Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10](I)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C@@:20]12[O:28][CH2:27][O:26][N:22]([CH2:23][C@H:24]1[CH3:25])[C:21]2=[O:29].C(=O)([O-])[O-].[K+].[K+].N>CN1CCCC1=O.C(OCC)(=O)C>[CH2:1]([C:8]1[C:13]([O:14][CH2:15][O:16][CH3:17])=[CH:12][CH:11]=[C:10]([N:22]2[CH2:23][C@:24]3([O:26][CH2:27][O:28][C@@:20]3([CH3:19])[C:21]2=[O:29])[CH3:25])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H]1CN2OCO[C@@]1(C)C2=O
Reactant: COCOc1ccc(I)nc1Cc1ccccc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COCOc1ccc(N2C[C@@]3(C)OCO[C@@]3(C)C2=O)nc1Cc1ccccc1
Temperature: 140 °C
Reaction time: 0.33 h
Yield: 54.5 %

Procedure:
3.6 g of 2-benzyl-3-methoxymethyloxy-6-iodopyridine (Production Example 12), 1.5 g of (3R,4R)-3,4-dimethylmethylenedioxy-2-pyrrolidinone synthesized by a method known in literature (J. Org. Chem., 1969, 34, 675), 1.1 g of cuprous iodide and 3.3 g of potassium carbonate were suspended in 20 ml of 1-methyl-2-pyrrolidinone, followed by heating stirring at 140° C. for 20 minutes in an oil bath in a nitrogen atmosphere. After cooling as it was, ethyl acetate and aqueous ammonia were added thereto, and the mixture was extracted with ethyl acetate. The organic phase was further washed with brine, dried over anhydrous sodium sulfate anhydride and the solvent was removed. The residue was subjected to silica gel column chromatography using 20-50% ethyl acetate/hexane as an eluent for separation and purification, to give 2 g of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[C:6]([CH:11]([CH3:13])[CH3:12])=[CH:7][N:8](C)C)C.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=1[NH:25]N.Cl>CCO>[CH3:1][O:3][C:4]([C:5]1[N:25]([C:19]2[C:18]([Cl:17])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:24])[N:8]=[CH:7][C:6]=1[CH:11]([CH3:13])[CH3:12])=[O:15]
Reactant: CCOC(=O)C(=O)C(=CN(C)C)C(C)C
Reactant: NNc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCO
Product: COC(=O)c1c(C(C)C)cnn1-c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 4-methyl-2-oxo-pentanoic acid methyl ester (3.8 g, 26 mmol) in N,N-dimethylformamide dimethyl acetal (7 mL, 52 mmol) is added p-toluenesulfonic acid monohydrate (30 mg) and the mixture is stirred at 80° C. overnight. The reaction mixture is concentrated under reduced pressure to give 3-isopropyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester as an orange oil. To a solution of 3-isopropyl-4-dimethylamino-2-oxo-but-3-enoic acid ethyl ester and 2,6-dichlorophenylhydrazine hydrochloride (2.8 g, 13 mmol) in EtOH (40 mL) is added concentrated HCl (0.5 mL). The mixture is stirred at ambient temperature for 2 h followed by refluxing overnight. The reaction mixture is concentrated and the residue is partitioned between EtOAc and 1N HCl. The organic phase is dried (Na2SO4) and concentrated to a residue. The residue is purified by column chromatography (0-15% EtOAc in hexanes) to give the title compound as an oil (2.2 g, 52%). 1H NMR (CDCl3): δ 7.76 (s, 1H), 7.43 (d, 2H), 7.34 (dd, 1H), 3.75 (s, 3H), 3.48 (m, 1H), 1.32 (d, 6H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[CH:3]=1.[F:24][C:25]([F:30])([F:29])C([O-])=O.[Na+].ClCCl.Cl>CN(C)C(=O)C.O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[S:6][C:2]([C:25]([F:30])([F:29])[F:24])=[CH:3][C:4]=2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=C([O-])C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(-c2cc(Br)sc2-c2ccc(F)cc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C(F)(F)F)sc2-c2ccc(F)cc2)cc1
Yield: 14.8 %

Procedure:
A mixture of 5-bromo-2-(4-fluorophenyl)-3-[4(methylsulfonyl)phenyl]thiophene (7.2 g), sodium trifluoroacetate (9.4 g) and cuprous iodide (6.5 g) in N,N-dimethylacetamide (109 ml), was stirred and refluxed for 5 hours. Dichloromethane (200 ml), 3N hydrochloric acid (100 ml) and water (100 ml) were added to the reaction mixture. The resulting mixture was filtered, and the filtrate was separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated. The residue (13.9 g) was purified by column chromatography on silica gel eluting with a mixture of toluene and ethyl acetate (50:1). The crude product (1.3 g) was recrystallized from ethanol to give pale brown crystal of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)thiophene (1.04 g).
Reaction SMILES: [NH2:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@H:3]1[OH:11].C(N(CC)CC)C.[C:19]([Si:23]([CH3:26])([CH3:25])Cl)([CH3:22])([CH3:21])[CH3:20].O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:19]([Si:23]([CH3:26])([CH3:25])[O:11][C@@H:3]1[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C@H:2]1[NH2:1])([CH3:22])([CH3:21])[CH3:20]
Reactant: N[C@@H]1c2ccccc2C[C@H]1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)O[C@@H]1Cc2ccccc2[C@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(1R,2R)-1-amino-2-indanol (2.00 g) is suspended in 20 mL DCM and combined with triethylamine (3.61 mL) as well as DMAP (0.32 g). Then tert-butyldimethylchlorosilane (4.04 g in 2 mL CH2Cl2) is added. The reaction mixture is stirred for 16 h at RT and, once the reaction is complete, it is mixed with water, extracted with CH2Cl2 and the organic phase is freed from the solvent using the rotary evaporator. The residue is taken up in MeOH and isolate is added. After elimination of the solvent once again the mixture is purified by normal phase chromatography (CH2Cl2/EA). The product-containing fractions are combined and freed from the solvent using the rotary evaporator.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]2[O:12][CH:11]([CH2:13][CH2:14][CH2:15]O)[S:10][C:9]=2[C:17]=1[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[Br:46]Br>C1C=CC=CC=1.O>[Br:46][CH2:15][CH2:14][CH2:13][CH:11]1[S:10][C:9]2[C:17]([CH3:18])=[C:5]([O:4][CH2:3][O:2][CH3:1])[C:6]([CH3:20])=[C:7]([CH3:19])[C:8]=2[O:12]1
Reactant: BrBr
Reactant: COCOc1c(C)c(C)c2c(c1C)SC(CCCO)O2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: COCOc1c(C)c(C)c2c(c1C)SC(CCCBr)O2
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2.6 g of 3-(5-methoxymethoxy-4,6,7-trimethyl-1,3-benzoxathiole-2-yl)propanol (prepared as described in Example 85) and 4.6 g of triphenylphosphine were dissolved in 30 ml of benzene, and 3 ml of dry pyridine were added to the solution. 4.4 g of bromine were then added dropwise at room temperature to this reaction mixture. The temperature rose as the bromine was added, and the mixture was allowed to stand until this temperature rise had finished and the mixture had returned to room temperature. The reaction mixture was then stirred for 40 minutes at room temperature, whereupon crystals formed. Water was added to the reaction mixture, which was then extracted with benzene. The extract was washed with water and then dried over anhydrous sodium sulfate. The benzene was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography. The title compound was obtained from the fraction eluted with a 2:3 by volume mixture of cyclohexane and benzene.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:17](=[O:18])[CH2:16][C:15](=[O:19])[N:14]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:13]2=[O:26])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1C=NC=C([N:33]=[C:34]=[O:35])C=1.C(C1C=CC(CN)=CC=1)(C)(C)C.C(OCC)(=O)[CH2:49][C:50]([O:52]CC)=[O:51].[O-]CC.[Na+]>ClCCl.C(O)C.C(OCC)(=O)C>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:17](=[O:18])[C:16]([C:34]([NH:33][CH2:49][C:50]([OH:52])=[O:51])=[O:35])=[C:15]([OH:19])[N:14]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[C:13]2=[O:26])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: O=C=Nc1cccnc1
Reactant: CC(C)(C)c1ccc(CN2C(=O)CC(=O)N(c3cccnc3)C2=O)cc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC(C)(C)c1ccc(CN)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)c1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(-c3cccnc3)c2=O)cc1
Reaction time: 8 h
Yield: 19 %

Procedure:
1-{[4-(1,1-Dimethylethyl)phenyl]methyl}-3-(3-pyridinyl)-2,4,6(1H,3H,5H)-pyrimidinetrione. A mixture of pyridine 3-isocyanate (622 mg, 5.18 mmoles) and 4-t-butylbenzylamine (912 uL, 5.18 mmoles) in dichloromethane (50 mL) was stirred overnight. The urea was purified by flash chromatography (ethyl acetate), taken up in methoxyethanol (10 mL), treated with diethyl malonate (1.0 mL, 6.58 mmoles) and sodium ethoxide (1.0 mL of a 21 molar solution in ethanol) and heated under reflux for 24 hours in an inert atmosphere. The mixture was cooled, diluted with ethyl acetate and washed with brine. The organic solution was evaporated and purified by flash chromatography (10-100% ethyl acetate in hexane) to give the title compound (340 mg, 19%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.62 (dd, J=4.80, 1.52 Hz, 1 H), 8.48 (d, J=2.02 Hz, 1 H), 7.75 (d, J=8.08 Hz, 1 H), 7.57 (dd, J=8.21, 4.93 Hz, 1 H), 7.29-7.36 (m, 4 H), 3.55 (s, 2 H), 1.26 (s, 9 H).
Reaction SMILES: [CH2:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[H-].[Na+].[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[C:21](Cl)=[O:22])([CH3:19])[CH3:18]>O1CCCC1.C(OCC)(=O)C>[CH:17]([N:20]([CH:24]([CH3:26])[CH3:25])[C:21](=[O:22])[O:14][C:11]1[CH:12]=[C:13]2[C:8]([CH2:7][CH2:6][CH2:5][N:4]2[CH2:1][C:2]#[CH:3])=[CH:9][CH:10]=1)([CH3:19])[CH3:18]
Reactant: CC(C)N(C(=O)Cl)C(C)C
Reactant: C#CCN1CCCc2ccc(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#CCN1CCCc2ccc(OC(=O)N(C(C)C)C(C)C)cc21
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
A solution of 1-(prop-2-ynyl)-1,2,3,4-tetrahydroquinolin-7-ol (400 mg, 2.14 mM) in dry tetrahydrofuran (THF; 5 mL) was added to the stirred solution of sodium hydride in dry THF at −10° C. during 5 minutes under nitrogen environment at room temperature (25° C.). The reaction, mixture was stirred for 30 minutes. Then, N,N-diisopropyl carbamoyl chloride (510 mg) was added to the stirring reaction mixture. The mixture was stirred further for 7 hours during which the temperature was allowed to reach the room temperature (35° C.). The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford 10h as semisolid. Yield: 72.6%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12](O)=[O:13]>O>[Cl:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][S:9][C:3]=2[CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CBr
Reactant: Nc1c(S)cccc1Cl
Solvent: O
Product: O=C1CSc2cccc(Cl)c2N1
Temperature: 70 °C
Reaction time: 3 h
Yield: 78.3 %

Procedure:
The zine salt (2.0 g) of 2-amino-3-chlorothiophenol was suspended in water (30 ml), and bromoacetic acid (1.6 g) was added thereto, followed by stirring at 70° C. for 3 hours. The precipitated crystals were filtered, washed with water and dried to obtain 1.8 g of the objective 5-chloro-2,3-dihydro-1,4-benzothiazine-3-one (m.p. 160°-161° C.).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[Br:11][C:12]1[C:13]([F:20])=[CH:14][C:15]([Cl:19])=[C:16]([OH:18])[CH:17]=1.O>CN(C)C=O>[CH2:9]([O:18][C:16]1[CH:17]=[C:12]([Br:11])[C:13]([F:20])=[CH:14][C:15]=1[Cl:19])[CH:8]=[CH2:7]
Reactant: Oc1cc(Br)c(F)cc1Cl
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1cc(Br)c(F)cc1Cl
Reaction time: 1 h

Procedure:
96.5 g (0.7 mol) of potassium carbonate and 54.9 g (0.45 mol) of allylbromide were added to a solution of 78.7 g (0.35 mol) of 5-bromo-2-chloro-4-fluorophenol in 350 ml of dimethylformamide. The reaction mixture was subsequently stirred for 1 hour and stirred into 2.5 l of water. The mixture was then extracted with dichloromethane (three times). The combined organic phases were washed with water (three times) and saturated aqueous sodium chloride solution (once), dried over magnesium sulfate and finally concentrated. The crude product was purified by distillation. Bp.: 106° C. (0.8 mbar); Yield: 85 g.
Reaction SMILES: [NH2:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:13])[C:6]=2[CH:5]=[C:4]([F:14])[CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.Cl[C:31]1[N:36]=[C:35]([NH:37][C@@H:38]2[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]2[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])[C:34]([Cl:49])=[CH:33][N:32]=1.C(=O)([O-])[O-]>COCCO.C(Cl)Cl.CO>[Cl:49][C:34]1[C:35]([NH:37][C@@H:38]2[CH2:43][CH2:42][CH2:41][CH2:40][C@H:39]2[NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[N:36][C:31]([NH:1][C:2]2[C:12]3[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:13])[C:6]=3[CH:5]=[C:4]([F:14])[CH:3]=2)=[N:32][CH:33]=1
Reactant: Nc1cc(F)cc2c1OCCNC2=O
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCO
Solvent: CO
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2cc(F)cc3c2OCCNC3=O)ncc1Cl
Temperature: 25 °C
Yield: 46.1 %

Procedure:
9-Amino-7-fluoro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (59 mg, 0.30 mmol), 10-Camphorsulfonic acid (11 mg, 0.047 mmol) and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (0.104 g, 0.306 mmol) in 2-Methoxyethanol (5 mL) were heated at 110° C. under an atmosphere of Nitrogen for 2 days. The mixture was cooled to r.t., neutralized with 100 mg MP-Carbonate and conc. in vacuo. The residue was partially taken up in DCM/MeOH, and the remainder was powdered onto Celite, then chromatographed (2×12 g silica gel, ISCO, 0-100% EtOAc:hexane, then 10% MeOH) to afford N-{(1R,2R)-2-[5-Chloro-2-(7-fluoro-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-9-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as a beige solid (69 mg, 46%). MP=177-181° C.; LCMS: 499 (M+H); 1H-NMR (CDCl3): 8.27 (dd, 1H, J=2.6, 10.9 Hz), 7.98 (1H, s), 7.62 (s, 1H), 7.03 (dd, 1H, J=2.9, 8.6 Hz), 6.95 (m, 1H), 6.85 (m, 1H), 6.02 (d, 1H, J=7.0 Hz), 4.21 (m, 1H), 4.15 (m, 1H), 3.82 (m, 1H), 3.32 (m, 3H), 2.98 (s, 3H), 2.33 (m, 1H), 2.18 (m, 1H), 1.87 (m, 1H), 1.78 (m, 1H), 1.64 (m, 1H), 1.41 (m, 2H), 1.22 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=1.[CH3:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1.C(OCC)C>[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:15])[CH2:9][NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[CH:4][CH:3]=2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: CC(CNS(C)(=O)=O)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(-c2ccc(C(C)CNS(C)(=O)=O)cc2)cc1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
To a degassed solution of 1.4 g (4.7 mmol) of the product of Example 1, 1.0 g (7.1 mmol) of 4-methylbenzene-boronic acid, 1.0 g (7.1 mmol) of potassium carbonate in 30 mL of toluene, and 10 mL of water was added 0.3 g (0.2 mmol) of tetrakis (triphenylphosphine)palladium(0). The mixture was heated to 100° C. for 2 hr, cooled to ambient temperature and the organic portion was separated. The aqueous portion was extracted three times with ethyl acetate and the combined organic portions were dried (MgSO4), filtered and concentrated in vacuo. The residue was chromatographed on silica gel (30% ethyl acetate/hexane) to afford an off-white solid. The solid was suspended in diethyl ether, filtered and dried in vacuo to afford 0.6 g (43%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12]([C:13]2([CH3:17])[CH3:16])=[CH:11][C:10](=[O:18])[CH:9]=[CH:8]3)=[CH:4][CH:3]=1.[S:19]([NH:29][C@H:30]([C:32](Cl)=[O:33])[CH3:31])([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20].N1C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[S:19]([NH:29][C@H:30]([C:32]([O:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12]([C:13]2([CH3:16])[CH3:17])=[CH:11][C:10](=[O:18])[CH:9]=[CH:8]3)=[CH:4][CH:3]=1)=[O:33])[CH3:31])([C:22]1[CH:23]=[CH:24][C:25]([CH3:26])=[CH:27][CH:28]=1)(=[O:20])=[O:21]
Reactant: CC1(C)C2=CC(=O)C=CC2=Nc2ccc(O)cc21
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Oc2ccc3c(c2)C(C)(C)C2=CC(=O)C=CC2=N3)cc1
Temperature: 25 °C

Procedure:
A solution of the dimethyl chromogen (20) prepared according to Example 2 (38 mg; 0.16 mmol) in anhydrous tetrahydrofuran (3.2 mL) was stirred at ambient temperature and treated portionwise, over 1.5 hours, with N-tosyl-L-alaninyl chloride (35) from step (a) of the present example (243 mg; 0.93 mmol) and anhydrous pyridine (280 μL) while maintaining an inert gas atmosphere over the reaction. Once the addition was complete, the reaction was stirred for an additional hour then blended into ethyl acetate (50 mL) and then extracted twice with aqueous 1 N citric acid (10 mL @). The combined aqueous extracts were washed once with ethyl acetate (10 mL) and the combined ethyl acetate layers were extracted thrice with 5% aqueous NaHCO3 (10 mL each). The combined NaHCO3 extracts were washed once with ethyl acetate (10 mL) then the combined ethyl acetate layers were washed once with brine (20 mL), dried over Na2SO4, filtered and evaporated to dryness in vacuo to give an orange viscous oil (110 mg). This was chromatographed on silica gel (50 g) using acetone/CHCl3 (9) solvent. The yellow major product band (Rf =0.32) was collected and evaporated to dryness in vacuo to obtain 7-(N-tosyl-L-alaninyloxy)-9,9-dimethyl-9H-acridin-2-one (36) (40 mg; 54%) in the form of a yellow glass.
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6].[H-].[Na+].Cl[C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1.O>O1CCCC1>[CH2:1]([O:7][C:11]1[C:15]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][S:13][N:12]=1)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH3:6]
Reactant: CCC/C=C/CO
Reactant: Clc1nsnc1-c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC/C=C/COc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-2-hexen-1-ol (900 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:12]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl.O>[NH:1]([C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[NH2:12]
Reactant: COC(=O)c1ccccc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccccc1NN
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
A 100-mL round-bottom flask was a solution of methyl 2-aminobenzoate (1 g, 6.62 mmol, 1.00 equiv) in HCl (30%, 10 mL). To this solution was added a solution of NaNO2 (500 mg, 7.25 mmol, 1.02 equiv) in H2O (10 mL) dropwise at 0° C. over 5 minutes. The resulting mixture was stirred at 0° C. for 30 minutes. Then, a solution of SnCl2.2H2O (2.75 g, 12.19 mmol, 2.00 equiv) in HCl (30%) (12 mL) was added dropwise at 0° C. The resulting solution was stirred for an additional 2 hours at room temperature. The solids were collected by filtration and washed with H2O (2×20 mL) affording methyl 2-hydrazinylbenzoate as white solid (0.6 g, 55%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]#N)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].S(=O)(=O)(O)[OH:21]>>[F:14][C:15]([F:19])([F:18])[CH2:16][O:17][C:12](=[O:21])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1
Reactant: CC(C)Cc1ccc(CC#N)cc1
Reactant: O=S(=O)(O)O
Reactant: OCC(F)(F)F
Product: CC(C)Cc1ccc(CC(=O)OCC(F)(F)F)cc1
Temperature: 0 °C
Yield: 51.1 %

Procedure:
A mixture of 1.73 g of 4-isobutylphenylacetonitrile and 10 g of 95% of 2,2,2-trifluoroethanol and 10 g of concentrated sulfuric acid were refluxed for 12 hours. After the reaction was complete, ice-water was added to the mixture. The resulting mixture was extracted with ether. The ether layer separated was dehydrated and concentrated to leave an oily residue. The residue was distilled in vacuo to give 1.4 g of 4-isobutylphenylacetic acid-2,2,2-trifluoroethyl ester as a pale yellow oil, boiling at 77°-79° C./1 mmHg. Analysis-Calculated for C14H17F3O2 : C, 61.30; H, 6.25. Found: C, 61.21; H, 6.23.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]2[CH:9]=[C:10]([CH2:12]Cl)[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:2][C:3]1[N:8]2[CH:9]=[C:10]([CH2:12][O:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=3)[N:11]=[C:7]2[CH:6]=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClCc1cn2c(Cl)cccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2cn3c(Cl)cccc3n2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98 %

Procedure:
A mixture of 5-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine hydrochloride (3.00 g), 4-hydroxybenzaldehyde (1.81 g), potassium carbonate (6.14 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 4-(5-chloroimidazo[1,2-a]pyridin-2-ylmethoxy)benzaldehyde (3.55 g, yield 98%) as colorless crystals. m.p. 126-130° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH2:42]([NH:46][CH3:47])[CH:43]([CH3:45])[CH3:44]>C(Cl)Cl.CN(C=O)C>[CH2:42]([N:46]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:34])[F:35])[C:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1)[CH3:47])[CH:43]([CH3:45])[CH3:44]
Reactant: CNCC(C)C
Reactant: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)CN(C)Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 286) (255 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with isobutyl-methyl-amine in DMF according to the general procedure of Example 288. Obtained as a light brown solid (199 mg, 69%).