Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1.[C:18](Cl)(=O)/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[N+:15]([C:13]1[CH:12]=[CH:11][C:3]2[N:4]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)[C:18](/[CH:19]=[CH:20]/[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:1][C:2]=2[CH:14]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)/C=C/c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1Nc1ccccn1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: O=[N+]([O-])c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 2-(2-amino-4-nitroanilino)pyridine (Runti, C. Ann. Chim. (Rome), 1956, 46, 406) and (E)-cinnamoyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:20].[ClH:20].[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][N:35]([CH2:19][CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]4[CH:27]=[CH:28][CH:29]=[C:23]4[CH:22]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:34][CH2:33]1
Reactant: CN(C)C1CCNCC1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Product: CN(C)C1CCN(CCOc2ccc3oc(-c4cc5cccn5cn4)cc(=NO)c3c2)CC1
Product: Cl

Procedure:
6-[2-(4-dimethylamino-piperidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, dihydrochloride was prepared in 30% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 4-dimethylaminopiperidine.
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH:4]=[CH2:5].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[O:30]1[CH2:5][CH:4]1[CH2:3][CH2:2][CH2:1][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2ccc(OCCCC3CO3)cc2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To 250 ml of methylene chloride is added 28.3 g of 4-(4-penteneoxy)-4'-nitrobiphenyl. The solution is cooled to 0° C.,and 18 g of meta-chloroperbenzoic acid is added slowly. The mixture is stirred at 0° C. for 24 hours, and allowed to warm to room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]O.C(N(CC)CC)C.S(Cl)([Cl:22])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH2:7][Cl:22])[CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(Cl)cc1CCl
Reaction time: 3 h
Yield: 98.2 %

Procedure:
To a solution of 5-chloro-2-nitrobenzyl alcohol (80 g, 0.42 mol) and triethylamine (64 ml, 0.46 mol) in dichloromethane (840 ml) was added drop wise thionyl chloride (34 ml, 0.46 mol) during a period of 30 minutes while the internal temperature was kept below 32° C. by cooling with a water bath. The reaction mixture was stirred for 3 h. The solvent was evaporated and the residue was triturated in warm tert-butyl methyl ether (970 ml). The ammonium salts were removed by filtration and the filtrate was concentrated in vacuo to give the title compound (85 g, 99%) as brown oil which was used in the next step without purification. MS m/e: 205 (M+).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:21](=[O:22])[C:20]4[CH:23]=[CH:24][S:25][C:19]=4[NH:18][C:17]3=[O:26])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:30][CH2:31][CH2:32][CH3:33]>>[CH2:30]([N:18]1[C:19]2[S:25][CH:24]=[CH:23][C:20]=2[C:21](=[O:22])[N:16]([CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:28][CH:27]=3)[CH2:9][CH2:10]2)[C:17]1=[O:26])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCBr
Reactant: O=C(c1ccc(F)cc1)C1CCN(CCn2c(=O)[nH]c3sccc3c2=O)CC1
Product: CCCCn1c(=O)n(CCN2CCC(C(=O)c3ccc(F)cc3)CC2)c(=O)c2ccsc21
Yield: 33.8 %

Procedure:
The title compound was prepared by the procedure of Example 14 using 2.0 g (5 mmol) of 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]thieno[2,3-d]pyrimidine-2,4-dione from Example 2 and bromobutane (819 mg, 6 mmol). There was obtained 774 mg (34% yield) of the title compound as a yellow solid after recrystallization from CH2Cl2 /hexane, mp 124°-125° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:39]([C:36]4[CH:37]=[CH:38][C:33]([Cl:32])=[CH:34][CH:35]=4)(=[O:41])=[O:40])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(Cl)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-chloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=596.1)=97%.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>CC(CC)=O>[ClH:16].[N:17]1([C:4]2[N:3]=[C:2]([NH2:1])[C:11]3[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1
Reactant: C1COCCN1
Reactant: COc1ccc2c(N)nc(Cl)nc2c1OC
Solvent: CCC(C)=O
Product: COc1ccc2c(N)nc(N3CCOCC3)nc2c1OC
Product: Cl
Temperature: 0 °C

Procedure:
To 500 ml. of methylethylketone is added 0.1 mole of 4-amino-2-chloro-7,8-dimethoxyquinazoline and 0.12 mole of morpholine and the mixture is refluxed overnight. After cooling in ice-water the solid precipitated is collected by filtration, washed with ether and air dried to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@@H:11]([CH3:12])[O:10]1.[SH:19]CCC(OC)=O.C[O-].[Na+].CO.CCCC(OC)=O>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@@H:11]([SH:19])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: COC(=O)CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CCCC(=O)OC
Solvent: CO
Product: C[C@H](S)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 3 h

Procedure:
In methanol (25 ml) were dissolved (2R,3R)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)-methyl]oxirane (0.98 g), methyl 3-mercaptopropionate (3.3 ml) and 28% sodium methoxide-methanol (3.0 g) and the solution was refluxed on an oil bath. After 2 and after 3 hours, methyl 3-methylpropionate (0.83 ml) and 28% sodium methoxide-methanol (0.75 g) were added at each time. The oil bath was removed after heating for 4 hours and the reaction mixture was neutralized with cold 1N-HCl (23.4 ml) and extracted with dichloromethane (200 ml). The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: hexane-ethyl acetate=1:3). The desired fraction was concentrated and the resulting crystals were recrystallized from ethyl acetate-hexane to give (2R,3S)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2-butanol (compound 118, 461 mg) as colorless needles. m.p. 141°-143° C.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].[CH:15]1[CH:20]=[CH:19][C:18]([CH:21]([NH2:25])[C:22](N)=[O:23])=[CH:17][CH:16]=1.CC1(C)S[C@@H]2[C@H](NC(CC3C=CC=CC=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+].Cl>>[CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH:9][C:22]([C@H:21]([NH2:25])[C:18]3[CH:17]=[CH:16][CH:15]=[CH:20][CH:19]=3)=[O:23])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13]
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(=O)C(N)c1ccccc1
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Agent: Cl
Agent: [K+]
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)[C@H](N)c3ccccc3)[C@H]2SC1

Procedure:
The reaction is carried out at 25° C. and pH 7.5 in a fixed bed reactor. 10 ml of an aqueous solution of a mixture 0.2 M 7-ADCA and 0.2 M D-phenylglycinamide are passed through a column with 0.5 ml of the immobilized penicillin amidase. During the reaction, the pH is kept constant by adding HCl in an attached stirred reservoir container. Samples are taken and analyzed by HPLC as shown in example 5 at particular time intervals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=1.C([Li])CCC.[O:17]=[C:18]1[CH2:24][CH:23]2[CH2:25][CH:19]1[CH2:20][N:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]2>C(OCC)C.C1COCC1>[OH:17][C:18]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH:9]([CH3:11])[CH3:10])[CH:7]=2)[CH2:24][CH:23]2[CH2:25][CH:19]1[CH2:20][N:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22]2
Reactant: CC(C)Oc1cncc(Br)c1
Reactant: CCOC(=O)N1CC2CC(=O)C(C2)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)N1CC2CC(C1)C(O)(c1cncc(OC(C)C)c1)C2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a solution of 3-bromo-5-isopropoxypyridine (0.66 g, 3.1 mmol) in dry diethyl ether (15 mL) at −78° C. was added 2.5 M n-butyllithium (1.2 mL, 3.0 mmol). The reaction was stirred for 30 min under nitrogen at −78° C. and then slowly transferred by cannula into a solution of ethyl 6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (0.30 g, 1.5 mmol) in THF (15 mL) at −78° C. The reaction was stirred 4 h at −78° C. and then warmed to ambient temperature overnight, at which time it was quenched with saturated aqueous ammonium chloride (20 mL). The reaction was then extracted with chloroform (2×10 mL), and the combined extracts were dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Excess pyridine was removed by repeated azeotropic rotary evaporation with toluene, and the residue was chromatographed on a silica gel column (with 5% methanol in chloroform) to yield the desired product (0.34 g, 61%).
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15]/[CH:16]=[C:17]3\[C:18](=[O:29])[NH:19][C:20](=[O:28])[C:21]4[C:26]\3=[CH:25][C:24]([I:27])=[CH:23][CH:22]=4)=[CH:11][CH:10]=2)[CH2:3]1.BrC1C=C2C(=CC=1)[C:37](=[O:41])NC(=O)C2=CNC1C=CC(N2CC(C)NC(C)C2)=CC=1>>[I:27][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[C:20](=[O:28])[NH:19][C:18](=[O:29])/[C:17]/2=[CH:16]/[O:41][CH3:37].[CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:3]1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Reactant: CC1CN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CCN1C
Product: CC1CN(c2ccc(N)cc2)CCN1C
Product: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, after purified from HPLC, 0.052 g (22.6% yield) of light brown solid is obtained from 0.15 g (0.46 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 4-(3,4-Dimethyl-piperazin-1-yl)-phenylamine (0.11 g, 0.50 mmol): mp 157-158° C.; MS (ESI) m/z 503.1 (M+H)+1
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1O)#[N:2].[C:10](=[O:13])([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]C>CC(=O)CC>[CH2:10]([O:13][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCBr
Reactant: N#Cc1ccccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCOc1ccc(C#N)cc1

Procedure:
To a solution of cyanophenol (25 g) and potassium carbonate (58 g) in 2-butanone (320 ml) was added bromooctane (61 ml) at room temperature. The stirred mixture was heated under reflux for 48 hrs (i.e., until TLC revealed complete reaction). The mixture was filtered, after which the solvent and excess alkyl bromide were removed in vacuo to give a colorless liquid.
Reaction SMILES: [CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][NH:5][C@H:4]1[CH3:8])[CH3:2].F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=1[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:1]([C@:3]1([OH:9])[CH2:7][CH2:6][N:5]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=2[C:19]([F:20])([F:22])[F:21])[C@H:4]1[CH3:8])[CH3:2]
Reactant: CC[C@]1(O)CCN[C@H]1C
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@]1(O)CCN(c2ccc(C#N)cc2C(F)(F)F)[C@H]1C

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-3-ethyl-2-methylpyrrolidin-3-ol 0.5 oxalate (257 mg), 4-fluoro-3-(trifluoromethyl)benzonitrile (419 mg) and lithium carbonate (218 mg), the title compound was obtained as colorless oil (yield: 218 mg, yield: 49%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]#[N:12])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:5]2=[N:6][CH:7]=1.C[O-].[Na+].[Cl-].[NH4+:25].[C:26]([OH:29])(=[O:28])[CH3:27]>CO>[C:26]([OH:29])(=[O:28])[CH3:27].[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[NH:25])[NH2:12])=[N:9][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:5]2=[N:6][CH:7]=1
Reactant: [NH4+]
Reactant: N#Cc1nn(Cc2ccccc2F)c2ncc(F)cc12
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: N=C(N)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
11.1 g (41.07 mmol) of 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (Example 8A) were added to 2.22 g (41.07 mmol) of sodium methoxide in methanol (270 ml), and the mixture was stirred at RT for 2 h. 2.64 g (49.29 mmol) of ammonium chloride and acetic acid (9.17 ml) were then added, and the mixture was heated at reflux overnight. The mixture was then concentrated to dryness and the residue was taken up in water (100 ml) and ethyl acetate (100 ml) and adjusted to a pH of 10 using 2N aqueous sodium hydroxide solution. The mixture was stirred intensively at RT for about 1 h. The resulting suspension was filtered with suction and the filter product was washed with ethyl acetate (100 ml), with water (100 ml) and once more with ethyl acetate (100 ml). The residue was dried under high vacuum over phosphorus pentoxide.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:15]([O:17]C)=[O:16])[C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].Cl>C1COCC1.[OH-].[Na+]>[C:1]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[C:11]([CH3:12])([CH3:13])[CH3:14])(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCC(=O)N[C@H](C(=O)OC)C(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCCCCC(=O)N[C@H](C(=O)O)C(C)(C)C
Yield: 84.7 %

Procedure:
A solution of methyl N-hept-6-enoyl-3-methyl-L-valinate (1.40 g, 5.48 mmol) in THF (10 mL) and 1 N NaOH (10 mL) was stirred at 22° C. for 2 hours. The reaction mixture was acidified to pH 3 with 1 N HCl and extracted with EtOAc (3×150 mL). The combined EtOAc layers were washed with water (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to give the title product (1.12 g, 84%). LRMS (ESI) m/z 242.3 [(M+H)+; calcd for C13H24NO3: 242.2].
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:43])[C@@H:24]([NH:25][C:26](=[O:42])[C:27]([C:32]3[N:33]=[C:34]([NH:37]C(=O)CCl)[S:35][CH:36]=3)=[N:28][O:29][CH2:30][CH3:31])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:44]([S:46][C:47]1[NH:51][N:50]=[N:49][N:48]=1)[CH3:45])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(N)=S>O1CCCC1.C(O)C.[Br-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:43])[C@@H:24]([NH:25][C:26](=[O:42])[C:27]([C:32]3[N:33]=[C:34]([NH2:37])[S:35][CH:36]=3)=[N:28][O:29][CH2:30][CH3:31])[C@H:21]2[S:20][CH2:19][C:18]=1[CH:44]([S:46][C:47]1[NH:51][N:50]=[N:49][N:48]=1)[CH3:45])=[O:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1csc(NC(=O)CCl)n1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: NC(N)=S
Agent: [Br-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 52.9 %

Procedure:
To a solution of 2.2 g of 7β-{α-ethoxyimino-[2-(chloroacetamido)thiazol-4-yl]acetamido}-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester in 20 ml of tetrahydrofuran is added a solution of 550 mg of thiourea in 20 ml of ethanol, followed by addition of 50 mg of triethylbenzylammonium bromide. The mixture is stirred for 20 hours at room temperature and concentrated. The residue is dissolved in a mixture of ethyl acetate and tetrahydrofuran and the solution was washed with aq. sodium bicarbonate solution and then water, followed by drying over anhydrous magnesium sulfate. The dried solution is subjected to distillation of the solvent to give powder which is washed with chloroform and ether and dried. The procedure yields 1.047 g of 7β-[α-ethoxyimino-(2-aminothiazol-4-yl)acetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid benzhydryl ester. Yield 52.9%.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:13][C:14]3[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=3[O:22][CH3:23])[C:8]([NH2:12])=[N:9]2)=[CH:4][CH:3]=1.[CH3:24]B1OB(C)OB(C)[O:26]1>>[C:19]([O-:20])(=[O:26])[CH3:14].[CH3:23][O:22][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([O:20][CH3:21])[C:14]=1[CH2:13][N:7]1[CH2:6][C:5]2[C:10](=[CH:11][C:2]([CH3:24])=[CH:3][CH:4]=2)[N:9]=[C:8]1[NH3+:12]
Reactant: CB1OB(C)OB(C)O1
Reactant: COc1cccc(OC)c1CN1Cc2ccc(Br)cc2N=C1N
Product: CC(=O)[O-]
Product: COc1cccc(OC)c1CN1Cc2ccc(C)cc2N=C1[NH3+]

Procedure:
Synthesis was performed according to EXAMPLE 82 from 7-bromo-3-(2,6-dimethoxybenzyl)-3,4-dihydroquinazolin-2-amine and trimethylboroxine in a CEM microwave at 100° C. (120 watt) for a total of 360 minutes (3×120 minutes).
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([C:17]([OH:22])([CH2:20][CH3:21])[CH2:18][OH:19])[CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]([CH3:26])=O>>[CH2:20]([C:17]1([C:13]2[CH:14]=[N:15][CH:16]=[C:11]([O:10][CH2:9][C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=2)[CH2:18][O:19][C:24]([CH3:26])([CH3:23])[O:22]1)[CH3:21]
Reactant: CC(C)=O
Reactant: CCC(O)(CO)c1cncc(OCC#Cc2ccccc2)c1
Product: CCC1(c2cncc(OCC#Cc3ccccc3)c2)COC(C)(C)O1
Yield: 59 %

Procedure:
Using the procedure described in Example 1, 2-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]butane-1,2-diol was reacted with acetone to give 4-ethyl-2,2-dimethyl-4-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]-1,3-dioxolane in 59% yield, as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2.[C-:21]#[N:22].[Na+].CCCCCC.CCOC(C)=O>C(#N)C.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.[Cu]I>[CH3:11][C:9]1[CH:10]=[C:2]([C:21]#[N:22])[CH:3]=[C:4]2[C:8]=1[C:7](=[O:12])[N:6]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[CH2:5]2
Reactant: [C-]#N
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc2c1C(=O)N(Cc1ccc(Cl)cc1)C2
Temperature: 80 °C
Reaction time: 18 h
Yield: 531.2 %

Procedure:
A mixture of 5-bromo-7-methyl-2-(4-chloro-benzyl)-2,3-dihydro-isoindol-1-one (0.205 g, 0.59 mmol), Pd(PPh3)4 (0.070 g, 0.06 mmol), sodium cyanide (0.038 g, 0.8 mmol), and CuI (0.013 g, 0.07 mmol) in acetonitrile (3 mL) was stirred at 80° C. for 18 h. Workup and silica gel column chromatography using 2:1 hexanes-ethyl acetate (typically 2:1 hexane-EtOAc) afforded 7-methyl-1-oxo-2-(4-chloro-benzyl)-2,3-dihydro-1H-isoindole-5-carbonitrile (0.93 g, 54%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.78 (s, 3H), 4.26 (s, 2H), 4.65 (s, 2H), 7.24 (d, 2H), 7.33 (d, 2H), 7.52 (d, 2H). GC-MS: m/z 296 (M)+, 261 (M−35)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:51][O:52][C:53]1[CH:61]=[CH:60][C:56]([CH:57]([OH:59])[CH3:58])=[CH:55][CH:54]=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:59][CH:57]([C:56]2[CH:60]=[CH:61][C:53]([O:52][CH3:51])=[CH:54][CH:55]=2)[CH3:58])=[C:18]([CH3:24])[CH:17]=1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: COc1ccc(C(C)O)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(C)OC(=O)Nc2cc(C)c(Oc3ccnc4cc(OC)c(OC)cc34)cc2C)cc1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (80 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (110 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 4-methoxy-α-methylbenzyl alcohol (56 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (80 mg, yield 60%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH:5]=[O:6].[OH:7][CH2:8][CH:9]([CH3:12])[CH:10]=[O:11]>O1CCCC1>[CH2:5]([OH:6])[CH2:4][CH2:3][CH2:2][OH:1].[CH3:12][CH:9]([CH2:10][OH:11])[CH2:8][OH:7]
Reactant: CC(C=O)CO
Reactant: O=CCCCO
Solvent: C1CCOC1
Product: CC(CO)CO
Product: OCCCCO

Procedure:
The invention relates to the preparation of tetrahydrofuran. In particular, a mixture of 4-hydroxybutanal and 3-hydroxy-2-methylpropanal is hydrogenated in the presence of a supported transition metal catalyst to give tetrahydrofuran as the major product, and 1,4-butanediol and 2-methyl-1,3-propanediol as minor products.