Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8](O)[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH2:16]([N:18](CC)CC)C.CS(Cl)(=O)=O.CN>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:18][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O[C@@H](CN1CCCC1)c1ccc(Br)cc1
Agent: CN
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CN[C@@H](CN1CCCC1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a magnetically stirred solution of (1R)-1-(4-bromophenyl)-2-(1-pyrrolidinyl)ethanol (29.43 g, 109 mmol) in CH2Cl2 (300 mL) at 0° C. was added triethylamine (55 mL, 394 mmol). Methanesulfonylchloride (30 mL, 388 mmol) was then added dropwise. The resulting mixture was warmed to room temperature, stirred for 5 h, and then quenched by the addition of H2O (200 mL). The layers were separated and the organic phase was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give an orange oil. The crude oil was taken up in CH2Cl2 (300 mL) and methylamine (33 wt % in EtOH, 135 mL, 1.08 mol) was added at room temperature. The resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and re-dissolved in CH2Cl2. The crude mixture was washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated under reduced pressure to give (1R)-1-(4-bromophenyl)-N-methyl-2-(1-pyrrolidinyl)ethanamine as a viscous red/orange oil (25.4 g, 90 mmol, 82% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:51])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:49][CH3:50])=[C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:37][C:38]4[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:39]=4[C:40]([NH:42][CH3:43])=[O:41])[C:20]4[C:25]([CH3:26])=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:51][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:49][CH3:50])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[C:25]([CH3:26])[C:20]4=[C:19]([NH:37][C:38]4[CH:47]=[CH:46][CH:45]=[C:44]([F:48])[C:39]=4[C:40]([NH:42][CH3:43])=[O:41])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)CN(C)C)nc2c1c(C)cn2S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCCN3C(=O)CN(C)C)[nH]c2ncc(C)c1-2
Temperature: 120 °C
Yield: 67.5 %

Procedure:
2-({2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (249 mg, 0.348 mmol) was dissolved in dioxane (3 mL) and 2N NaOH (2 mL) was added in a microwave safe vessel. The reaction was then heated in a microwave at 120° C. for 17 min. Reaction was diluted with EtOAc and the organic layer was washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide (132 mg, 0.235 mmol) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-1.93 (m, 2 H) 2.11 (br. s., 6 H) 2.42 (s, 3H) 2.68 (br. s., 2 H) 2.81 (d, J=4.49 Hz, 3 H) 3.21 (s, 2 H) 3.66-3.74 (m, 2 H) 3.84 (s, 3 H) 6.70-6.78 (m, 1 H) 6.79-6.88 (m, 1 H) 6.88-6.98 (m, 1 H) 7.31-7.41 (m, 1H) 7.43 (s, 1 H) 8.34-8.42 (m, 2 H) 8.63-8.72 (m, 1 H) 9.49-9.59 (m, 1 H) 11.00-11.12 (m, 1 H). ESIMS (M+H)+=561
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[CH:4][CH:3]=1.[C:17]1([C:23]2[O:27][N:26]=[CH:25][C:24]=2[CH2:28][CH2:29][C:30](O)=[O:31])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH2:12]([O:11][P:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][C:24]2[CH:25]=[N:26][O:27][C:23]=2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:16][CH:15]=1)([O:8][CH2:9][CH3:10])=[O:14])[CH3:13]
Reactant: CCOP(=O)(Cc1ccc(N)cc1)OCC
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cnoc2-c2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A mixture of diethyl 4-aminobenzylphosphonate (1.25 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (1.00 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.80 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.08 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. 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. The residue was subjected to silica gel column chromatography, and N-(4-diethylphosphonomethylphenyl)-3-(5-phenyl-4-isoxazolyl)propionamide (1.89 g, yield 93%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 139–140° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]([CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:8])[CH3:2].Br[CH2:19][CH2:20][CH2:21][Cl:22].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]([CH3:16])[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:19][CH2:20][CH2:21][Cl:22])=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)CC(C)C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CC(C)C(=O)c1ccc(OCCCCl)cc1
Temperature: 60 °C
Reaction time: 15 h
Yield: 58.6 %

Procedure:
A mixture of 4-(4-hydroxyphenyl)-3-methyl-4-oxo-butyric acid ethyl ester (12.5 g, 52.9 mmol), 1-bromo-3-chloropropane (11.3 mL, 114.6 mmol) and K2CO3 (21.9 g, 159 mmol) in acetone (200 mL) was stirred at 60° C. for 15 h. The reaction was cooled to RT and filtered over celite and the filtrate was evaporated at reduced pressure to give a crude residue. The crude residue was partitioned between methylene chloride and saturated aqueous sodium bicarbonate solution and the aqueous layer was extracted twice with methylene chloride. The combined organics was washed with brine, dried (Na2SO4), filtered, and concentrated to provide a crude product. The crude product was purified by ISCO (330 g) chromatography using 15% EtOAc in hexane to produce 4-[4-(3-chloro-propoxy)-phenyl]-3-methyl-4-oxo-butyric acid ethyl ester (9.7 g, 56%), MS m/z 267 (M-45).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]2[CH2:13][CH2:14][CH2:15][C:16](=[O:17])[C:4]=12.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:15]1[CH2:14][CH2:13][C:5]2=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:7][C:3]([S:2][CH3:1])=[C:4]2[C:16]1=[O:17]
Reactant: BrBr
Reactant: CCOC(=O)c1sc(SC)c2c1CCCC2=O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1sc(SC)c2c1CCC(Br)C2=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87.1 %

Procedure:
Ethyl 4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (25.12 g) was dissolved in chloroform (400 ml); a solution of bromine (15.59 g) in chloroform (20 ml) was added dropwise at room temperature over a period of 30 minutes. After the reaction mixture was stirred at room temperature for 40 minutes, it was washed with a 2% aqueous solution of sodium sulfite (400 ml), water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-bromo-4,5,6,7-tetrahydro-3-methylthio-4-oxobenzo[c]thiophene-1-carboxylate (28.27 g, 87.1%), which was then recrystallized from ethyl acetate-hexane. Light-yellow prisms. Melting point 147-148° C.
Reaction SMILES: Cl[CH:2]([CH2:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])[C:3]#[N:4]>C(Cl)(Cl)Cl>[C:9]1([S:6]([CH:5]=[CH:2][C:3]#[N:4])(=[O:7])=[O:8])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: N#CC(Cl)CS(=O)(=O)c1ccccc1
Solvent: ClC(Cl)Cl
Product: N#CC=CS(=O)(=O)c1ccccc1

Procedure:
Benzenesulfinic acid sodium salt (9.4 g, 57 mmol) was dissolved in a mixture of water (18.3 mL) and acetic acid (9.1 mL). 2-Chloroprop-2-enenitrile (4.6 mL, 57 mmol) was added, followed by MeOH (18.3 mL). The resulting mixture was allowed to stir for 10 minutes before the solid product was collected by filtration and rinsed with minimal water. The majority of the solid filtered through with the rinse and so all material was rinsed through the filter. The filtrate was extracted with DCM (2×) and the combined organic layers were washed with saturated aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 2-chloro-3-(phenylsulfonyl)propanenitrile as a crude residue. Crude 2-chloro-3-(phenylsulfonyl)propanenitrile (6.1 g, 27 mmol) was dissolved in chloroform (41 mL) cooled in an ice-salt bath and stirred before adding TEA (3.7 mL, 27 mmol) dropwise. The mixture was allowed to stir at 0° C. for 20 minutes. The reaction mixture was then washed sequentially with dilute 1N aqueous HCl, followed by saturate aqueous NaHCO3. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo (23° C. water bath) to afford (2E and 2Z)-3-(phenylsulfonyl)prop-2-enenitrile as a crude residue. The crude residue (4.9 g, 25 mmol) and (buta-1,3-dien-2-yloxy)(trimethyl)silane (4.2 g, 29 mmol) were refluxed together in benzene (63.8 mL) under nitrogen for 16 hours. The reaction mixture was then concentrated in vacuo to afford an oily mixture of the intermediate adducts. The residue was dissolved in aqueous acetic acid (80%) and allowed to stir. After 1 hour at ambient temperature, the mixture was diluted with water and extracted with DCM (2×). The combined organic extracts were concentrated in vacuo and the residue was dissolved in DCM. A solid precipitated from the solution and was collected by filtration to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=4)[CH:14]=[CH:15][C:9]=3[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1.[CH3:29][N:30]([CH2:32][C:33](O)=[O:34])[CH3:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH3:29][N:30]([CH3:31])[CH2:32][C:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([O:25][CH3:26])[CH:17]=4)[CH:14]=[CH:15][C:9]=3[C:8](=[O:27])[NH:7][C:6]=2[CH:28]=1)=[O:34]
Reactant: CN(C)CC(=O)O
Reactant: COc1cc(-c2ccc3c(c2)Nc2ccc(N)cc2NC3=O)ccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(-c2ccc3c(c2)Nc2ccc(NC(=O)CN(C)C)cc2NC3=O)ccc1[N+](=O)[O-]

Procedure:
A mixture of Example 120 (38 mg, 0.10 mmol), dimethylaminoacetic acid (17 mg, 0.12 mmol), HATU (46 mg, 0.12 mmol) and Et3N (0.1 g) in 1 mL of DMF was stirred overnight. The reaction mixture was partitioned between H2O and ethyl acetate, and the organic layer was separated, washed with brine, dried, filtered, and concentrated under vacuum. The residue was purified by preparative HPLC to give the desired product. MS (DCI) m/e 462 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 10.68 (s, 1H), 10.03 (s, 1H), 8.10 (s, 1H), 8.01 (d, J=8.59 Hz, 1H), 7.80 (d, J=8.29 Hz, 1H), 7.53 (d, J=1.23 Hz, 1H), 7.43 (s, 1H), 7.21-7.36 (m, 4H), 7.03 (d, J=8.59 Hz, 1H), 4.11 (s, 2H), 4.03 (s, 3H), 2.86 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[CH:21]=[N:20][N:19]=[C:18]2[CH2:22][N:23]2[C:27](=[O:28])[C:26]3=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]3[C:24]2=[O:33])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8].[Br:34]N1C(=O)CCC1=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[C:18]([CH2:22][N:23]3[C:27](=[O:28])[C:26]4=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]4[C:24]3=[O:33])=[N:19][N:20]=[C:21]2[Br:34])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1ccccc1F)c1cc(Cl)ccc1-n1cnnc1CN1C(=O)c2ccccc2C1=O
Product: O=C(c1ccccc1F)c1cc(Cl)ccc1-n1c(Br)nnc1CN1C(=O)c2ccccc2C1=O

Procedure:
Following the procedure of Example 1, 5-chloro-2-(3-phthalimidomethyl-4H-1,2,4-triazol-4-yl)-2'-fluorobenzophenone is reacted with N-bromosuccinimide to form 5-chloro-2-(3-bromo-5-phthalimidomethyl-4H-1,2,4-triazol-4-yl)-2'-fluorobenzophenone.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:20]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[C:10]([CH:9]([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:29]=[CH:30][C:31]([O:33][CH3:34])=[CH:32][C:19]=1[Cl:18])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(OCCCCCCBr)c(Cl)c1
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(OCCCCCCC(C(=O)c2ccccc2)C(=O)c2ccccc2)c(Cl)c1
Yield: 38.8 %

Procedure:
A mixture of 11.2 g (0.05 m) of dibenzoylmethane, 16.1 g (0.05 m) of 6-(2-chloro-4-methoxyphenoxy)hexyl bromide, 20.6 g (0.15 m) of milled potassium carbonate, 2.0 g of potassium iodide and 250 ml of 2-butanone was heated at reflux for 18 hours. The reaction mixture was filtered hot and concentrated to a brown oil. The latter was stirred with cold ether and seeded with a sample of the desired product having the m.p. 69°-70° C. The solid product thus obtained was collected to afford 9.0 g of 2-benzoyl-8-[2-chloro-4-methoxyphenoxy]-1-phenyl-1-octanone; MIC=3 microg/ml (herpes 2).
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])C.C(O[C:15]([C:17]1[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=1)=[O:16])C>>[CH2:15]([O:16][C:10]1[CH:9]=[CH:8][N:7]=[C:6]([C:4](=[O:5])[CH2:20][C:21](=[O:23])[CH2:22][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH2:24][CH3:25])[CH:20]=[CH:19][N:18]=2)=[O:16])[CH:11]=1)[CH3:17]
Reactant: CCOC(=O)c1cc(OCC)ccn1
Reactant: CCOC(=O)c1ccccn1
Product: CCOc1ccnc(C(=O)CC(=O)CC(=O)c2cc(OCC)ccn2)c1

Procedure:
This compound is prepared in a manner analogous to that described in Example 1, Step 1, for pyridine-2-carboxylic acid ethyl ester, but instead 4-ethoxy-pyridine-2-carboxylic acid ethyl ester from Example 17 is used. The yellowish crude product is used for further syntheses without special purification steps. IR (cm−1): 1557 (vs); 1469 (w); 1436 (w); 1300 (m); 1207 (m); 1186 (m); 1035 (m); 818 (m).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[O:33])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)CCCCSc1ccc(-c2ccc(C(=N)N)cc2)cc1
Solvent: ClCCl
Product: COC(=O)CCCCS(=O)c1ccc(-c2ccc(C(=N)N)cc2)cc1

Procedure:
Prepared from 4-amidino-4'-(4-methoxycarbonyl-butylthio)biphenyl by oxidation with m-chloro-perbenzoic acid in methylene chloride at -20° C. for 15 hours.
Reaction SMILES: [C:1]1([CH:7]([CH3:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]=[CH:11][CH3:12].B(F)(F)F>F>[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:11]([CH3:12])[CH3:10])([CH3:9])[CH3:8]
Reactant: C=CC
Reactant: CC(C)c1ccccc1
Agent: F
Agent: FB(F)F
Product: CC(C)c1ccccc1C(C)C
Reaction time: 0.25 h
Yield: 41 %

Procedure:
12 g. (0.1 mol) cumene is dissolved in 150 ml anhydrous hydrogen fluoride and while keeping the stirred solution at -20° C. to 0° C., 0.05 mol of propylene is introduced and stirring continued for 15 min. The reaction mixture is then saturated with boron trifluoride and stirring continued for another 15 min. After workup, 41% diisopropylbenzene was obtained, comprised of 99.6% of meta and 0.4% para isomer, together with about 15% 1,3,5-triisopropylbenzene, which can be recycled under conditions of Example 6 to produce more meta-diisopropylbenzene.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.I[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1>O1CCCC1.C(OCC)C.[Cl-].[Zn+2].[Cl-]>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: c1cocn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(-c2ncco2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C., stirred solution of oxazole (190 μL, 3.8 mmol) in tetrahydrofuran (10 mL) is added n-butyl lithium (2.6 mL of a 1.6 M solution in hexanes, 4.2 mmol). After 30 min, zinc chloride (11.5 mL of a 1.0 M solution in diethyl ether, 11.5 mmol) is added. The reaction mixture is warmed to 0° C. and methyl 4-iodobenzoate (1 g, 3.8 mmol) and palladium(0)tetrakis(triphenylphosphine) (530 mg, 0.4 mmol) are added. The reaction mixture is heated at 70° C. for 20 h under argon, cooled to room temperature, and then partitioned between ethyl acetate and water. The organic layer is washed with water and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (3:1 hexanes/ethyl acetate) yields the title compound. 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 4H), 8.07-8.05 (m, 1H), 7.36-7.35 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH:17]1([CH2:20][O:21][NH:22][CH3:23])[CH2:19][CH2:18]1>>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:22]([CH3:23])[O:21][CH2:20][CH:17]2[CH2:19][CH2:18]2)[N:3]=1)[CH2:14][CH3:15]
Reactant: CNOCC1CC1
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Product: CCCNc1nc(NCCC)nc(N(C)OCC2CC2)n1
Yield: 99 %

Procedure:
2-Chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) was reacted with O-cyclopropylmethyl-N-methyl-hydroxylamine hydrochloride (XC) as described in Example 13, yielding (XCI) in 99% yield. 400 MHz 1H NMR (DMSO-d6, ppm) 6.91-6.77 (1H, m), 6.75-6.58 (1H, m), 3.77-3.64 (2H, m), 3.21-3.09 (7H, m), 1.54-1.41 (4H, m), 1.11-1.00 (1H, m), 0.88-0.80 (6H, m), 0.56-0.44 (2H, m), 0.32-0.20 (2H, m). ESI-MS (m/z) 295 [M+H]+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]([F:22])([F:21])[C:8]([N:10]1[CH2:13][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH2:11]1)=[O:9]>C(OCC)(=O)C>[F:20][C:16]1[CH:17]=[CH:18][C:19]([S:2]([Cl:1])(=[O:5])=[O:3])=[C:14]([CH:12]2[CH2:11][N:10]([C:8](=[O:9])[C:7]([F:6])([F:21])[F:22])[CH2:13]2)[CH:15]=1
Reactant: O=S(=O)(O)Cl
Reactant: O=C(N1CC(c2cccc(F)c2)C1)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C(N1CC(c2cc(F)ccc2S(=O)(=O)Cl)C1)C(F)(F)F

Procedure:
Chlorosulphonic acid (5 mL) was added to 2,2,2-trifluoro-1-[3-(3-fluorophenyl)azetidin-1-yl]ethanone (Intermediate 90, 1.15 g) with stirring and ice cooling. The mixture was stirred for 1 hour then poured carefully onto a mixture of ice and ethyl acetate. The organic layer was washed with water and concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-20% to give 4-fluoro-2-[1-(2,2,2-trifluoroacetyl)azetidin-3-yl]benzenesulfonyl chloride (0.910 g) as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][CH2:12][CH2:13][N:14]([C:21]([N:23]1[C:27]2[CH:28]=[C:29](OC)[CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[S:34]([CH2:36][C:37]1[C:42]([CH3:43])=[C:41]([O:44][CH3:45])[C:40]([CH3:46])=[CH:39][N:38]=1)=[O:35])=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:10])[CH3:9].[O:47]1CCC[CH2:48]1>>[C:8]([O:11][CH2:12][CH2:13][N:14]([C:21]([N:23]1[C:27]2[CH:28]=[CH:29][C:30]([O:47][CH3:48])=[CH:31][C:26]=2[N:25]=[C:24]1[S:34]([CH2:36][C:37]1[C:42]([CH3:43])=[C:41]([O:44][CH3:45])[C:40]([CH3:46])=[CH:39][N:38]=1)=[O:35])=[O:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)(=[O:10])[CH3:9]
Reactant: COc1ccc2nc(S(=O)Cc3ncc(C)c(OC)c3C)n(C(=O)N(CCOC(C)=O)c3ccccc3)c2c1
Reactant: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)nc(S(=O)Cc1ncc(C)c(OC)c1C)n2C(=O)N(CCOC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of bis(trichloromethyl)carbonate (0.291 g) in tetrahydrofuran (10 mL) was added dropwise a solution of pyridine (0.243 mL) in tetrahydrofuran (1 mL) under ice-cooling. The reaction solution was stirred for 30 minutes under ice-cooling, and 2-anilinoethyl acetate hydrochloride (0.647 g) obtained in Reference Synthetic Example 27 was added thereto. A solution of triethylamine (0.419 mL) in tetrahydrofuran (1 mL) was added dropwise, and stirred at room temperature for 3 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (20 mL), and then extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). To the solution were added 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazole (0.829 g), triethylamine (0.669 mL) and 4-dimethylaminopyridine (0.012 g), and stirred at 60° C. for 14 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (40 mL), and extracted with ethyl acetate (80 mL). The ethyl acetate layer was washed with saturated brine (15 mL), and dried over anhydrous magnesium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=1:2) to give a mixture of 1:1 of title compound and 2-[[[6-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-benzimidazol-1-yl]carbonyl](phenyl)amino]ethyl acetate as colorless amorphous solid (1.10 g).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14](OCC)=[O:15])[N:6]=1.[NH4+:23].CO>O>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][C:5]1[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]2=[C:7]([C:14]([NH2:23])=[O:15])[N:6]=1
Reactant: CCOC(=O)c1nc(Cc2ccccc2F)n2ccccc12
Reactant: [NH4+]
Solvent: CO
Solvent: O
Product: NC(=O)c1nc(Cc2ccccc2F)n2ccccc12

Procedure:
560 mg (1.88 mmol) of ethyl 3-(2-fluorobenzyl)imidazo[1,5-a]pyridine-1-carboxylate from example 7A are heated in 55 ml of 33% strength aqueous ammonium solution in a microwave at 130° C. for 3 h. The mixture is diluted with water, and, after addition of some methanol, extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated. 229 mg (87.5% purity, 40% of theory) of the desired compound are obtained as greenish crystals which are reacted without further purification.