Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6](=O)[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH2:2][CH2:3][CH3:4].C([O:22][C:23]([C:25]1[C:26]2[CH2:34][CH:33]([CH3:35])[CH2:32][CH2:31][C:27]=2[S:28][C:29]=1[NH2:30])=O)C>>[CH2:1]([N:5]1[C:23](=[O:22])[C:25]2[C:26]3[CH2:34][CH:33]([CH3:35])[CH2:32][CH2:31][C:27]=3[S:28][C:29]=2[N:30]=[C:6]1[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)c1cc(OC)c(OC)c(OC)c1
Reactant: CCOC(=O)c1c(N)sc2c1CC(C)CC2
Product: CCCCn1c(-c2cc(OC)c(OC)c(OC)c2)nc2sc3c(c2c1=O)CC(C)CC3

Procedure:
According to the method described for the compound No. 1 using N-butyl-3,4,5-trimethoxybenzamide a nd 2-amino-5-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-3-carboxylic acid ethyl ester as starting materials.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]1=2.O[C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCOC(C)=O>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CC=C(c2cccs2)c2cc(C(=O)O)ccc21
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1

Procedure:
A solution of 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid (Compound E6, 50.0 mg, 0.177 mmol), ethyl 4-hydroxybenzoate (38.2 mg, 0.230 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44.0 mg, 0.230 mmol), and 4-N,N-dimethylaminopyridine (28.0 mg, 0.230 mmol) in 2.0 mL DMF was stirred overnight at room temperature. EtOAc (50 mL) was added and the solution washed with H2O, 5% HCl, saturated aqueous NaCO3, and saturated aqueous NaCl before being dried over MgSO4. Removal of the sovents under reduced pressure and column chromatography (10% EtOAc-hexanes) of the residual oil afforded the title compound as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2O.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Cl:22])[NH2:18].Cl>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([OH:12])[CH:6]=[C:5]2[NH:18][C:17]1[CH:19]=[CH:20][C:21]([Cl:22])=[C:15]([Cl:14])[CH:16]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Oc1cc(O)c2cc(Br)ccc2n1
Agent: Cl
Solvent: CCOCC
Product: Oc1cc(Nc2ccc(Cl)c(Cl)c2)c2cc(Br)ccc2n1

Procedure:
Prepared using general procedure 1; 6-Bromo-2,4-quinolinediol (3 g, 12.5 mmol), 3,4-dichloroaniline, 6.25 mL of 2 M HCl in Et2O were irradiated to 180° C. (400 W max) for 40 min. to afford 1.94 g (5.05 mmol, 40%). 1H NMR (300 MHz, DMSO): 11.36 (s, 1H), 8.83(s, 1H), 8.28(s, 1H), 7.70(dd, 1H, J=8.88, 1.61 Hz), 7.64(d, 1H, J=8.88 Hz), 7.55(d, 1H, J=2.02 Hz), 7.33(dd, 1H, J=8.88, 2.42 Hz), 7.25(d, 1H, J=8.88 Hz), 5.86(s, 1H).
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[CH2:11][C:12]([NH:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=1[CH:17]=[CH:18]O[C:20]3=[O:25])=[O:13])[CH2:8]2.[NH3:26]>C(O)C>[CH:3]12[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]([CH2:10]3)[CH:2]1[CH2:11][C:12]([NH:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=1[CH:17]=[CH:18][NH:26][C:20]3=[O:25])=[O:13])[CH2:9]2
Reactant: N
Reactant: O=C(CC1C2CC3CC(C2)CC1C3)Nc1cccc2c(=O)occc12
Solvent: CCO
Product: O=C(CC1C2CC3CC(C2)CC1C3)Nc1cccc2c(=O)[nH]ccc12
Temperature: 115 °C
Yield: 45 %

Procedure:
90 mg (0.27 mmol) of 2-adamantyl-N-(1-oxo-1H-isochromen-5-yl)acetamide (1) was treated with 10 mL (20 mmol) of a 2 M ammonia solution in ethanol at room temperature in a resealable tube. The reaction vessel was sealed and heated at 115° C. for 48 h. After the reaction mixture was cooled down to room temperature, the solvent was evaporated and residue obtained was purified by prep. HPLC to yield 2-adamantyl-N-(1-oxo-1,2-dihydroisoquinolin-5-yl)acetamide (2a) (41 mg, 0.122 mmol, 45%) as an off-white powder. HPLC ret. time 2.07 min, 10-100% CH3CN, 3.5 min gradient; ESI-MS m/z 337.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[CH:7]=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[Cl:14][S:15](O)(=[O:17])=[O:16]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[C:7]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:8][N:9]2[CH3:12])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cn1ccc(=O)c2ccc(Cl)cc21
Product: Cn1cc(S(=O)(=O)Cl)c(=O)c2ccc(Cl)cc21
Temperature: 140 °C

Procedure:
7-Chloro-1-methyl-4-quinolone (6.9 g) and chlorosulphonic acid (14 ml) can be stirred and heated at 140° C. for 2 hours. The reaction mixture can be cooled to room temperature and carefully added dropwise to ice water (200 ml). The solid which forms can be collected, washed with water and dried in air to give the compound 7-chloro-1-methyl-4-oxo-1,4-dihydroquinoline-3-sulphonyl chloride, m.p. >300° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[CH:10][C:11]([OH:15])=[CH:12]2)=[CH:7][CH:6]=1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O>[CH3:27][O:26][C:24](=[O:25])[CH2:23][O:15][C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][CH:7]=2)[CH:12]=1
Reactant: C=CCOc1ccc2ccc(O)cc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2ccc(OCC(=O)OC)cc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 7.9 g of 7-(2-propenyloxy)-2-naphthalenol and 8.3 g of potassium carbonate in 50 ml of anhydrous acetone was stirred at room temperature for 1.5 hours. Methyl bromoacetate (4.7 ml), was added and stirring was continued for 18 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to yield (8.4 g) of [[7-(2-propenyloxy)-2-naphthalenyl]oxy]acetic acid methyl ester, mp 69°-70° after recrystallization from ether-hexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:19][C:18](=[O:20])[C:17]3[CH:21]=[C:22]([Cl:26])[CH:23]=[C:24]([CH3:25])[C:16]=3[N:15]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1.[CH3:27][NH:28][NH2:29].O1CCCC1>O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([NH:15][C:16]2[C:24]([CH3:25])=[CH:23][C:22]([Cl:26])=[CH:21][C:17]=2[C:18]([N:28]([CH3:27])[NH2:29])=[O:20])=[O:19])[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH:6]=1
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)cn3-c3ncccc3Cl)nc12
Reactant: CNN
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)cc(C(=O)N(C)N)c1NC(=O)c1cc(Br)cn1-c1ncccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
A mixture of 0.86 g of 2-[4-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrrol-2-yl]-6-chloro-8-methyl-4H-3,1-benzoxazine-4-one, 0.11 g of methylhydrazine and 15 ml of tetrahydrofuran was stirred at room temperature for 2 hours. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 0.17 g of 4-bromo-N-[4-chloro-2-(N-methylhydrazinocarbonyl)-6-methylphenyl]-1-(3-chloro-2-pyridinyl)-1H-pyrrole-2-carboxamide of the formula:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:28]([C:30]1[N:34]([CH3:35])[C:33](B(O)O)=[CH:32][CH:31]=1)#[N:29]>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:33]3[N:34]([CH3:35])[C:30]([C:28]#[N:29])=[CH:31][CH:32]=3)[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Reactant: Cn1c(C#N)ccc1B(O)O
Product: Cn1c(C#N)ccc1-c1cc(C(=O)Nc2ccc(OC(F)(F)Cl)cc2)cnc1N1CC[C@@H](O)C1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 32.1 using (R)-5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(3-hydroxypyrrolidin-1-yl)nicotinamide (Stage 22.1) and 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid to afford an off-white powder. HPLC (Condition 4) tR=5.96 min, UPLC-MS (Condition 3) tR=1.11 min, m/z=486 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C@H:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1.[ClH:36].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:36].[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:28][CH:27]=2)[C:13]([C@H:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:22][CH:23]=1
Reactant: COc1ccc2c(c1)[C@H](C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)[C@H](C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
(R)-7-Methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.65 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (1.0 g) were reacted and treated in the same manner as in Example 12. The obtained solid was dissolved in ethyl acetate. Thereto was added 4 mol/L-HCl/ethyl acetate (1 mL). The solvent was evaporated under reduced pressure. The precipitated solid was recrystallized twice from ethanol to give (R)—N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride ½ ethanol (0.20 g).
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].[F:15][C:16]([F:21])([F:20])[C:17](O)=[O:18].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH:14][C:17](=[O:18])[C:16]([F:21])([F:20])[F:15])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(=O)N1CCc2ccc(N)cc2C1
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(=O)N1CCc2ccc(NC(=O)C(F)(F)F)cc2C1
Yield: 92.5 %

Procedure:
A solution of 14 (3.0 g, 17 mmol), trifluoroacetic acid (2 ml, 28 mmol) and trifluoroacetic anhydride (4 ml, 28 mmol) in CH2Cl2 is refluxed for 15 minutes, cooled, and the mixture is poured onto ice, extracted twice with CH2Cl2 and evaporated. The mixture is chromatographed on silica gel to give 4.5 g of compound 15 (94% yield). 1H NMR [300 MHz, (CD3)2SO], a 3:2 mixture of amide conformers doubling most signals, δ 11.24 (0.8H, s, NH), 11.21 (1.2H, s, NH), 7.55-7.40 (2H, m, H5.8), 7.22 (0.6H, s, H-6), 7.20 (0.4H, s, H-6), 4.64 (0.8H, s, ArCH2N), 4.57 (1.2H, s, ArCH2N), 3.65 (2H, t, ArCH2CH2N), 2.84 (1.2H, t, ArCH2CH2N), 2.73 (0.8H, t, ArCH2CH2N), 2.06 (1.2H, s, COCH3), 2.05 (1.8H, s COCH3).
Reaction SMILES: [CH:1]1([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[O:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]1.CN(C)P(N(C)C)(N(C)C)=O>C1COCC1>[OH:20][C:17]1([C:1]2([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]2)[CH2:18][CH2:19][O:15][CH2:16]1
Reactant: O=C1CCOC1
Reactant: N#CC1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: N#CC1(C2(O)CCOC2)CCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 44.3 %

Procedure:
To a solution of cyclobutanecarbonitrile (405 mg, 5 mmol) in THF (7 ml) was added 2.0M lithium diisopropylamide (2.5 ml, 5 mmol) dropwise at −78° C. The reaction solution was stirred at −78° C. for 40 minutes, followed by the addition of a solution of dihydrofuran-3(2H)-one (473 mg, 5.5 mmol) in hexamethylphosphoramide (268 mg, 1.5 mmol). The mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with 1N aqueous HCl solution and extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluted with petroleum ether:EtOAc=20:1) to provide the title compound as a corloless oil (0.37 g, yield 44%). 1H NMR (400 MHz, CDCl3): δ 4.15-4.05 (m, 2H), 3.86 (d, J=10.0 Hz, 1H), 3.74 (d, J=9.6 Hz, 1H), 2.47-2.42 (m, 4H), 2.39-2.31 (m, 3H), 2.01-1.94 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:4][N:5]([CH3:17])[C:6]=1[CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[CH3:26][C:27]1[C:31](B(O)O)=[C:30]([CH3:35])[O:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[Si:10]([O:9][CH2:8][CH2:7][C:6]1[N:5]([CH3:17])[N:4]=[C:3]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:2]=1[C:31]1[C:27]([CH3:26])=[N:28][O:29][C:30]=1[CH3:35])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: COc1ccc(-c2nn(C)c(CCO[Si](C)(C)C(C)(C)C)c2Br)cc1
Reactant: Cc1noc(C)c1B(O)O
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc(-c2nn(C)c(CCO[Si](C)(C)C(C)(C)C)c2-c2c(C)noc2C)cc1
Yield: 23.6 %

Procedure:
A mixture of 4-bromo-5-(2-(tert-butyldimethylsilyloxy)ethyl)-3-(4-methoxyphenyl)-1-methyl-1-H-pyrazole (140 mg, 0.33 mmol), 3,5-dimethylisoxazol-4-ylboronic acid (92.8 mg, 0.66 mmol), K2CO3 (328 mg, 2.37 mmol) and Pd(PPh3)4 (19.0 mg, 0.02 mmol) in DME (1 mL) and water (1 mL) was flushed with argon and irradiated in the microwave at 140° C. for 20 min. Full conversion was not achieved. The mixture was filtered to remove palladium black. Irradiation in the microwave was continued until full conversion was achieved. Altogether 3,5-dimethylisoxazol-4-ylboronic acid (233 mg, 1.66 mmol) and Pd(PPh3)4 (57.0 mg, 0.06 mmol) were used and three irradiations were run. Water was added and the crude mixture was extracted with EtOAc. Purification on silica gel gave 4-(5-(2-(tert-butyldimethylsilyloxy)ethyl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)-3,5-dimethylisoxazole (34.4 mg, 0.078 mmol, 24%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]([CH3:32])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[C:24]([O:30][CH3:31])[CH:23]=1>>[CH3:32][N:21]([CH3:20])[C:22]1[CH:29]=[CH:28][C:25]([C:26]2[NH:1][C:2]3=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]4[C@@H:15]5[CH2:16][C@@H:12]([CH:13]=[CH:14]5)[C@@H:11]4[C:17]([NH2:19])=[O:18])=[C:7]3[N:8]=2)=[C:24]([O:30][CH3:31])[CH:23]=1
Reactant: COc1cc(N(C)C)ccc1C=O
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: COc1cc(N(C)C)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)ccnc2[nH]1
Yield: 24.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 4-dimethylamino-2-methoxy-benzaldehyde (38.0 mg, 0.212 mmol) were reacted to produce 20 mg (29%) of the title compound. mp: 185-190° C., 1H NMR (300 MHz, DMSO-d6): 11.78 (s, 1H), 8.00 (d, J=8 Hz, 1H), 7.85 (d, J=5 Hz, 1H), 7.65 (s, 1H), 7.14 (s, 1H), 6.69 (d, J=8 Hz, 2H), 6.46 (d, J=8 Hz, 1H), 6.36 (d, J=8 Hz, 1H), 6.32 (br s, 3H), 3.96 (s, 3H), 3.01 (s, 6H), 2.86 (s, 1H), 2.75 (s, 1H), 2.59 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.42 (d, J=8 Hz, 1H). MS: 419 (M+H), HPLC: 2.09 min (G method).
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=O)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:26][OH:27]>O>[OH:27][N:26]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8]1
Reactant: O=C1CC(c2ccccc2)c2ccccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: ON=C1CC(c2ccccc2)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of 3-phenylindan-1-one (80 g), methanol (935 ml), water (90 ml), potassium carbonate (103.8 g), and hydroxylamine HCl (104.3 g) was heated at reflux for 16 hours, then poured into ice-water: the title compound was filtered, washed with water, with a small portion of ether, then dried in air. Yield: 74.7 g; m.p. 133°-139°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[CH2:13][C@@H:12]([C:14]([F:17])([F:16])[F:15])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:33])[O:23][C:24]1[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:18][C:10]1[O:11][C@H:12]([C:14]([F:16])([F:17])[F:15])[CH2:13][C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30](=[O:31])[C:27]3[CH:26]=[CH:25][C:24]([O:23][CH:22]([F:33])[F:21])=[CH:29][N:28]=3)[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: C[C@@]1(c2cc(N)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Product: C[C@@]1(c2cc(NC(=O)c3ccc(OC(F)F)cn3)ccc2F)C[C@@H](C(F)(F)F)OC(N)=N1

Procedure:
The coupling of (4S,6S)-4-(5-amino-2-fluorophenyl)-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-amine (XI-1) and 5-(difluoromethoxy)picolinic acid [J. D. Scott et al. WO2011044181 (2011)] following General Procedure G yielded the title compound as a colorless amorphous solid. MS: m/z=463.4 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[CH:7][C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2].C(N(CC)C(C)C)(C)C.O=P(Cl)(Cl)[Cl:27]>O1CCOCC1>[C:1]([NH:4][C:5]1[N:6]=[C:7]([Cl:27])[C:8]2[N:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:9]=2[N:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncc2nc(Cl)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(Cl)c2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-acetamido-6-chloro-pyrido[3,2-d]pyrimidine (1.19 g, 5 mmol), N,N-diisopropylethylamine (2.6 ml, 15 mmol) and POCl3 (0.7 ml, 7.5 mmol) in dioxane (50 ml), was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was redissolved in dichloromethane (500 ml) and extracted with cold water (200 ml) till pH=6-7. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude title compound which was characterised as follows: MS (m/z): 257, 259 ([M+H]+, 100). This compound was used for further reactions without any purification.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[F:25][C:26]1[CH:39]=[CH:38][C:29]([C:30]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[O:31])=[CH:28][CH:27]=1.[I-].[Na+]>CN(C)C=O>[F:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([CH:32]2[CH2:37][CH2:36][N:35]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:34][CH2:33]2)=[O:31])=[CH:38][CH:39]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)C1CCN(CCN2c3cccc4cccc(c34)S2(=O)=O)CC1
Temperature: 20 °C
Yield: 26.4 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (6.7 g), triethylamine (3.5 cc), 4-(4-fluorobenzoyl)piperidine (5.2 g) and sodium iodide (3.7 g) in dimethylformamide (100 cc). The mixture is heated for 6 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under current of argon at medium pressure (0.5-1.5 bar) with dichloromethane as eluant, and recrystallization from boiling acetonitrile (8 cc), 2-{2-[4-(4-fluorobenzoyl)piperidino}ethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (2.9 g) is obtained, m.p. 145° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].Br[CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[O:14][CH2:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:18]
Reactant: O=C(CBr)c1ccccc1
Reactant: Oc1ccc(-c2ccccc2)cc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(COc1ccc(-c2ccccc2)cc1Br)c1ccccc1

Procedure:
A mixture of 137 g. (0.55 mole) of 2-bromo-4-phenylphenol, 109 g. (0.55 mole) of α-bromoacetophenone and 75 g. of sodium carbonate in 1.5 liters of acetone is heated at its reflux temperature for six days, filtered, then evaporated. The white residue is recrystallized from a benzene-hexane mixture to provide white needles of α-(2-bromo-4-phenylphenoxy)acetophenone, m.p. 93°-95° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[C:4]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19].O>CN(C)C=O>[CH:15]1[CH:14]=[CH:13][C:12]([CH2:11][O:10][C:4]2[C:5]3[NH:9][C:18]([NH:8][C:6]=3[N:7]=[C:2]([NH2:1])[N:3]=2)=[O:19])=[CH:17][CH:16]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1nc(N)c(N)c(OCc2ccccc2)n1
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nc(OCc2ccccc2)c2[nH]c(=O)[nH]c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4,5-Triamino-6-benzyloxypyrimidine (Pfleiderer et al., Chem. Ber., 94, 12-18 (1961)) (1.85 g, 8 mmol) and 1,1′-carbonyldiimidazole (1.30 g, 8 mmol) were dissolved in anhydrous N,N-dimethylformamide (5 mL) under argon. The solution was stirred at room temperature overnight and was mixed with water (200 mL) to precipitate a white solid. The solid was collected by filtration, and dissolved in 250mL of aqueous 2 N NaOH solution. Undissolved material was removed by filtration, and the filtrate was neutralized with glacial acetic acid to precipitate a white solid. The solid was collected by filtration, was washed with water, and was recrystallized from 50% aqueous ethanol to afford analytically pure 1c: yield, 1.63 g (79%); mp 256-257 ° C. dec.; UV (pH 1) λmax 243 nm (ε=0.717×104), 306 (1.499×104); (pH 6.9) 243 (0.915×104), 290 (1.108×104); (pH 13) 249 (sh) (0.443×104), 293 (1.368×104); 1H NMR δ5.41 (s, 2 H, ArCH2), 6.13 (s, 2 H, NH2, exchange with D2O), 7.33-7.51 (m, 5 H, ArH), 10.46 (s, 1 H, exchanges with D2O), 11.04 (s, 1 H, exchanges with D2O); MS (EI) Calcd. m/z for C12H11N5O2: 257.0912. Found: 257.0914. Anal. (C12H11N5O2. {fraction (1/2+L )} H2O) C, N, H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22]([C:24]3[C:25]([O:30][CH3:31])=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].C([O-])(O)=O.[Na+]>OS(O)(=O)=O.C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22]([C:24]3[C:25]([O:30][CH3:31])=[N:26][CH:27]=[CH:28][CH:29]=3)=[O:23])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:35])([F:33])[F:34]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccnc1OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ncccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 4.9 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (330.06 mg, mmol) in 5% H2SO4 in TFA (2 mL) and water (1 mL) was stirred at 50° C. for overnight. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and treated slowly with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified via column chromatography (SiO2, 5% MeOH in EtOAc) to afford 4-chloro-N-[5-chloro-2-(2-methoxy-pyridine-3-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzene sulfonamide (15 mg) in 50% yield. ESMS m/z (relative intensity): 505.9 (M+H)+ (100), 527.9 (M+Na)+ (20).