Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([NH:31][C@@H:32]2[C@@H:37]3[CH2:38][C@@H:34]([CH:35]=[CH:36]3)[C@@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21](CN4CCOCC4)=[CH:20][CH:19]=3)[NH:15][C:12]2=[N:13][CH:14]=1.NC1C(N)=C(N[C@H]2[C@H]3C[C@H](C=C3)[C@H]2C(N)=O)C(Cl)=CN=1.[CH3:62][N:63]1[CH2:68][CH2:67][N:66](C2C=CC(C=O)=CC=2)[CH2:65][CH2:64]1>>[Cl:8][C:9]1[C:10]([NH:31][C@H:32]2[C@H:37]3[CH2:38][C@H:34]([CH:35]=[CH:36]3)[C@H:33]2[C:39]([NH2:41])=[O:40])=[C:11]2[N:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([N:66]4[CH2:67][CH2:68][N:63]([CH3:62])[CH2:64][CH2:65]4)=[CH:22][CH:23]=3)[NH:15][C:12]2=[N:13][CH:14]=1
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Agent: NC(=O)[C@H]1[C@@H](Nc2c(Cl)cnc(N)c2N)[C@@H]2C=C[C@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(-c3nc4c(N[C@@H]5[C@H](C(N)=O)[C@H]6C=C[C@@H]5C6)c(Cl)cnc4[nH]3)cc2)CC1
Yield: 66 %

Procedure:
In the same fashion as for Compound III, (1R,2R,3S,4S)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-(4-Methyl-piperazin-1-yl)-benzaldehyde were reacted to produce the title compound (66%). 1H NMR (d-chloroform): 15.63 (br s, 1H) 8.36 (d, J=9 Hz, 1H), 8.02 (d, J=9 Hz, 2H), 7.78 (s, 1H), 7.03 (d, J=9 Hz, 2H), 6.48 (m, 1H), 6.42 (m, 1H), 5.95 (s, 1H), 5.59 (s, 1H), 5.54 (t, J=8 Hz, 1H), 3.38-3.92 (m, 8H), 3.17 (s, 1H), 3.04 (m, 1H), 3.02 (s, 1H), 2.91 (s, 3H), 2.68 (d, J=9 Hz, 1H), 2.32 (d, J=9 Hz, 1H), 1.67 (d, J=9 Hz, 1H). MS: 478.15 (M+H). HPLC retention time: 1.79 minutes (G Method).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][CH2:7][S:6]1)=[O:4].Cl.[NH2:12]O.CCOCC>C(#N)C>[NH2:12][C:9]1[CH:8]=[CH:7][S:6][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1SCCC1=O
Reactant: NO
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: COC(=O)c1sccc1N

Procedure:
2-Methoxycarbonyl-3-oxotetrahydrothiophene (2 g) was dissolved in acetonitrile (20 ml) with heating and stirring. Hydroxylamine hydrochloride (0.8 g) was added to the refluxing solution and the mixture was refluxed for 11/2hour. After cooling, ether (50 ml) was added and the precipitated straw-coloured solid was filtered off. The solid was dissolved in water and basified with 4M ammonia solution and extracted with dichloromethane (2×25 ml). The combined extracts were washed with water and with brine and dried over sodium sulphate. Filtration and evaporation gave an oil which solidified on cooling and was crystallised from petrol ether bp 60°-80° to afford the title compound, 1.34 g (73%); mp 62°-63°.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=2[N:6]=1.[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[Br:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:5]=3[N:6]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc2sc(Br)nc2c1
Reactant: Nc1ccc(Br)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1ccc2sc(Nc3ccc(Br)cc3)nc2c1

Procedure:
The mixture containing 2-bromo-5-methoxybenzthiazole (1 eq), 4-Bromoaniline (2 eq) and diisopropylethylamine was subjected to microwave in NMP at 220° C. The resultant mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was washed with brine and dried. Purification on silica gel gave the desired product. MS: MH+=335
Reaction SMILES: C([Li])CCC.[CH:6]1([C:9]#[CH:10])[CH2:8][CH2:7]1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@@:21]23[C:27]([CH3:29])([CH3:28])[C@@:24]([CH3:30])([CH2:25][CH2:26]2)[C:23](=[O:31])[O:22]3)=[O:20])=[C:14]([C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH:13]=1>O1CCCC1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C@@:21]23[C:27]([CH3:28])([CH3:29])[C@@:24]([CH3:30])([CH2:25][CH2:26]2)[C:23](=[O:31])[O:22]3)=[O:20])=[C:14]([C@@:32]([OH:37])([C:10]#[C:9][CH:6]2[CH2:8][CH2:7]2)[C:33]([F:34])([F:35])[F:36])[CH:13]=1
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)OC2=O
Reactant: C#CC1CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Reaction time: 0.5 h

Procedure:
2.5 M n-Butyllithium (14.8 mL, 37.16 mmol) was added slowly to a solution of cyclopropyl acetylene (2.46 g, 37.16 mmol) in tetrahydrofuran (20 mL) in an ice-salt-bath under argon, and then (1S,4R)-N-(4-chloro-2-(2,2,2-trifluoroacetyl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide(9, 5 g, 12.39 mmol) was added. The reaction mixture was stirred for 0.5 hour. The reaction was quenched with 10% citric acid aqueous, the mixture was extracted with ethyl acetate and the two layers were separated. The organic layer was evaporated to dryness to give crude oil which was further crystallized with ethyl acetate and petroleum ether to give (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl)phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10) as a white or off-white powder. 1H NMR spectrum of the product was identical to that of Example 5.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[S:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH2:28])=[CH:22][CH:21]=1>>[ClH:19].[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][NH:28][S:16]([C:14]2[S:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])=[CH:22][CH:21]=1
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)s2)c(C)[nH]c1=O
Reactant: NCCc1ccncc1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCCc3ccncc3)s2)c(C)[nH]c1=O
Product: Cl
Yield: 40 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)thiophene-2-sulfonyl chloride is reacted with 2-pyridin-4-yl-ethylamine as described in Steps 5 and 6, Example 24 to give the title compound as a yellow-orange solid (40% yield). LC/MS: RT 2.02 min, m/e 404 (M+H); 1H NMR (δ, ppm): 11.86 (1H, s), 8.84 (2H, s), 8.07 (1H, t), 7.95 (2H, d), 7.54 (1H, d), 7.33 (1H, s), 7.16 (1H, d), 3.29 (2H, dt), 3.06 (2H, t), 2.41 (2H, q), 2.31 (3H, s), 1.10 (3H, t).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:23]([C:27]1[CH:31]=[C:30]([NH2:32])[O:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24].CCN(C(C)C)C(C)C>>[C:23]([C:27]1[CH:31]=[C:30]([NH:32][C:16](=[O:18])[CH2:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[O:29][N:28]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)c1cc(N)on1
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(OCc3ccccc3)cc2)on1
Temperature: 45 °C
Reaction time: 8 h

Procedure:
(4-Benzyloxy-phenyl)-acetic acid (50 mg, 0.2 mmol, 1 eq) was stirred with 1 mL of thionyl chloride at 80° C. for approximately three hours. The completion of the reaction was checked by TLC. Excess thionyl chloride was removed in vacuo, the residue was dissolved in dichloromethane and added to a mixture of 3-tert-butyl-isoxazol-5-ylamine (28 mg, 0.2 mmol, 1 eq) and DIEA (35 μL, 0.2 mmol, 1 eq). The reaction was stirred overnight at 45° C. The solvent was removed and the product purified by HPLC. Yield: 42 mg (57%), LC/MS [MH+] 365.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1.C(OC(=O)[C@@H](OC)CC1C=CC(O[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=CC=1)C>>[CH3:1][O:2][C:3](=[O:15])[CH:4]([O:13][CH3:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:7]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)OC(C)(C)C)cc1)OC
Reactant: COC(=O)C(Cc1cccc(O)c1)OC
Product: COC(=O)C(Cc1cccc(OCC(=O)OC(C)(C)C)c1)OC

Procedure:
The title compound was prepared from 3-(3-hydroxy-phenyl)-2-methoxy-propionic acid methyl ester (example 9, step 4) via the same procedure used to prepare (2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 1) to produce a yellow oil. MS (ES) for C17H24O6 [M+H]+: 325.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([CH3:10])[N:5]=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[C:14]([F:21])[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:7]([CH:8]=[O:9])=[C:6]([CH3:10])[N:5]=[CH:4][CH:3]=2)=[C:14]([F:21])[CH:13]=1
Reactant: Cc1nccc(Cl)c1C=O
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nccc(-c2ccc(Cl)cc2F)c1C=O
Temperature: 90 °C
Yield: 93.5 %

Procedure:
A mixture of 4-chloro-2-methylnicotinaldehyde (100 mg, 0.643 mmol), (4-chloro-2-fluorophenyl)boronic acid (123 mg, 0.707 mmol), Cs2CO3 (628 mg, 1.928 mmol) and Pd(Ph3P)4 (52.0 mg, 0.045 mmol) in toluene (5 mL) was heated at 90° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc (10 mL) and water (10 mL). The ethyl acetate layer was concentrated and purified by silica gel chromatography (2:1 Hexane-EtOAc) to afford 4-(4-chloro-2-fluorophenyl)-2-methylnicotinaldehyde (0.15 g, 0.601 mmol, 35% yield) as a yellow solid. LCMS (ESI) m/e 250.04 [(M+H)+, calcd for C13H10ClFNO 250.0]; LC/MS retention time (Method G): tR=0.96 min.
Reaction SMILES: [I:1][C:2]1[C:3]([C:7]2[S:8][CH:9]=[C:10]([Cl:12])[CH:11]=2)=[N:4][NH:5][CH:6]=1.[H-].[Na+].I[CH:16]([CH2:18][CH3:19])[CH3:17].C(N1C=C(I)C(C2SC=C(Cl)C=2)=N1)(CC)C>CN(C)C=O.CC(OC)(C)C.O>[CH:16]([N:4]1[C:3]([C:7]2[S:8][CH:9]=[C:10]([Cl:12])[CH:11]=2)=[C:2]([I:1])[CH:6]=[N:5]1)([CH2:18][CH3:19])[CH3:17]
Reactant: Clc1csc(-c2n[nH]cc2I)c1
Reactant: CCC(C)I
Agent: CCC(C)n1cc(I)c(-c2cc(Cl)cs2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCC(C)n1ncc(I)c1-c1cc(Cl)cs1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a solution of 4-iodo-3-(4-chloro-2-thienyl)-1H-pyrazole (3.3 mmol) in 10 mL dry N,N-dimethylformamide under argon atmosphere was added sodium hydride (3.9 mmol, 60% dispersion in mineral oil) in portions. The reaction mixture was stirred at room temperature for 15 min, then 2-iodobutane (4.9 mmol) was added dropwise. After 2 days at room temperature, water and MTBE were added to the reaction mixture. The phases were separated and the aqueous phase was extracted with MTBE. The combined organic extracts were successively washed with water and brine, dried over MgSO4, filtered and concentrated to afford 1.2 g of a mixture of 1-sec-butyl-3-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole and 1-sec-butyl-5-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (88:12; 100% yield). The mixture was purified by chromatography on silica gel (toluene:ethyl acetate 100:0 to 0:100) to afford 923 mg 1-sec-butyl-3-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (74% yield) and 150 mg of 1-sec-butyl-5-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (11% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=2)[C:5]2[CH:19]=[CH:20][C:21]3[C:26]([C:4]=2[NH:3]1)=[CH:25][CH:24]=[CH:23][CH:22]=3.[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH2:30].C1(NC(C2C=CC(N3C(=O)CC(=O)NC4C5C(C=CC3=4)=CC=CC=5)=CC=2)=O)C=CC=CC=1>>[Cl:27][C:28]1[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=1[NH:30][C:14]([C:13]1[CH:17]=[CH:18][C:10]([N:6]2[C:7](=[O:9])[CH2:8][C:2](=[O:1])[NH:3][C:4]3[C:26]4[C:21]([CH:20]=[CH:19][C:5]2=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:11][CH:12]=1)=[O:15]
Reactant: Nc1ccccc1Cl
Reactant: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Agent: O=C1CC(=O)N(c2ccc(C(=O)Nc3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(C(=O)Nc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 15 %

Procedure:
By using 4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoic acid obtained in Example 102, (4), and 2-chloroaniline, the title compound (yield 15%) was obtained in the same manner as that of Example 102, (5).
Reaction SMILES: CC1C=CC(C=O)=CC=1.[CH3:10][C:11]1[C:12]([N+:21]([O-])=O)=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[N:16][CH:15]=[CH:14]2.[Sn](Cl)(Cl)(Cl)Cl>C(O)(=O)C.Cl>[NH2:21][C:12]1[C:11]([CH3:10])=[CH:20][CH:19]=[C:18]2[C:13]=1[CH:14]=[CH:15][N:16]=[CH:17]2
Reactant: Cc1ccc2cnccc2c1[N+](=O)[O-]
Agent: Cc1ccc(C=O)cc1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc2cnccc2c1N
Reaction time: 12 h

Procedure:
By carrying out the preparation according to Stages 1 and 2 of PREPARATION IX above and by using 4-methylbenzaldehyde as starting reactant, 6-methyl-5-nitroisoquinoline is prepared. 4.0 g of 6-methyl-5-nitroisoquinoline are dissolved in a solution of 80 ml of acetic acid and 40 ml of concentrated hydrochloric acid, 40.0 g of tin chloride are then added and the reaction mixture is heated at reflux for 3 hours and then left for 12 hours at room temperature. The crystals formed are filtered off, taken up in water and basified with 10N sodium hydroxide. The extraction is carried out with dichloromethane and the organic phase is dried and evaporated to dryness to obtain 0.52 g of yellow crystals. 1H NMR (CDCl3): 2.37 (s, 3H, --CH3), 4.18 (broad s exchangeable with D2O, 2H, --NH2), 7.29 (d, J=8.8, 1H, H7), 7.44 (d, J=8.8, 1H, H4), 7.53 (d, J=6.2, 1H, H8), 8.49 (d, J=5.8, 1H, H3), 9.13 (s, 1H, H1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[Cl:17]CC(Cl)=O.[Cl:22][CH2:23][C:24](NC1C=CC(C2SC3C=CC=CC=3N=2)=CC=1)=[O:25]>C1C=CC=CC=1>[ClH:17].[Cl:22][CH2:23][C:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1)=[O:25]
Reactant: Nc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=C(Cl)CCl
Reactant: O=C(CCl)Nc1ccc(-c2nc3ccccc3s2)cc1
Solvent: c1ccccc1
Product: Cl
Product: O=C(CCl)Nc1ccc(-c2nc3ccccc3o2)cc1

Procedure:
2-(4'-Aminophenyl)benzoxazole (0.28 g, 1.33 mmol) was treated with chloroacetyl chloride (0.5 ml) in benzene (15 ml) according to the procedure described above for preparation of 2-(4'-chloroacetamidophenyl)benzothiazole. 2-(4'-Chloroacetamidophenyl)benzoxazole hydrochloride was obtained (0.31 g, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][OH:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>C(O)C>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[N+:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O-:9])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: ONc1ccc(Cl)cc1
Solvent: CCO
Product: [O-][N+](=Cc1ccc(Br)cc1)c1ccc(Cl)cc1

Procedure:
p-Chlorophenylhydroxylamine (0.05 moles) was dissolved in warm 95% ethanol (20 cc) and was treated with p-bromobenzaldehyde (0.05 moles) with vigorous stirring. The solid which formed was collected, washed with 95% ethanol, and was recrystallized from ethanol to give α-p-bromophenyl-N-p-chlorophenylnitrone.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=3)[CH:12]=[C:11]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:10]=2[O:27][CH3:28])=[O:7])=[CH:4][CH:3]=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1.CCOC(C)=O>[C:23]([C:11]1[C:10]([O:27][CH3:28])=[C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:32]([CH3:31])(=[O:34])=[O:33])=[CH:3][CH:4]=2)[CH:14]=[C:13]([C:15]2[C:16]([O:21][CH3:22])=[N:17][CH:18]=[CH:19][CH:20]=2)[CH:12]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ncccc1-c1cc(NC(=O)c2ccc(N)cc2)c(OC)c(C(C)(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ncccc1-c1cc(NC(=O)c2ccc(NS(C)(=O)=O)cc2)c(OC)c(C(C)(C)C)c1
Reaction time: 2 h
Yield: 99.3 %

Procedure:
step 5—To a solution of 104 (0.10 g, 0.25 mmol) in pyridine (2 mL) at 0° C. was added methanesulfonyl chloride (0.034 g, 0.30 mmol). Stirring was continued at 0° C. for two h, then at RT for an additional two h. The reaction mixture was diluted with EtOAc, washed sequentially with aqueous CuSO4 and 2N HCl, dried (Na2SO4), filtered and concentrated. The crude residue was purified by SiO2 chromatography (EtOAc/hexane) to afford 0.12 g of N-[3-tert-butyl-2-methoxy-5-(2-methoxypyridin-3-yl)phenyl]-4-methanesulfonylaminobenzamide (106) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12][CH3:13])[N:8]=[CH:7][NH:6][C:5]2=[O:14].Br[CH2:16][C:17](=[O:33])[CH2:18][C@H:19]1[C@H:24]([O:25][CH3:26])[CH2:23][CH2:22][CH2:21][N:20]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[S:12][CH3:13])[N:8]=[CH:7][N:6]([CH2:16][C:17](=[O:33])[CH2:18][C@H:19]1[C@H:24]([O:25][CH3:26])[CH2:23][CH2:22][CH2:21][N:20]1[C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])[C:5]2=[O:14]
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Reactant: CSc1cc2nc[nH]c(=O)c2cc1Cl
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(SC)c(Cl)cc2c1=O

Procedure:
In the manner of Example 4, 0.679 g (0.003 mol) of 6-chloro-7-methylthioquinazolin-4(3H)-one and 1.0 g (0.003 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate were converted into the title compound: yield 0.56 g (39%). 1H--NMR(CDCl3) 1.4-2.2 ppm (multiplet, 4H, OCHCH2CH2CH2N), 2.6 (singlet, 3H, SCH3), 2.8-3.4 (multiplet, 4H, NCH2, COCH2CH), 3.4 (singlet, 3H, OCH3), 4.0 (broad singlet, 1H, CHNCO), 4.6 (doublet, 2H, CH2CH=CH2), 5.0 (singlet, 2H, NCH2CO), 5.0-5.5 (multiplet, 2H, CH=CH2), 5.6-6.1 (octet, 1H, CH2 =CH), 7.4 (singlet, 1H, aromatic H), 7.9 (singlet, 1H, N=CH--N), 8.2 (singlet, 1H, aromatic H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15](=[O:23])OC2C=CC=CC=2)=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2].[CH2:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[CH3:25]>>[CH2:1]([O:3][C:4]1[C:13]([NH:14][C:15]([N:35]2[CH2:36][CH2:37][N:32]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[CH2:24][CH3:25])[CH2:33][CH2:34]2)=[O:23])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCc1ccccc1N1CCNCC1
Reactant: CCOc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Product: CCOc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2CC)CC1
Yield: 77.5 %

Procedure:
Phenyl N-(2-ethoxyquinoxalin-3-yl)carbamate and 1-(2-ethylphenyl)piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1B(O)O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2([CH3:15])[CH2:13][O:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC1(c2cccc(Br)c2)COCC(N)=N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: CC1(c2cccc(-c3ccc(F)cc3F)c2)COCC(N)=N1
Temperature: 100 °C

Procedure:
A degassed solution of (RS)-5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (intermediate XII-1) (100 mg, 0.37 mmol) in 1,2-dimethoxyethane was treated with tetrakis(triphenylphosphine)palladium(0) (42.7 mg, 0.037 mmol), then purged again with argon for 15 minutes. Thereafter, a solution of sodium hydrogencarbonate (1 M, 0.5 ml) and 2,4-difluoro-benzene-boronic acid (116.5 g, 0.74 mmol) were added. The tube was sealed and the mixture heated to 100° C. for 3 hours. For the workup, the reaction mixture was filtered through Celite®, then extracted with dichloromethane (2×15 ml). The combined organic layers were evaporated and the residue was repeatedly (3×) purified by chromatography on a silica-amine phase. The (RS)-5-(2′,4′-difluoro-biphenyl-3-yl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine was obtained as an off-white solid (20 mg, 18% of theory). MS (ISP): m/z=303.4 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([OH:20])[CH:16]=[C:17]([CH3:19])[CH:18]=1)(=[O:11])=[O:10])#[N:2].[CH2:21](P(CCCC)CCCC)CCC.[OH:34][CH2:35][C:36]1(CO)[CH2:38][CH2:37]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([O:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[O:20][CH2:21][CH:35]([CH:36]1[CH2:38][CH2:37]1)[OH:34])(=[O:11])=[O:10])#[N:2]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C#N)c1
Reactant: CCCCP(CCCC)CCCC
Reactant: OCC1(CO)CC1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCC(O)C2CC2)cc(OS(=O)(=O)c2ccccc2C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of 3-(2-cyanophenylsulfonyloxy)-5-methylphenol (1.45 g, 5.0 mmol), as prepared in the step a of example 13), tri-n-butylphosphine (1.62 g, 8.0 mmol) and 1,1-dihydroxymethylcyclopropane (1.52 g, 15 mmol), as prepared in U.S. Pat. No. 5,472,964, in anhydrous tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl)dipiperidine (2.02, 8.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (80 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (10% ethyl acetate in dichloromethane) to give the title compound as a white solid (1.15, 62%). 1H-NMR (300 MHz, CDCl3) δ 8.09 (m, 1H), 7.93 (m, 1H), 7.80 (m, 2H), 6.66 (s, 1H), 6.60 (s, 1H), 6.56 (s, 1H), 3.86 (s, 2H), 3.60 (s, 2H), 2.26 (s, 3H), 1.85 (br s, 1H), 0.62 (s, 4H).
Reaction SMILES: B(O)(O)O.[CH3:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=O.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:16].O>C1(C)C(C)=CC=CC=1>[N+:23]([C:20]1[CH:19]=[CH:18][C:17]([C:15](/[CH:14]=[CH:5]/[C:6]2[CH:13]=[CH:12][CH:11]=[C:8]([CH3:9])[CH:7]=2)=[O:16])=[CH:22][CH:21]=1)([O-:25])=[O:24]
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc(C=O)c1
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1cccc(/C=C/C(=O)c2ccc([N+](=O)[O-])cc2)c1
Reaction time: 8 h

Procedure:
10 g of boric acid are added to a solution of 76 g (0.63 mole) of 3-methylbenzaldehyde and 104.5 (0.63 mole) of 4-nitroacetophenone in 1 l of xylene, and the mixture is refluxed for 8 hours under a water separator. A further 5 g of boric acid are added, after which the mixture is boiled for a further 8 hours. This process is repeated until the theoretical amount of water has been separated off (2-3 times). The cooled reaction mixture is filtered under suction and the residue is washed with toluene and dried under reduced pressure to give 131 g (77% of theory) of a yellowish brown powder of melting point 130°-132° C.