Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].C(N(CC)CC)C.Cl[C:30]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1)=[O:31]>O1CCCC1>[CH:9]1([C:7]2[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]([CH3:20])[C:3](=[O:21])[CH:2]([NH:1][C:30]([O:32][C:33]3[CH:34]=[CH:35][C:36]([N+:39]([O-:41])=[O:40])=[CH:37][CH:38]=3)=[O:31])[N:8]=2)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: CN1C(=O)C(N)N=C(C2CCCCCC2)c2ccccc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1C(=O)C(NC(=O)Oc2ccc([N+](=O)[O-])cc2)N=C(C2CCCCCC2)c2ccccc21
Reaction time: 3 h

Procedure:
The amine was dissolved in anhydrous tetrahydrofuran (9 ml) under an atmosphere of nitrogen, at room temperature, and triethylamine (221 μl) was added dropwise. A solution of 4-nitrophenyl chloroformate (322 mg) in anhydrous tetrahydrofuran (9 ml) was then added, and the reaction mixture stirred for a further 3 h. After this time the undissolved solid was filtered off, washed with tetrahydrofuran, and the filtrate evaporated in vacuo. The residue was azeotroped with toluene (2×50 ml) and the residue triturated with anhydrous ether to afford the title compound (425 mg) as a white solid. TLC (silica, petrol (60/80):ethyl acetate 2:1). Rf=0.3. 1H NMR (360 MHz, CDCl3) δ 1.22-2.10 (12H, m), 2.98 (1H, m), 3.45 (3H, s), 5.15 (1H, d, J=8.2 Hz), 6.89 (1H, d, J=9.2 Hz), 7.26-7.35 (4H, m), 7.49-7.60 (2H, m), 8.22 (2H, d, J=7.1 Hz).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[N:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]=2[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:29].O1CCOCC1>C(Cl)Cl>[ClH:29].[NH2:8][C@@H:9]1[CH2:21][C:20]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[N:13]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:12]=2[CH2:11][CH2:10]1
Reactant: CCOC(=O)Cn1c2c(c3cc(F)ccc31)C[C@@H](NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)Cn1c2c(c3cc(F)ccc31)C[C@@H](N)CC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cold (0° C.) solution of (S)-ethyl 2-(3-((tert-butoxycarbonyl)amino)-6-fluoro-3,4-dihydro-1H-carbazol-9(2H)-yl)acetate (8.2 g, 0.021 mol) in dry DCM (50 ml) was added dropwise 4N HCl in dioxane (52.5 ml, 0.21 mol). The resulting reaction mixture was stirred at 0° C. for 2 h and then at rt for 5 h. The reaction mixture was concentrated in vacuo and the resulting solid was dissolved in EtOH (70 ml) and was added at 0° C. 3N HCl in EA (7 ml). The reaction mixture was stirred at reflux overnight. After cooling to rt, the reaction mixture was concentrated in vacuo to afford the title compound as a beige powder.
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][CH2:10][CH2:11]Cl)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC>C1COCC1>[C:1]([NH:5][S:6]([CH:9]1[CH2:11][CH2:10]1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)CCCCl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)C1CC1
Temperature: 25 °C
Yield: 56.4 %

Procedure:
To a solution of N-tert-butyl-(3-chloro)propylsulfonamide (2.14 g, 10.0 mmol) in THF (100 mL) was added n-BuLi (2.5 M in hexane, 8.0 mL, 20.0 mmol) at −78° C. The reaction mixture was allowed to warm up to room temperature over period of 1 h. The volatiles were removed in vacuo. The residue was partitioned between EtOAC and water (200 mL, 200 mL). The separated organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was recrystallized from hexane to yield the desired product as a white solid (1.0 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[Cl:19][C:20]1[CH:21]=[C:22]([N:27]=[C:28]=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([NH:27][C:28]([NH:18][C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:10]([C:3]3[N:4]([CH:7]([CH3:9])[CH3:8])[N:5]=[CH:6][C:2]=3[Cl:1])[CH:11]=2)=[O:29])[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: COc1ccc(N)cc1-c1c(Cl)cnn1C(C)C
Reactant: O=C=Nc1ccc(F)c(Cl)c1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)c(Cl)c2)cc1-c1c(Cl)cnn1C(C)C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
To a solution of 3-(4-chloro-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.1 g, 0.433 mmol) in CH2Cl2, was added 3-chloro-4-fluoro-phenyl isocyanate (0.082 g, 0.476 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 56 as a colorless solid (0.052 g, 28%). LCMS m/z (%)=439 M+H+ (37Cl, 29), 437 M+H+ (35Cl, 26), 1H NMR (400 MHz, acetone-d6) δ: 8.764 (bs, 1H), 8.673 (bs, 1H), 8.31-8.28 (m, 1H), 8.110 (d, J=2.72 Hz, 1H), 8.088 (d, J=2.71 Hz, 1H), 7.974 (s, 1H), 7.878 (d, J=2.68 Hz, 1H), 7.828-7.788 (m, 1H), 7.68-7.64 (m, 1H), 7.635-7.563 (m, 1H), 4.668 (m, 1H), 4.246 (s, 3H), 1.874 (d, J=6.61 Hz, 3H), 1.713 (d, J=6.61 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1cc(Br)ccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
Then, 8.47 g of 4-bromo-2-trifluoromethylphenol, 5.34 g of potassium carbonate, 4.49 g of benzyl chloride and 100 ml of N,N-dimethylformamide were charged into a reaction vessel, and stirred under ice cooling. After 24 hours, the reaction solution was poured into ice-water and extracted three times with 50 ml of diethyl ether. The ether layers were combined, washed with an aqueous 10 % sodium hydroxide solution, dried over anhydrous magnesium sulfate and then concentrated to give a crude product. This crude product was subjected to silica gel chromatography to give 9.38 g of 4-bromo-2-trifluoromethyl-1-benzyloxybenzene, (yield, 81%).
Reaction SMILES: [ClH:1].C1(C(=[N:15][N:16]2[CH:20]([CH3:21])[CH2:19][CH2:18][C:17]2=[O:22])C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[Cl-:1].[CH3:21][CH:20]1[CH2:19][CH2:18][C:17](=[O:22])[N:16]1[NH3+:15]
Reactant: CC1CCC(=O)N1N=C(c1ccccc1)c1ccccc1
Reactant: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1CCC(=O)N1[NH3+]
Product: [Cl-]
Reaction time: 1 h

Procedure:
At room temperature 50 ml of 37% strength hydrochloric acid are added to a solution of 17.8 g (63.9 mmol) of 1-[(diphenylmethylene)amino]-5-methylpyrrolidin-2-one in 100 ml of tetrahydrofuran, and the mixture is stirred for 1 h. Ethyl acetate is then added to the reaction mixture, and the organic phase is separated off. Repeatedly, ethanol/toluene (1:1) is added to the hydrochloric acid phase and the mixture is concentrated under reduced pressure. The crude product obtained is reacted further without further purification. 1H-NMR (ppm): δ (DMSO-d6)=1.24 (d, 3H), 1.60-1.65 (m, 1H), 2.20-2.42 (m, 3H), 3.88 (m, 1H).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[C:6]([CH:17]=O)[C:7]3[C:12]([C:13]=2[CH:15]=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[NH:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[NH2:20]>C(O)(=O)C.C(O)C>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:19][N:20]=[CH:15][C:13]1[C:14]2[C:5]([C:6]([CH:17]=[N:20][NH:19][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: O=Cc1c2ccccc2c(C=O)c2ccccc12
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Solvent: CCO
Product: C(=NNc1ccccn1)c1c2ccccc2c(C=NNc2ccccn2)c2ccccc12

Procedure:
A suspension of 4.68 g. of 9,10-anthracenedicarboxaldehyde in 200 ml. of ethanol containing 4.37 g. of 2-hydrazinopyridine and 2 drops of acetic acid is stirred and heated under reflux for two hours, then allowed to cool. Collection by filtration and washing with ethanol gives the desired product as an orange solid, which sinters from 267° C. to 272° C. (dec.).
Reaction SMILES: CS[CH:3]1[N:6]([CH2:7][C:8](=[O:15])[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[C:5](=[O:16])[CH2:4]1.[Cl:17]Cl>C(Cl)(Cl)(Cl)Cl>[Cl:17][CH:3]1[N:6]([CH2:7][C:8](=[O:15])[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[C:5](=[O:16])[CH2:4]1
Reactant: ClCl
Reactant: COC(=O)C(C)C(=O)CN1C(=O)CC1SC
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)C(=O)CN1C(=O)CC1Cl
Temperature: 0 °C
Reaction time: 0.05 h
Yield: 104.2 %

Procedure:
Methyl 4-(4-methylthio-2-oxoazetidin-1-yl)-2-methyl-3-oxobutyrate (280 mg, 1.14 mmole) was dissolved in dry carbon tetrachloride (15 ml) and to the stirred ice-cooled solution chlorine (80 mg, 1.13 mmole) in carbon tetrachloride (3.2 ml) was added in one portion. After addition of the chlorine, the cooling bath was removed and stirring was continued for 3 minutes. The solvent was evaporated under reduced pressure to yield methyl 4-(4-chloro-2-oxoazetidin-1-yl)-2-methyl-3-oxobutyrate as a pale yellow gum (275 mg). νmax (CHCl3): 1780 (β-lactam C=O), 1755 (ester C=O), 1725 (ketone C=O) cm-1.
Reaction SMILES: CO[C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].[OH:22][CH2:23][C@@H:24]([NH2:26])[CH3:25]>>[CH2:23]([CH2:24][NH2:26])[OH:22].[OH:22][CH2:23][C@@H:24]([NH:26][C:3]([C:5]1[O:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])[CH3:25]
Reactant: CCCCc1noc(C)c1COc1cc(C(=O)OC)on1
Reactant: C[C@H](N)CO
Product: CCCCc1noc(C)c1COc1cc(C(=O)N[C@@H](C)CO)on1
Product: NCCO
Yield: 108.3 %

Procedure:
As described for example 24b, 3-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester (199 mg, 0.68 mmol), was converted using (S)-1-hydroxymethylethylamine (61 mg, 0.81 mmol), instead of ethanolamine, to the title compound (148 mg, 65%) which was obtained as a colourless gum after purification by chromatography (silica, heptane:ethyl acetate=1:1 to 0:1). MS: m/e=338.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH:22]=[C:23]([OH:25])[CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([F:26])=[C:9]([CH3:27])[C:8]=1[F:28])#[N:2].[C:32](=O)([O-])[O-].[Cs+].[Cs+].IC>C(#N)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH:22]=[C:23]([O:25][CH3:32])[CH:24]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:10]([F:26])=[C:9]([CH3:27])[C:8]=1[F:28])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(O)cc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)c1cc(OC)cc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Reaction time: 15 h

Procedure:
To acetonitrile (5 mL) was added 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]-5-hydroxybenzoic acid, ethyl ester (0.20 g, 0.47 mmol), cesium carbonate (0.31 g, 0.94 mmol), and iodomethane (0.13 g, 0.94 mmol). After stirring for 15 hours the mixture was partitioned with ethyl acetate and water. The organic layer was dried (MgSO4) and the solvent was removed in vacuo to give 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methyl-pyridin-2-yl)oxy]-5-methoxybenzoic acid, ethyl ester; NMR (CDCl3) 7.3 (m,6), 6.8 (s,1), 4.4 (q,2), 3.8 (s,3), 2.4 (s,3), 1.4 (s,3) ppm.
Reaction SMILES: [C:1]([C:7]#[N:8])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Br.O.C(=O)(O)[O-:12].[Na+]>C(O)(=O)C>[CH3:3][C:2]([CH3:5])([CH3:4])[C:1](=[O:6])[C:7]([NH2:8])=[O:12]
Reactant: O=C([O-])O
Reactant: CC(C)(C)C(=O)C#N
Agent: Br
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)C(N)=O
Yield: 88 %

Procedure:
111.0 g (1 mole) of pivaloyl cyanide were added dropwise to 800 g of a 36% strength solution of hydrogen bromide in glacial acetic acid at room temperature, while stirring. When the addition had ended, the mixture was subsequently stirred at room temperature for 3 hours. 9 ml (0.5 mole) of water were then added dropwise at 20° to 25° C. and the mixture was subsequently stirred at room temperature for 1 hour. The reaction solution was then poured into an excess of saturated sodium bicarbonate solution. It was extracted three times with 200 ml of methylene chloride each time. The combined organic phases were washed with 200 ml of water, dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. After some time, the oil which remained crystallized completely. The recrystallization from petroleum ether gave 113.5 g (88% of theory) of trimethylpyruvic acid amide of melting point 69° to 70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[N:27][C:28]#[N:29])[C:6]=2[CH:30]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C@@:9]([CH:12]([O:15][CH3:16])[O:13][CH3:14])([CH3:11])[C@H:8]([OH:17])[C@@H:7]([N:18]3[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[NH:20][C:19]3=[N:27][C:28]#[N:29])[C:6]=2[CH:30]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COC(OC)[C@@]1(C)Oc2ccc(N)cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(OC)[C@@]1(C)Oc2ccc(NS(C)(=O)=O)cc2[C@H](n2c(=NC#N)[nH]c3ccccc32)[C@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 24.8 %

Procedure:
120 mg (0.29 mmol) of the compound obtained in example 5 was dissolved in 2 ml of methylenechloride, then 23 μl (0.29 mmol) of methanesulfonyl chloride and 76 μl (0.44 mmol) of diisopropylethylamine were added thereto. The reaction was stirred at room temperature for 14 hours, saturated NaHCO3 solution was added, and aqueous layer was extracted with 30 ml of methylenechloride. Organic layer was dried over anhydrous MgSO4, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1), to give 35 mg (yield: 26%) of the target compound.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[C:25]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:24][CH:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C(Cl)(Cl)Cl>[N:26]1([C:25]2[C:20]([C:9]3[CH:10]=[C:11]4[CH:17]=[CH:16][NH:15][C:12]4=[N:13][CH:14]=3)=[N:21][CH:22]=[CH:23][N:24]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Clc1nccnc1N1CCCC1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClC(Cl)Cl
Solvent: COCCOC
Product: c1cnc(N2CCCC2)c(-c2cnc3[nH]ccc3c2)n1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (50 mg, 0.2048 mmol, 1 eq) and 2-chloro-3-(pyrrolidin-1-yl)pyrazine (72) (33 mg, 0.184 mmol, 1 eq) in DME (8 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (133 mg, 0.409 mmol, 2 eq) followed by addition of Pd(dpp)Cl2 (6 mg, 0.00819 mmol, 0.04 eq) and degassing and purging under argon for additional min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through Celite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound 5-(3-(pyrrolidin-1-yl)pyrazin-2-yl)-1H-pyrrolo[2,3-b]pyridine 128 in 10 mg quantity. The compound 128 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 9.50 (s, 1H), 8.58 (d, J=1.95, 1H), 8.15 (d, J=1.58, 1H), 8.04 (m, J=2.56, 2H), 7.38 (m, J=3.45, 1H), 6.56 (m, J=1.58, 1H), 3.18 (m, J=6.70, 1H), 1.81 (m, J=2.92, 4H; MS m/z 265.9 (M+H)+.
Reaction SMILES: BrBr.[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24]C(CCC)=CC=3)=CC=2)=C)=[C:8]([F:29])[C:7]=1[F:30])[CH3:4].C(N([CH2:36][CH3:37])CC)C.C([N-][CH:42]([CH3:44])[CH3:43])(C)C.[Li+]>ClCCl.C(#N)C.C1COCC1>[CH2:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:14][C:19]2[CH:18]=[CH:17][C:20]([C:37]3[CH:36]=[CH:8][C:7]([CH2:44][CH2:42][CH3:43])=[CH:6][CH:11]=3)=[CH:25][CH:24]=2)=[C:8]([F:29])[C:7]=1[F:30])[CH3:4]
Reactant: CC(C)[N-]C(C)C
Reactant: CCN(CC)CC
Reactant: C=C(c1ccc(-c2ccc(CCC)cc2)cc1)c1ccc(OCC)c(F)c1F
Agent: BrBr
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: CCCc1ccc(-c2ccc(C#Cc3ccc(OCC)c(F)c3F)cc2)cc1

Procedure:
0.065 mol of bromine are added to a stirred solution of 0.065 mol of this ethen derivative in a mixture of 100 ml of dichloromethane and 50 ml of acetonitrile. After addition of 10 g of triethylamine and customary working up the crude product is dissolved in 50 ml of THF. 0.13 mol of lithium diisopropylamide in 120 ml of THF are added dropwise to this solution at -50° C. Customary working up gives 1-(4-Ethoxy-2,3-difluorophenyl)-2-(4'-propylbiphenyl-4-yl)-ethine.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH:21]=O)=[CH:16][CH:15]=3)=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:30])[CH3:2].[CH2:31]([CH2:33][NH2:34])[OH:32].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Cl>C(#N)C>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][NH:34][CH2:33][CH2:31][OH:32])=[CH:16][CH:15]=3)=[C:8]2[C:4]=1[CH2:5][NH:6][C:7]2=[O:30])[CH3:2]
Reactant: CCc1ccc(-c2cc3cc(C=O)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Reactant: NCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCc1ccc(-c2cc3cc(CNCCO)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 95.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-ethyl-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (68.0 mg, 0.168 mmol) was dissolved in acetonitrile (5.4 mL), and the solution was treated with ethanolamine (0.041 mL, 0.67 mmol), acetic acid (0.192 mL, 3.36 mmol) and sodium triacetoxyborohydride (71.0 mg, 0.336 mmol). The reaction mixture was added with 1 mol/L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with sodium carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 4-ethyl-7-{1-(tert-butoxycarbonyl)-5-[(2-hydroxyethylamino)methyl]indol-2-yl}isoindolinone (72.0 mg, yield 95%).
Reaction SMILES: [CH3:1]/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.Cl.[NH2:14][CH:15]1[C:42](=[O:43])[N:17]2[C:18]([C:26]([O:28][CH:29]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])=[C:19](/[CH:22]=[CH:23]\[CH2:24][Cl:25])[CH2:20][S:21][C@H:16]12.Cl.[NH2:45][C:46]1[S:50][N:49]=[C:48](/[C:51](=[N:55]/[O:56][CH2:57][CH3:58])/[C:52](Cl)=[O:53])[N:47]=1>C(Cl)Cl.C(OCC)(=O)C>[CH:29]([O:28][CH:26]([CH3:18])[CH3:1])([CH3:30])[CH3:36].[NH2:45][C:46]1[S:50][N:49]=[C:48](/[C:51](=[N:55]/[O:56][CH2:57][CH3:58])/[C:52]([NH:14][CH:15]2[C:42](=[O:43])[N:17]3[C:18]([C:26]([O:28][CH:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])=[C:19]([CH:22]=[CH:23][CH2:24][Cl:25])[CH2:20][S:21][C@H:16]23)=[O:53])[N:47]=1
Reactant: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\CCl)CS[C@H]12
Reactant: CCO/N=C(\C(=O)Cl)c1nsc(N)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)OC(C)C
Product: CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CCCl)CS[C@H]12)c1nsc(N)n1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a mixture of N,O-bis(trimethylsilyl)acetamide (2.3 ml, 9 mmoles) and crystalline diphenylmethyl 7-amino-3-[3-chloro-1-(Z)-propen-1-yl]-3-cephem-4-carboxylate hydrochloride (XVIII) (1.338 g, 2.8 mmoles) (from Preparation No. 12) in methylene chloride (10 ml) was added 2-(5-amino-1,2,4-thiadiazol-3-yl)-2-(Z)-ethoxyiminoacetyl chloride hydrochloride (800 mg, 2.95 mmoles) portionwise, with stirring, at -10° C. and the mixture was allowed to stand at 0° C. for 2 hours. The mixture was diluted with ethyl acetate (200 ml), washed with water and evaporated under reduced pressure. Trituration of the residue with isopropyl ether afforded the title product VIII-2 as an amorphous powder. Yield 1.70 g (95%). Mp. >150° C. (dec.).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:30]=[N+:31]=[N-:32].[Na+]>>[N:30]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Cl:29])[CH:23]=3)[C:15]=2[O:14]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4ccc(F)c(Cl)c4)c3O2)cc1
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3ccc(F)c(Cl)c3)c2O1

Procedure:
Treatment of (±)-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.68 g, 1.57 mmol) with sodium azide (0.25 g, 3.92 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.035 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 0.186 g (38%) of (±)-1-[7-(3-chloro-4-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >210° C.; Anal. calcd. for C15H13ClFNOHCl: C, 57.34; H, 4.49; N, 4.46. Found: C, 57.38; H, 4.32; N, 4.55.
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[C:6]([O:8][CH2:9][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])(=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:1]([O:13][CH2:14][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])=[O:12])=[CH:3][CH:4]=1
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: CCCCCCCCCCCCCCCCCCO
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc(C(=O)OCCCCCCCCCCCCCCCCCC)cc1
Temperature: 130 °C
Yield: 96.2 %

Procedure:
To a 2L Buchi reactor equipped with a double turbine agitator and distillation apparatus was charged Dimethyl terephthalate (315.8 grams), Stearyl Alcohol (879.7 grams) and heated to 130° C. under Nitrogen purge for 1 hour, after which stirring was commenced followed by the addition of Tyzor catalyst (3.0 grams, available from Dupont). The reaction mixture was then heated to 145° C., followed by slowly ramping the temperature to 190° C. over a 3-4 hour period such that the evolution of methanol is distilled in a controlled manner. The reaction temperature was maintained at 190° C. for an additional 16 hours until >96% conversion to the product was achieved as determined by 1H NMR spectroscopy. The product was discharged as a low viscosity liquid which solidified on cooling to give a 1050 gram of a white solid (96.2% yield). The product was shown to be pure by 1H NMR spectroscopy with trace amounts of the mono-ester. Physical properties of this compound are shown in Table 2.