3:14])[CH2:9]2)=[CH2:7].[CH:16](=[O:19])[CH2:17][CH3:18].C(OOC(C)(C)C)(C)(C)C>>[C:16]([CH:3]1[CH2:4][CH2:5][C:6]2([CH3:7])[C:2]1([CH3:1])[CH2:13][CH2:12][CH:11]1[CH:8]2[CH2:9][C:10]1([CH3:15])[CH3:14])(=[O:19])[CH2:17][CH3:18]
Reactant: CCC=O
Reactant: C=C1CCC=C(C)CC[C@@H]2[C@@H]1CC2(C)C
Agent: C=C1CC/C=C(/C)CC[C@@H]2[C@@H]1CC2(C)C
Agent: CC(C)(C)OOC(C)(C)C
Product: CCC(=O)C1CCC2(C)C3CC(C)(C)C3CCC12C

Procedure:
Above mentioned compound was prepared as described in example I from 80 g caryophyllene, 220 g propanal and 6 g di-tert.butyl peroxide in an ampoule of glass having a volume of 300 ml. Yield: 10 g reaction product; boiling point: 145°-150° C./0.3 kPa; nD23 =1.4930.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21]CC)=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1)#[N:2].[OH-:27].[Na+]>CO.C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([OH:21])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)=[N:7][CH:8]=1)(=[O:27])[NH2:2]
Reactant: [OH-]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccc(C#N)cn3)cc(C)c21
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(C(N)=O)cn2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(6-(5-cyanopyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate in MeOH/THF (12 mL, 1:1) was added aqueous NaOH solution (250 mg in 3 mL water). After stirring at room temperature for two hours, the reaction mixture was evaporated, acidified to pH 3 with 1 N HCl and then concentrated. HPLC purification gave product as a white powder. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J=2 Hz, 1H), 8.20 (dd, J=8.4, 2.4 Hz, 1H), 7.96 (s, 1H), 7.41 (s, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.02 (d, J=8.4 Hz, 1H), 5.46 (dd, J=9.6, 2.4 Hz, 1H), 3.02 (dd, J=15.6, 2.4 Hz, 1H), 2.24 (s, 3H), 2.09 (dd, J=15.2, 9.6 Hz, 1H). 3 protons assumed to be exchanged with solvents. MS (ESI) m/z=341 [M−H]+.
Reaction SMILES: O[CH2:2][CH:3]1[CH2:7][NH:6][C:5](=[O:8])[C:4]1([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.S(Cl)([Cl:23])=O.N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:23][CH2:2][CH:3]1[CH2:7][NH:6][C:5](=[O:8])[C:4]1([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1NCC(CO)C1(c1ccccc1)c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C1NCC(CCl)C1(c1ccccc1)c1ccccc1

Procedure:
To 30.0 g. (0.11 mole) of 4-(hydroxymethyl)-3,3-diphenyl-2-pyrrolidinone in 200 ml. of chloroform was added 25.0 g. (0.20 mole) of thionyl chloride. To this stirring solution was added dropwise with ice bath cooling 20.0 g. (0.26 mole) of dry pyridine maintaining room temperature. The solution was refluxed for 2.5 hours. Upon cooling, the chloroform solution was washed successively with dilute hydrochloric acid solution and dilute sodium hydroxide solution. The chloroform was dried, filtered and concentrated in vacuo. The solid residue was recrystallized twice from ethyl acetate-isopropanol to give product melting at 218°-219° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2[NH:12][C:13](=O)[C:14]3[N:15]([CH:17]=[CH:18][CH:19]=3)[CH2:16][C:10]=2[CH:9]=[CH:8]1.O.[OH-].[Na+]>O1CCCC1>[O:7]1[C:11]2[NH:12][CH2:13][C:14]3[N:15]([CH:17]=[CH:18][CH:19]=3)[CH2:16][C:10]=2[CH:9]=[CH:8]1
Reactant: O=C1Nc2occc2Cn2cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1cc2n(c1)Cc1ccoc1NC2
Reaction time: 8 h

Procedure:
To a suspension of 4 mmol of lithium aluminum hydride in 25 ml of anhydrous tetrahydrofuran is added 1 mmol of 9,10-dihydro-4H-furo[2,3-e]pyrrolo[1,2-a]-[1,4]diazepin-9-one. The mixture is refluxed for 12 hours and allowed to stand overnight. To the mixture is added dropwise 0.12 ml of water and then 6 ml of 1N sodium hydroxide. The mixture is extracted with ethyl acetate and the extract dried(Na2SO4). The volatiles are removed in vacuo to give the desired product as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]12[CH2:13][CH:10]([CH2:11][CH2:12]1)[CH:9]([C:14](O)=O)[CH2:8][CH2:7]2)=[O:5])C.Cl.[NH2:18][C:19]1[C:20](=[O:33])[N:21]([CH2:30][CH2:31][CH3:32])[C:22](=[O:29])[N:23]([CH2:26][CH2:27][CH3:28])[C:24]=1[NH2:25]>>[O:29]=[C:22]1[N:23]([CH2:26][CH2:27][CH3:28])[C:24]2[N:25]=[C:14]([CH:9]3[CH:10]4[CH2:13][C:6]([C:4]([OH:3])=[O:5])([CH2:12][CH2:11]4)[CH2:7][CH2:8]3)[NH:18][C:19]=2[C:20](=[O:33])[N:21]1[CH2:30][CH2:31][CH3:32]
Reactant: CCOC(=O)C12CCC(C1)C(C(=O)O)CC2
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Agent: Cl
Product: CCCn1c(=O)c2[nH]c(C3CCC4(C(=O)O)CCC3C4)nc2n(CCC)c1=O
Yield: 110.3 %

Procedure:
Using the procedure described in Example 50, Step D, bicyclo[3.2.1]octane-1,4-dicarboxylic acid 1-ethyl ester (0.84 mmol, 0.19 g) was reacted with 5,6-diamino-1,3-dipropyl-1H-pyrimidine-2,4-dione hydrochloride (0.84 mmol, 0.22 g) to provide the desired product (0.36 g, 100%) as a mixture of axial and equatorial amides. MS (ESP+, 60V): 456.95 (M+Na, 45%), 435.00 (M+H, 8%), 325.12 (42%), 280.05 (100%).