Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[C:15]([NH2:20])[C:16]([O:18][CH3:19])=[CH:17][C:10]=2[CH2:9][CH2:8]1)(=[O:4])=[O:3].Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:42][CH3:43])[C:25]([Cl:44])=[CH:24][N:23]=1>>[Cl:44][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:42][CH3:43])=[N:27][C:22]([NH:20][C:15]2[C:16]([O:18][CH3:19])=[CH:17][C:10]3[CH2:9][CH2:8][N:7]([CH2:6][CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:13][CH2:12][C:11]=3[CH:14]=2)=[N:23][CH:24]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc2c(cc1N)CCN(CCS(C)(=O)=O)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C)CC4)cc3OC)n1)CCN(CCS(C)(=O)=O)CC2

Procedure:
The title compound was prepared from 3-(2-Methanesulfonyl-ethyl)-8-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and (2,5-Dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in an analogous manner to Example 61e. Product isolated as an off-white solid (0.052 g, 61%). MP: 138-145° C. 1H NMR (400, MHz, CDCl3, δ, ppm): 8.18 (d, 1H, J=8.6 Hz), 8.11 (s, 1H), 8.01 (d, 1H, J=1.0 Hz), 7.48 (br s, 1H), 7.43 (br s, 1H), 6.62 (s, 1H), 6.58-6.56 (m, 1H), 6.54-6.50 (m, 1H), 3.91 (s, 3H), 3.86 (s, 3H), 3.23-3.13 (m, 6H), 3.07 (s, 3H), 3.01 (t, 3H, J=6.2 Hz), 2.88-2.83 (m, 2H), 2.81-2.77 (m, 2H), 2.71-2.64 (m, 2H), 2.64-2.58 (m, 4H), 2.38 (s, 3H). MS: 630 (MH)+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.Cl.[O:15]1[CH2:20][CH2:19][CH2:18][C@H:17]([NH2:21])[CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:21][C@H:17]2[CH2:18][CH2:19][CH2:20][O:15][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N[C@H]1CCCOC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CCCOC1
Temperature: 60 °C
Yield: 38.4 %

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.060 g, 0.28 mmol), (3S)-tetrahydro-2H-pyran-3-amine hydrochloride (from J&W Pharmatech, 0.059 g, 0.43 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.84 mmol) in isopropyl alcohol (0.95 mL) was heated at 60° C. overnight. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 50% ethyl acetate (EtOAc) in hexanes) to give the desired product (30 mg, 38%). LCMS calculated for C12H14N3O3S (M+H)+: m/z=280.1. Found: 280.0.
Reaction SMILES: [OH:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[C:25]([Si:22]([CH3:24])([CH3:23])[O:1][CH:2]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[CH2:3][CH2:4][CH:5]1[NH:9][C:8](=[O:10])[CH2:7][CH2:6]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: O=C1CCC(CCC(O)Cc2cccc(C(F)(F)F)c2)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)OC(CCC1CCC(=O)N1)Cc1cccc(C(F)(F)F)c1

Procedure:
Analogous to the procedure described for Compound 1A, Step C, 5-[3-hydroxy-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one (1.19 g, 3.95 mmol) was protected with tert-butyidimethylsilyl chloride (893 mg, 6.22 mmol). Purification by medium pressure chromatography eluting with EtOAc provided 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-(3-trifluoromethyl-phenyl)-butyl]-pyrrolidin-2-one. 1H NMR (CDCl3) δ7.47-7.32 (m, 4H), 5.73 (m, 1H), 3.86 (m, 1H), 3.59 (m, 1H), 2.75 (m, 2H), 2.35-2.20 (m, 3H), 1.70-1.40 (m, 5H), 0.81 (s, 9H), −0.05 (d, 3H), −0.3 (d, 3H); MS 416.1 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH:11]([C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH2:13])[CH:10]([CH:18]([O:20]C(OCC2C=CC=CC=2)=O)[CH3:19])[C:9]1=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.N1C=CN=C1.[Si:42](Cl)([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43]>CO.[Pd]>[CH2:1]([N:8]1[CH:11]([CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])[CH:10]([CH:18]([O:20][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH3:19])[C:9]1=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C(=O)OC)C1C(C(C)OC(=O)OCc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Pd]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)C(C)C1C(C(C)O[Si](C)(C)C(C)(C)C)C(=O)N1Cc1ccccc1
Temperature: 0 °C
Yield: 77.5 %

Procedure:
To a solution of 28 mg (0.07 mmol) of 1-benzyl-3-(1-benzyloxycarbonyloxyethyl)-4-(1-methoxycarbonylethenyl)-2-azetidinone dissolved in 2 ml of methanol, 5 mg of 5% palladium charcoal was added and the mixture was stirred under hydrogen atmosphere for a night. The reaction solution was filtered with selite and the filtrate was washed with ethyl acetate and concentrated. To the concentrate were added 1 ml of DMF, 20 mg (0.3 mmol) of imidazole and 45 mg (0.3 mmol) of t-butyldimethylsilylchloride and the mixture was stirred for a night. Ice water was added to the reaction solution and the resultant was extracted with ether, washed with a saturated solution of NaCl, dried with magnesium sulfate, concentrated and purified with 2 g of silica-gel column (hexane:ether 1:1) to give 22 mg of 1-benzyl-4-(1-methoxycarbonylethyl)-3-(1-t-butyldimethylsilyloxyethyl)-2-azetidinone (yield: 84%). Comparison with the NMR data showed α:β=1:1.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([O:19][CH3:20])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][CH2:17]Br)=[CH:9][CH:8]=1)C.[F:22][C:23]1[CH:37]=[CH:36][CH:35]=[CH:34][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)=[O:26]>>[F:22][C:23]1[CH:37]=[CH:36][CH:35]=[CH:34][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:19][CH3:20])[C:4]([OH:3])=[O:21])=[CH:12][CH:11]=2)=[CH:29][CH:28]=1)=[O:26]
Reactant: CCOC(=O)C(Cc1ccc(C#CCCCBr)cc1)OC
Reactant: O=C(c1ccc(O)cc1)c1ccccc1F
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(=O)c3ccccc3F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from 3-[4-(5-Bromo-pent-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 24, Step A and 2-fluoro-4′-hydroxybenzophenone in a manner analogous to that described for Example 24, Step B. MS(ES) for C28H25FO5[M+H]+:461.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=O)[CH2:20]Br.C(=O)(O)[O-].[Na+].O>C(O)C>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:1]=[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[CH:4][N:3]2[CH:20]=1
Reactant: Cc1ccccc1C(=O)CBr
Reactant: Nc1nccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccccc1-c1cn2ccc3ccccc3c2n1
Yield: 81.9 %

Procedure:
A mixture of 3.0 g of 1-aminoisoquinoline, 6.7 g of 2'-methyl-2-bromoacetophenone and 17.5 g of sodium bicarbonate in 50 ml of ethanol was refluxed for 2 hours. After being cooled, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel and recrystallized from dichloromethane/petroleum ether to give 4.4 g of the title compound as pale brown prisms.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=[N:30][N:29]=3)=[CH:18][CH:17]=2)[C:13](=[O:52])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:53]([O-])=O)[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]>CCOC(C)=O.[Pd]>[NH2:53][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:14]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[N:32]([C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)[N:31]=[N:30][N:29]=3)=[CH:20][CH:21]=1)[C:13]2=[O:52]
Reactant: CCCCc1nc2ccc([N+](=O)[O-])cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCc1nc2ccc(N)cc2c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 98.3 %

Procedure:
A solution of 3.2 g (4.4 mmol) of 2-n-Butyl-3-[(2'-(N-triphenylmethyl-tetrazol-5-yl)-biphen-4-yl)-methyl]-6-nitro quinazolin-4(3H)-one in 100 mL of EtOAc was hydrogenated over night under atmospheric pressure in the presence of 0.5 g of 10% Pd/C. The solution was filtered through celite and the celite was washed with CH2Cl2 to remove any of the yellow coloured product. The filtrate was concentrated in vacuo to give 3.0 g of a pale yellow solid. The material was not purified further. 98% yield. 1H-NMR (CDCl3 -300 MHz): 0.89 (t, 3H, J=7.3 Hz), 1.32 (m, 2H), 1.69 (m, 2H), 2.62 (3 line m, 2H, J=7.9 Hz), 4.00 (bs, 2H), 5.29 (bs, 2H), 6.88-7.02 (m, 6H), 7.08-7.15 (m, 4H), 7.22-7.38 (m, 11H), 7.45-7.55 (m, 4H), 7.93 (dd, 1H, J=2.5, 7.0 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:11]([O-])=O)=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[H][H]>CCO.[Pd]>[NH2:1][C:2]1[C:3]([NH2:11])=[CH:4][C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: [H][H]
Reactant: Nc1cc2c(cc1[N+](=O)[O-])OCC2
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2c(cc1N)OCC2

Procedure:
The product obtained in Step 5 (2.5 g, 13.9 mmol) and Pd/C (0.5 g) were dissolved in EtOH (50 mL), hydrogenated in a Parr hydrogenation apparatus at room temperature and a hydrogen pressure of 50 PSI for 12 h. The catalyst was removed by filtration, the ethanol solution of the product was directly used in the next step of reaction.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:15]([CH3:17])[CH3:16])[C:5]=1[CH2:6][Cl:7])([CH3:3])[CH3:2].[Br:18]Br>[Fe].C(Cl)(Cl)(Cl)Cl>[Br:18][C:9]1[C:8]([CH:15]([CH3:17])[CH3:16])=[C:5]([C:4]([CH:1]([CH3:3])[CH3:2])=[CH:11][C:10]=1[CH:12]([CH3:14])[CH3:13])[CH2:6][Cl:7]
Reactant: BrBr
Reactant: CC(C)c1cc(C(C)C)c(CCl)c(C(C)C)c1
Agent: [Fe]
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)c1cc(C(C)C)c(CCl)c(C(C)C)c1Br

Procedure:
To a solution of 25 parts of 2,4,6-triisopropylbenzyl chloride (Organic Reactions, Vol. I, p. 68) in 150 parts of carbon tetrachloride is added 1 part of iron powder. The mixture is cooled and maintained at 15°-20°C, and then a solution of 16 parts bromine in 15 parts carbon tetrachloride is added dropwise during two hours. The resulting solution is washed with dilute sodium bicarbonate solution and water. It is dried with magnesium sulfate and stripped of solvent in vacuo giving 3-bromo-2,4,6-triisopropylbenzyl chloride, b.p. 111°C. (0.05 mm.)
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH3:12]>>[C:1]1(=[O:6])[NH:12][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: N
Reactant: O=C1OC(=O)c2ccccc21
Product: O=C1NC(=O)c2ccccc21

Procedure:
1.2-Benzoisothiazole-3-on-1.1-dioxide has also been produced by the reaction sequence shown in Reaction scheme (2), in which: (1) phthalic anhydride is reacted with ammonia; (2) phthalimide produced in the first step is subjected to the Hoffmann reaction; (3) o-aminobenzoic acid produced in the second step is diazotized; (4) sodium sulfide is reacted with the diazobenzoic acid produced in the third step; (5) sodium dithiodibenzoate produced in the fourth step is treated with an acid; (6) dithiodibenzoic acid produced in the fifth step is methyl esterified; (7) dimethyl dithiodibenzoate produced in the sixth step is reacted with chlorine; and (8) methyl o-sulfochlorobenzoate produced in the seventh step is reacted with ammonia. (Chemical Engineering, Vol. 61, No. 7, page 128, 1954). ##STR5##
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:10]([O:12][CH2:13][CH3:14])=[CH2:11].Cl.C([O-])([O-])=O.[Na+].[Na+]>C(OCC)(=O)C>[CH2:10]([O:12][CH2:13][CH2:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH3:11]
Reactant: C=COCC
Reactant: O=Cc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
After dissolving 24.4 g (0.2 mole) of 4-hydroxy benzaldehyde in 200 ml of ethyl acetate, 21.6 g (0.3 mole) of ethyl vinyl ether and 0.2 ml (2 millimole) of hydrochloric acid were added, and the mixture was stirred overnight at room temperature. Then, after adding Na2CO3 aqueous solution to neutralize, the mixture was separated and the upper layer was washed with water until pH thereof reached 7. After adding MgSO4 to dry, the mixture was filtered, concentrated and dried, and distilled under reduced pressure to obtain EEBA (100–105° C./0.4 mmHg). Amount obtained was 20 g (yield was 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:19](=O)[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:10]=3[NH:11][N:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:24].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][N:11]([CH3:24])[C:10]3=[C:13]4[C:18](=[CH:19][C:9]=23)[CH:17]=[CH:16][CH:15]=[CH:14]4)=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C1c2ccccc2-c2[nH]nc(-c3ccc(Cl)cc3)c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1[nH]c(-c2ccc(Cl)cc2)c2cc3ccccc3c1-2
Reaction time: 0.5 h

Procedure:
3-(4-Chlorophenyl)indeno[1,2-c]pyrazol-4(1H)-one (0.68 g) was dissolved in N,N-dimethylformamide (30 ml) under nitrogen at 20° C. Sodium hydride (106 mg, of a 60% dispersion in mineral oil) was added and the mixture was stirred for 30 minutes, then iodomethane (0.38 g) was added. The mixture was stirred at 20° C. for 2 hours and then poured into water (50 ml). A yellow solid was collected by filtration and washed with petroleum ether (25 ml). The solid was dissolved in hot ethyl acetate and pre-absorbed onto silica which was applied to the top of the silica column. The mixture was separated by flash column chromatography using dichloromethane/petroleum ether/methanol (50:50:1). Fractions were collected, combined as appropriate, and evaporated to give a solid which was crystallised from ethyl acetate to give 3-(4-chlorophenyl)-1-methylindeno [1,2-c]pyrazol-4(1H-one, m.p. 219-221° C. δH[2H6] DMSO (250 MHz) 4.07 (3H, s, NMe), 7.41 (1H, t, Ar), 7.55 (4H, m, Ar), 7.65 (1H, d, Ar-8-H), 8.13 (2H, d, Ar). The structure was identified by the presence of a Nuclear Overhauser Effect.
Reaction SMILES: [CH:1]1([CH:8](O)[CH:9]2[C:13](=[O:14])[C:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])=[C:11]([O:24]C)[CH2:10]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>CC(C)=O.O>[CH:1]1([CH:8]=[C:9]2[CH2:10][C:11](=[O:24])[CH:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:13]2=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCCCCC2)C1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C)c(C2C(=O)CC(=CC3CCCCCC3)C2=O)c(C)c1
Yield: 96.9 %

Procedure:
To a solution of 5-(Cycloheptyl-hydroxy-methyl)-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (100 mg, 0.28 mmol) in acetone (4 ml) in a 10 ml vial was added 2M HCl (4 ml). The reaction was capped and heated to 120 C for 30 minutes under microwave irradiation. The reaction was diluted with H2O (20 ml) and extracted with EtOAc (3×15 ml). The combined organic extracts were washed with brine (10 ml), dried over MgSO4, filtered and evaporated to dryness under reduced pressure to give a brown oil (88 mg). The crude material was purified by flash chromatography over SiO2 using a 100% isohexane to 100% EtOAc gradient to give the desired product as a colourless oil (62 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].ClC1C=CC=CC=1.[Br:19]N1C(=O)CCC1=O>C1(C)C=CC=CC=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:19][CH2:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:11])[CH3:10])=[C:2]([Cl:1])[CH:7]=1
Reactant: CC(=O)c1ccc(C)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: Clc1ccccc1
Product: CC(=O)c1ccc(CBr)cc1Cl
Temperature: 142.5 °C
Yield: 70 %

Procedure:
A mixture of 1-(2-chloro-4-methylphenyl)ethanone (1.6 g, 9.50 mmol) (preparation 15) and chlorobenzene (60 ml) was prepared at room temperature and N-bromosuccinimide (NBS) (1.86 g, 10.44 mmol) added followed by a catalytic amount of benzoyl peroxide (ca. 1.5 mg, 0.005 mmol), and the resulting mixture was heated to 140-145° C. for 16 h. The mixture was then allowed to cool to room temperature, diluted with toluene (50 ml) and filtered through a celite pad. The pad was washed with toluene (2×50 ml) and the filtrate concentrated under reduced pressure and purified by column chromatography (0-10% EtOAc/Hexanes) to afford 1-(4-(bromomethyl)-2-chlorophenyl)ethanone (1.65 g, 6.65 mmol, 70%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][O:7][CH2:8][C:9]2[N:14]=[C:13]([NH2:15])[CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:15][C:13]2[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][O:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)[N:14]=2)(=[O:26])=[O:27])=[CH:21][C:20]=1[C:29]([F:32])([F:30])[F:31]
Reactant: Nc1cccc(COCc2ccc(F)cc2)n1
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Product: O=S(=O)(Nc1cccc(COCc2ccc(F)cc2)n1)c1ccc(F)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(4-fluoro-benzyloxymethyl)-pyridin-2-ylamine (0.07 g) and 4-fluoro-3-(trifluoromethyl)-benzenesulfonyl chloride (0.087 g) as alight yellow gum (0.11 g). MS (ESI−): 457.2 ([M−H]−).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4]([S:17]([CH3:19])=O)[N:3]=1.SC[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[C:5]([C:15]#[N:16])=[C:4]([S:17][CH2:19][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccccc2F)c1C#N
Reactant: SCCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(SCCc2ccccn2)nc(N)nc1-c1ccccc1F

Procedure:
From 2-amino-4-(2-fluoro-phenyl)-6-methanesulfinyl-pyrimidine-5-carbonitrile, 2-mercaptoethylpyridine and DBU in DME. ES-MS m/e (%): 352 (M+H+, 100).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([O:10][CH3:11])=[O:9])([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1Oc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 150 °C

Procedure:
A mixture of methyl salicylate (15.2 g, 0.1 mol), 4-chloro-3-nitrobenzotrifluoride (22.6 g, 0.1 mol), and potassium carbonate (8.3 g, 0.06 mol) in dimethylformamide (100 mL) was stirred under argon and heated in an oil bath to 150° C. for 70 min. The reaction mixture was diluted with ethyl acetate (300 mL), filtered, and the residue washed with ethyl acetate. The combined filtrates were evaporated, and the crude product was purified by flash chromatography (silica gel, ethyl acetate/hexane) to give the title compound as a pale yellow solid; mp 69°-70° C.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]1[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=1>>[CH3:6][N:7]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][N:9]=[C:8]1[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23](=[O:2])[NH2:24])[CH:18]=1
Reactant: O=S(=O)(O)O
Reactant: Cn1c([N+](=O)[O-])cnc1C=Cc1cccc(C#N)c1
Product: Cn1c([N+](=O)[O-])cnc1C=Cc1cccc(C(N)=O)c1
Temperature: 0 °C

Procedure:
To 5 ml. of cold 90% sulfuric acid was added 1 g. (0.004 mole) of 1-methyl-5-nitro-2-[2-(3-cyanophenyl)vinyl]imidazole, and the resulting solution was warmed on a steam bath for five minutes and then poured into ice water. The solid which separated was collected by filtration, washed with water, dried and recrystallized from ethanol to give 1-methyl-5-nitro-2-[2-(3-carbamylphenyl)vinyl]imidazole, m.p. 254°-256° C.
Reaction SMILES: [CH:1]12[N:9]([C:10]3[C:29](Br)=[CH:28][C:13]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=4)=[O:15])=[CH:12][N:11]=3)[CH:5]([CH2:6][O:7][CH2:8]1)[CH2:4][O:3][CH2:2]2.[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[CH:1]12[N:9]([C:10]3[C:29]([C:35]4[CH:36]=[N:31][CH:32]=[N:33][CH:34]=4)=[CH:28][C:13]([C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=4)=[O:15])=[CH:12][N:11]=3)[CH:5]([CH2:6][O:7][CH2:8]1)[CH2:4][O:3][CH2:2]2
Reactant: OB(O)c1cncnc1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C3COCC2COC3)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2C3COCC2COC3)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 133 using 6-(3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl)-5-bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 150.1) and pyrimidin-5-ylboronic acid to afford a solid. HPLC (Condition 4) tR=5.08 min, UPLC-MS (Condition 3) tR=1.00 min, m/z=488.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=2[O:5][C:4]([CH2:17][CH3:18])([CH2:15][CH3:16])[N:3]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O>>[CH2:15]([C:4]1([CH2:17][CH3:18])[N:3]=[C:2]([C:23]2[CH:22]=[CH:21][C:20]([F:19])=[CH:25][C:24]=2[F:26])[C:7]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=2[O:5]1)[CH3:16]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CCC1(CC)N=C(Cl)c2ccc([N+](=O)[O-])cc2O1
Product: CCC1(CC)N=C(c2ccc(F)cc2F)c2ccc([N+](=O)[O-])cc2O1

Procedure:
The compound obtained in (3) described above (1.0 g) and 2,4-difluorophenylboronic acid (1.2 g) were treated in the same manner as Reference Example 39(2) to give the titled compound (0.6 g) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][C:27]([CH3:32])([CH2:30][NH2:31])[CH2:28][NH2:29]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:29][CH2:28][C:27]([CH3:32])([CH3:26])[CH2:30][NH2:31])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CC(C)(CN)CN
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(C)(C)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 9-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 2,2-dimethylpropane-1,3-diamine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 8.07 (d, J=1.2 Hz, 1 H), 7.99 (s, 1 H), 7.88 (d, J=7.2 Hz, 1 H), 7.73-7.70 (m, 2 H), 7.61-7.57 (m, 2 H), 6.07 (s, 1 H), 5.31 (s, 2 H), 4.50 (s, 2 H), 3.73 (s, 2 H), 3.49 (s, 2 H), 2.99 (s, 2 H), 2.47 (s, 3 H), 1.10 (s, 6 H).