Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3](=[O:15])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][CH:7]=1.[N:16]([C:19]1[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=1)[C:22]([O:24][CH3:25])=[O:23])=[C:17]=[O:18]>C1(C)C=CC=CC=1>[CH3:25][O:24][C:22](=[O:23])[C:21]1[CH:26]=[CH:27][CH:28]=[C:19]([N:16]2[C:3](=[O:15])[CH2:4][N:5]([C:6]3[CH:7]=[CH:8][C:9]([CH:12]([CH3:13])[CH3:14])=[CH:10][CH:11]=3)[C:17]2=[O:18])[CH:20]=1
Reactant: COC(=O)c1cccc(N=C=O)c1
Reactant: COC(=O)CNc1ccc(C(C)C)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(N2C(=O)CN(c3ccc(C(C)C)cc3)C2=O)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of methyl-2-(4-isopropylanilino)acetate (1.10 g, 5.31 mmol) in toluene (30 mL) was treated with methyl 3-isocyanatobenzoate (1.03 g), and the resulting solution was stirred at ambient temperature for 20 h. The reaction mixture was evaporated, and a portion (0.6 g) of the resulting solid material used directly in the next step. The compound was dissolved in methanol, and treated with sodium methoxide (0.84 mL of 0.5 M in methanol). The resulting solution was stirred for 1 h, then evaporated and partitioned between water and ethyl acetate (50 mL each). The organic extract was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residual material was separated by preparative thin-layer chromatography (silica gel, 30:70 ethyl acetate-hexane) to afford pure product, methyl-3-[3-(4-isopropylphenyl)-2,5-DIOXO-imidazolidin-1-yl]-benzoate, as a waxy solid. 1H NMR (CDCl3, 300 MHz): δ 8.16 (1H, t, J=1.8 Hz), 8.07 (1H, dt, J=7.6, 1.5 Hz), 7.67 (1H, ddd, J=8.0, 2.0, 1.1 Hz), 7.56 (1H, t, J=7.9 Hz), 7.51 (2H, d, J=8.8 Hz), 7.27 (2H, d, J=8.8 Hz), 4.47 (2H, s), 3.92 (3H, s), 2.91 (1H, m, J=7.0 Hz), 1.25 (6H, d, J=7.0 Hz). Mass spectrum (ES+): m/z 353 (36), 321 (100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:19]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([Cl:45])[C:31]=1[OH:46]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[CH:19]=2)=[CH:3][C:2]([C:34]2[CH:35]=[C:30]([Cl:29])[C:31]([OH:46])=[C:32]([Cl:45])[CH:33]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C)CCc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)c1
Product: CN(C)CCc1cccc(Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)c1
Yield: 71.3 %

Procedure:
Following general procedure F, {6-Bromo-4-[3-(2-(dimethylamino)ethyl)phenylamino]quinolin-3-yl}(cyclopropyl)methanone (58 mg, 0.132 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (57 mg, 0.198 mmol) to afford the desired product (49 mg, 71%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.46 (s, 1H), 8.22 (dd, J=8.7, 2.0 Hz, 1H), 8.02 (d, J=8.7 Hz, 1H), 7.89 (s, 1H), 7.67-7.59 (m, 1H), 7.56 (d, J=7.7 Hz, 1H), 7.8 (s, 1H), 7.39 (d, J=7.7 Hz, 1H), 7.20 (s, 2H), 3.40-3.34 (m, 2H), 3.19-3.12 (m, 2H), 2.98-2.85 (s, 8H), 1.27-1.16 (m, 4H); ESI MS m/z 520 [C29H27Cl2N3O2+H]+; HPLC 95.9% (AUC), tR=11.40 min.
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][C:5]([C:11]([O:13]C)=O)=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:7]=1.O.[NH2:16][NH2:17]>CO>[NH2:2][C:3]1[S:4][C:5]([C:11]([NH:16][NH2:17])=[O:13])=[C:6]([CH:8]2[CH2:10][CH2:9]2)[N:7]=1
Reactant: COC(=O)c1sc(N)nc1C1CC1
Reactant: NN
Agent: Br
Solvent: O
Solvent: CO
Product: NNC(=O)c1sc(N)nc1C1CC1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
Methyl 2-amino-4-cyclopropyl-1,3-thiazole-5-carboxylate hydrobromide (1.78 g) was dissolved in methanol (4.0 ml), hydrazine monohydrate (2.0 ml) was added thereto, followed by stirring at 55° C. for 3 days. After cooling to room temperature, an insoluble substance was filtered, the mother solution was mixed with basic silica gel and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel chromatography (chloroform:methanol) to obtain, as a dark brown solid, 2-amino-4-cyclopropyl-1,3-thiazole-5-carbohydrazide (224 mg).
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:10]=[C:11]([NH:22][C:23](=[O:31])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)[CH:12]=[C:13]([O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=1.[ClH:32]>C(#N)C>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:11]1[CH:12]=[C:13]([O:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[CH:14]=[C:9]([Cl:32])[CH:10]=1)=[O:31]
Reactant: Nc1cc(NC(=O)c2cccc(Cl)c2)cc(Oc2cccnc2)c1
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: O=C(Nc1cc(Cl)cc(Oc2cccnc2)c1)c1cccc(Cl)c1
Temperature: 55 °C
Yield: 63 %

Procedure:
CuCl2 (47.5 mg, 0.353 mmol, 1.20 eq) was dissolved in acetonitrile (2 mL) in a flame-dried 3-neck flask flushed with argon and equipped with a condenser. t-Butyl nitrite (45.5 mg, 0.441 mmol, 1.50 eq) was added and the reaction heated at 55° C. Compound 2 (100 mg, 0.294 mmol, 1.00 eq) was dissolved in acetonitrile (0.1 mL) and added dropwise to the reaction. After 10 minutes the reaction was cooled to rt, poured into 20% HCl and extracted with CH2Cl2 (3×). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 67 mg (63%) of the title compound as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) 10.50 (s, 1H), 8.47 (d, J=2.8 Hz, 1H), 8.45 (dd, J=4.6, 1.3 Hz, 1H), 7.96 (t, J=1.8 Hz, 1H), 7.86 (dt, J=7.9, 1.2 Hz, 1H), 7.77 (t, J=1.8 Hz, 1H), 7.68-7.66 (m, 1H), 7.58 (ddd, J=8.4, 3.0, 1.5 Hz, 1H), 7.56 (t, J=7.9 Hz, 1H), 7.48 (dd, J=8.4, 4.6 Hz, 1H), 7.40 (t, J=2.0 Hz, 1H), 6.94 (t, J=2.0 Hz, 1H); ES-MS [M+1]+: 359.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[C:8](=[CH:19][N:20]([CH3:22])[CH3:21])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: CCOC(OCC)N(C)C
Product: COc1cc2c(cc1OC)C(=O)C(=CN(C)C)CC2

Procedure:
The 3,4-dihydro-6,7-dimethoxy-2-(dimethylaminomethylene)-1(2H)-naphthalenone starting material was prepared from 6,7-dimethoxy-1-tetralone (4.12 g, 20 mmol) and N,N-dimethyl formamide diethyl acetal (10.3 ml, 60 mmol) to give the product as red-brown crystals (3.26 g) m.p. 138-140°. MS (ES+) 284 (MNa+, 12%), 262 (MH+, 100%), 189 (28%).
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].[CH3:5][CH:6]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][C:16]2=[O:19])=[CH:11][CH:10]=1)[CH3:7].O.C(=O)([O-])[O-].[Na+].[Na+]>FC(F)(F)C(O)=O>[CH3:5][CH:6]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][CH2:14][CH2:15][C:16](=[O:19])[NH:1][C:17]=2[CH:18]=1)[CH3:7]
Reactant: CC(C)Oc1ccc2c(c1)C(=O)CCC2
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)Oc1ccc2c(c1)NC(=O)CCC2
Yield: 14.4 %

Procedure:
900 mg of sodium azide are added at ambient temperature to a solution of 2.24 g of 7-(propan-2-yloxy)-3,4-dihydronaphthalen-1(2H)-one in 35 ml of trifluoroacetic acid. The reaction medium is refluxed for 3 hours and is then brought back to ambient temperature. The reaction medium is poured into 100 ml of water and the pH is adjusted to pH 7 by adding sodium carbonate. The mixture is extracted twice with 100 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. The residue is purified by flash chromatography on silica gel, elution being carried out with dichloromethane and then a dichloromethane/methanol (9/1) mixture, so as to obtain 346 mg of 8-(propan-2-yloxy)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one in the form of an orangey-coloured oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[Li]CCCC.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18]>C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([CH:17]([C:4]2[N:3]([CH3:7])[C:2]([Cl:1])=[N:6][CH:5]=2)[OH:18])[CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1cccc(F)c1
Reactant: Cn1ccnc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C(O)c2cccc(F)c2)cnc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and an addition funnel is added 2-chloro-1-methyl-1H-imidazole (1 equiv.) and THF (0.5 M). The reaction mixture is cooled to −78° C. and n-BuLi (2.5 M in hexanes, 1.05 equiv.) is added. The resulting mixture is stirred for 1 h and a solution of 3-fluorobenzaldehyde (1.05 eq) in THF (2.5 M) is then added dropwise. After the addition is complete, the cooling bath is removed and the reaction is allowed to warm to rt. The reaction mixture is quenched with satd. aq. NH4Cl, transferred to a separatory funnel, and extracted with EtOAc. The organic layer is washed with water, brine and dried over anhydrous Na2SO4. After filtration, the solvents are evaporated under reduced pressure to yield the product. The material is purified by recrystallization or column chromatography.
Reaction SMILES: [NH2:1][C:2]1[C:10]([NH2:11])=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:13]/[C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[O:19][CH3:20])/[C:5](=[O:12])[NH:6]2.[CH:21]1[CH:25]=[C:24]([C:26]([C:28]([C:30]2[O:34][CH:33]=[CH:32][CH:31]=2)=O)=O)[O:23][CH:22]=1>C(O)C>[O:23]1[CH:22]=[CH:21][CH:25]=[C:24]1[C:26]1[C:28]([C:30]2[O:34][CH:33]=[CH:32][CH:31]=2)=[N:11][C:10]2[CH:9]=[CH:8][C:7]3[NH:6][C:5](=[O:12])/[C:4](=[CH:13]\[C:14]4[NH:15][CH:16]=[CH:17][C:18]=4[O:19][CH3:20])/[C:3]=3[C:2]=2[N:1]=1
Reactant: O=C(C(=O)c1ccco1)c1ccco1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(N)c21
Solvent: CCO
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc3nc(-c4ccco4)c(-c4ccco4)nc3c21
Yield: 86 %

Procedure:
Using Method A above, (Z)-4,5-diamino-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.22 mmol) (Starting Material 5) was condensed with furil (200 mg) (Aldrich) in ethanol (3 mL) at reflux to give (Z)-7,9-dihydro-2,3-di-(2-furanyl)-9-[(3-methoxy-1H-pyrrol-2-yl)methylene]-8H-pyrrolo[3,2-f]quinoxalin-8-one in 86% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:6]([N:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].[H][H]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[C:6]([N:24]([CH3:25])[CH3:26])=[N:7][C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=2)=[N:9][C:10]=1[N:11]([CH3:12])[CH3:13]
Reactant: [H][H]
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc([N+](=O)[O-])cc2)nc1N(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(N)cc2)nc1N(C)C
Yield: 98.5 %

Procedure:
A solution of methyl[4,6-bis(dimethylamino)-2-(4-nitrobenzyl)pyrimidin-5-yl]acetate (5.00 g, 13.39 mmol) in methanol (150 mL) was treated with palladium on charcoal (10% Pd, 0.50 g) and the resulting black suspension was stirred under a blanket of hydrogen gas at room temperature for 10 hours. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo to give methyl[2-(4-aminobenzyl)-4,6-bis(dimethylamino)pyrimidin-5-yl]acetate (4.53 g, 98%).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Cl[C:22]1[C:31]([Cl:32])=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:33][CH3:34])[CH:28]=2)[N:23]=1>>[Cl:32][C:31]1[C:22]([C:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH:10]=2)=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:33][CH3:34])=[CH:26][CH:25]=2
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc2nc(Cl)c(Cl)cc2c1
Product: CCOC(=O)C1CC=C(c2nc3ccc(OC)cc3cc2Cl)CC1

Procedure:
Followed Scheme 2, Step 1 (see Example 8, Step 1) starting from ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate and 2,3-dichloro-6-methoxyquinoline (Intermediate 4).
Reaction SMILES: [C:1]([C:4]1[O:8][N:7]=[C:6]([CH3:9])[CH:5]=1)(=[O:3])[CH3:2].[Br:10]C1(Br)C(=O)NC(=O)NC1=O>C1COCC1>[Br:10][CH2:2][C:1]([C:4]1[O:8][N:7]=[C:6]([CH3:9])[CH:5]=1)=[O:3]
Reactant: O=C1NC(=O)C(Br)(Br)C(=O)N1
Reactant: CC(=O)c1cc(C)no1
Solvent: C1CCOC1
Product: Cc1cc(C(=O)CBr)on1
Temperature: 25 °C
Yield: 68.5 %

Procedure:
A solution of 0.43 g (3.43 mmol) of 5-acetyl-3-methylisoxazole (for synthesis see S. Chimichi, B. Cosimelli, Synth. Comm. 1992, 22, 2909-2920) in 10 mL of THF was added to a solution of 688 mg (2.41 mmol) of dibromobarbituric acid in 10 mL of THF. The colorless solution was heated at reflux for 20 h, cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phase was washed with water, brine, dried(MgSO4) and the solvent removed in vacuo. Flash chromatography (silica gel, 40-50% dichloromethane-hexanes) afforded 337 mg (48%) of the title compound: 1H NMR (400 MHz, CDCl3) 6.87 (s, 1H), 4.39 (s, 2H), 2.38 (s, 3H).
Reaction SMILES: II.Cl[CH:4]1[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]1.[CH3:11][CH:12]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[C:16](=[O:22])[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[CH2:13]1.[Cl-].[NH4+]>C(Br)CBr.O1CCCC1>[CH3:11][CH:12]1[C:18]2[S:19][CH:20]=[CH:21][C:17]=2[C:16]([CH:4]2[CH2:9][CH2:8][N:7]([CH3:10])[CH2:6][CH2:5]2)([OH:22])[C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[CH2:13]1
Reactant: CN1CCC(Cl)CC1
Reactant: CC1Cc2ccccc2C(=O)c2ccsc21
Agent: II
Agent: [Cl-]
Agent: [NH4+]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: CC1Cc2ccccc2C(O)(C2CCN(C)CC2)c2ccsc21
Reaction time: 2 h

Procedure:
4.8 g of iodine-activated magnesium are covered with a layer of 60 cc of anhydrous tetrahydrofuran and cauterized with a few drops of ethylene bromide. A solution of 25.0 g of 4-chloro-1-methylpiperidine in 160 cc of anhydrous tetrahydrofuran is then added dropwise at such a rate that the solvent boils continually, and stirring is subsequently effected at the boil for 2 hours. The reaction mixture is cooled to 10°, and a solution of 20.0 g of 9,10-dihydro-10-methyl-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-one in 100 cc of anhydrous tetrahydrofuran is added dropwise at this temperature. After stirring at room temperature for 11/2 hours and at the boil for 30 minutes, the reaction mixture is cooled, poured on 300 cc of a 20% ammonium chloride solution, and the organic phase is separated. The aqueous solution is extracted with methylene chloride, the combined organic solutions are washed with water, dried over sodium sulphate and concentrated by evaporation. The 9,10-dihydro-10-methyl-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta-[1,2-b]thiophen-4-ol, obtained as residue, is recrystallized twice from isopropanol. M.P. 177°-178°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:18]2[C:13](=[CH:14][C:15]([F:21])=[C:16](OC)[N:17]=2)[C:12](=[O:22])[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10]1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:16]1[N:17]=[C:18]2[C:13]([C:12](=[O:22])[C:11]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10][N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][C:15]=1[F:21]
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(OC)c(F)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cn(-c2ccc(F)cc2F)c2nc(Cl)c(F)cc2c1=O
Yield: 85 %

Procedure:
In 2.5 ml of phosphorus oxychloride was suspended 500 mg of ethyl 1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate, and the resulting suspension was subjected to reaction under reflux for 1.5 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and the crystalline material thus obtained was washed with 10 ml of diethyl ether to obtain 430 mg (yield 85.0%) of ethyl 7-chloro-1-(2,4-difluorophenyl)-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate having a melting point of 216°-219° C. The physical properties of this compound were identical with those of the compound obtained in Example 51.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH2:13]([N:20]=[C:21]=S)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: S=C=NCc1ccccc1
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Product: Cn1c(NCc2ccccc2)nc2cc([N+](=O)[O-])ccc21
Yield: 70.8 %

Procedure:
N1-Methyl-4-nitro-benzene-1,2-diamine (2.0 g, 12.0 mmol) and benzyl isothiocyanate (1.75 ml, 13.2 mmol) were coupled using the procedure of example one part B to give the title compound as a yellow solid (2.4 g, 71%). 1H NMR (300 MHz, d6-DMSO) δ 7.97 (d, J=2.4 Hz, 1H), 7.90 (dd, J=8.7 and 2.4 Hz, 1H), 7.77 (t, J=5.7 Hz, 1H), 7.21-7.41 (m, 6H), 4.63 (d, J=5.7 Hz, 2H), 3.62 (s, 3H) ppm.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][CH2:6][Cl:7])[CH3:2].C(O)C[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CS(O)(=O)=O>[N+](C)([O-])=O>[Cl:7][CH2:6][CH2:5][CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH2:2][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(CCCl)OCC
Reactant: OCCc1ccccc1
Agent: CS(=O)(=O)O
Solvent: C[N+](=O)[O-]
Product: CCOC(CCCl)OCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
3-Chloropropionaldehyde diethyl acetal (LXII, 30.66 g, 0.184 mol) is added to an ice-cooled solution of phenethyl alcohol (XLV, 20.44 g, 0.167 mol) in nitromethane (50 ml) is added and methanesulfonic acid (1.61 g, 0.0167 mol). After 30 min the ice bath is removed and the mixture is allowed to stir overnight. The mixture is then warmed in a water bath at approximately 40°-50° under reduced pressure for 10-20 min (no appreciable removal of nitromethane occurs but there is some further reaction observed). The mixture is partitioned between ethyl ether and saline, the layers are separated and the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The crude material is stored overnight in the refrigerator and then chromatographed on silica gel eluting with hexane and then ethyl acetate/hexane (2/98). The appropriate fractions are pooled and concentrated to give the title compound, NMR (CDCl3) 1.20, 2.05, 2.87, 3.43-3.86, 4.69 and 7.24 δ.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:17])=[C:5]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:6]=[C:7]([F:10])[C:8]=1[F:9].[Cl:18][C:19]1[N:24]=[C:23]2[NH:25][N:26]=[CH:27][C:22]2=[CH:21][N:20]=1>>[Cl:18][C:19]1[N:24]=[C:23]2[N:25]([CH2:2][C:3]3[C:4]([F:17])=[C:5]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)[CH:6]=[C:7]([F:10])[C:8]=3[F:9])[N:26]=[CH:27][C:22]2=[CH:21][N:20]=1
Reactant: Fc1cc(N2CCOCC2)c(F)c(CBr)c1F
Reactant: Clc1ncc2cn[nH]c2n1
Product: Fc1cc(N2CCOCC2)c(F)c(Cn2ncc3cnc(Cl)nc32)c1F

Procedure:
4-(3-(bromo methyl)-2,4,5-trifluorophenyl)morpholine and 6-chloro-1H-pyrazolo[3,4-d]pyrimidine were coupled as in Example 1 (Step ii) to afford 4-(3-((6-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-2,4,5-trifluorophenyl)morpholine followed by Example 1 (Step i) using tert-butyl 4-amino-1H-pyrazole-1-carboxylate to afford the title product. 1H NMR (d6-DMSO) δ 12.55 (s, 1H), 9.87 (br s, 1H), 8.89 (s, 1H), 8.15 (br s, 1H), 8.00 (s, 1H), 7.70 (s, 1H), 7.21-7.14 (m, 1H), 5.58 (s, 2H), 3.68 (t, 4H), 2.93 (t, 4H); LC-MS method B, (ES+) 431.1, RT=7.59 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].O[N:21]=[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:25]=1)[NH2:23]>>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:12][N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][OH:33])=[CH:26][CH:25]=3)[N:21]=2)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: NC(=NO)c1ccc(OCCO)cc1
Product: COCc1cc(-c2nc(-c3ccc(OCCO)cc3)no2)ccc1-c1ccccc1C

Procedure:
The title compound was prepared following the general procedure 4 starting from Intermediate 3 and Intermediate 27 affording the product as colorless oil. LC/MS (Method B): 417.3 (M+H)+. HPLC (Method A) Rt 5.43 min (Purity: 96.4%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([Cl:13])=[CH:7][CH:8]=2)[N:3]=1.[CH3:14][O-:15].[Na+].[H-].[Na+]>CO>[Cl:13][C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH3:12])=[CH:11][C:2]([O:15][CH3:14])=[N:3]2)=[CH:8][CH:7]=1
Reactant: C[O-]
Reactant: Cc1cc(Cl)nc2cc(Cl)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C)c2ccc(Cl)cc2n1

Procedure:
2-Chloroquinoline 14 (7.0 g; 32.8 mmol) was added to a solution of sodium methoxide in methanol generated from 1.08 g (36.1 mmol) of 80% sodium hydride in 80 ml of methanol. The resulting mixture was refluxed overnight. It was filtered while still hot to remove undissolved matter. The product crystallized from the methanol upon cooling to deliver 6.1 g (70%) of 15 as a white solid. 1H NMR (CDCl3);: δ2.62 (s, 3H); 4.10 (s, 3H); 6.78 (s, 1H); 7.38 (d, 1H); 7.81 (d, 1H); 7.93 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=[O:15])[CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:17]1([CH2:20]O)[CH2:19][CH2:18]1>>[CH:17]1([CH2:20][O:15][C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:19][CH2:18]1
Reactant: OCC1CC1
Reactant: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)O
Product: C[C@H](NC(=O)Cc1cccc(Cl)c1)C(=O)OCC1CC1

Procedure:
Following General Procedure C above, and using N-(3-chlorophenylacetyl alanine (from Example D above) and cyclopropylmethanol (Aldrich), the title compound can be prepared. The reaction was monitored by tlc on silica gel and purification was by liquid chromatography using 3:7 EtOAc:hexane as the eluant.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.Cl.[NH2:10][NH:11][C:12](N)=[O:13]>Cl.C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:12](=[O:13])[NH:11][N:10]=2)[N:3]=1
Reactant: NNC(N)=O
Reactant: Clc1ccc(Cl)nn1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1[nH]nc2ccc(Cl)nn12

Procedure:
To a stirring solution of 3 g (20 mmol) of 3,6-dichloropyridazine and 4.5 g (40 mmol) semicarbazide hydrochloride in 100 mL of a 3:1 mixture of ethanol/water was added 5 drops of concentrated hydrochloric acid. The resulting solution was heated to reflux for 24 h under nitrogen then evaporated in vacuo and the resulting solid was recrystallized from ethanol to yield the title compound as a yellow crystalline solid. A similar route to this compound is described in the literature (P. Francavilla, et. al. J. Heterocyclic Chem., 1971, 8, 415-419). LC/MS 171.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]3[CH2:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH2:15][CH:9]3[C:8]([CH3:21])([CH3:20])[O:7][C:6]=2[CH:5]=[C:4]([C:22]([CH3:30])([CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:3]=1>[Pd].C(O)C>[OH:1][C:2]1[C:11]2[CH:10]3[CH2:12][CH:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:14][CH2:15][CH:9]3[C:8]([CH3:20])([CH3:21])[O:7][C:6]=2[CH:5]=[C:4]([C:22]([CH3:29])([CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:3]=1
Reactant: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)C1CC=C(NC(C)=O)CC21
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)C1CCC(NC(C)=O)CC21
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 1.177 g. of dl-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-(acetamido)-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran in 100 ml. of ten percent aqueous ethanol containing 0.5 g. of five percent palladium suspended on carbon was stirred at 50° C. for 12 hours under a hydrogen atmosphere at 50 psi. The reaction mixture then was cooled to room temperature and filtered. The filtrate was concentrated to dryness by evaporation under reduced pressure to provide 1.06 g. of dl-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-(acetamido)-6a,7,8,9,10,10a-hexahydro-6H-dibenzo[b,d]pyran.