Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:16]=[C:17]([CH:33]=[C:34]([O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39])[CH:35]=1)[CH2:18][N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[C:21]([CH3:31])=[C:20]1[CH3:32]>>[Cl:14][C:15]1[CH:35]=[C:34]([CH:33]=[C:17]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28](=[O:29])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:25][CH:26]=3)[C:21]([CH3:31])=[C:20]2[CH3:32])[CH:16]=1)[O:36][C@H:37]([CH3:42])[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)[C@@H](C)Oc1cc(Cl)cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)c1
Reactant: CC(C)c1cccc([C@H](C)N)c1
Agent: Cl
Product: COC(=O)[C@@H](C)Oc1cc(Cl)cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (R)-1-(3-chloro-5-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16](NC)=[O:17])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33].NC[C@@H](O)[CH2:37][OH:38].CN1CCOCC1>>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C@@H:16]([OH:17])[CH2:37][OH:38])=[O:13])[CH:5]=[N:4][C:3]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[F:33]
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2cnc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: NC[C@@H](O)CO
Solvent: CN1CCOCC1
Product: Cc1ccc(C(=O)NC[C@@H](O)CO)cc1-n1cnc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 40 %

Procedure:
The title compound was prepared by a procedure similar to the one described for 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide using (R)-(+)-3-amino-1,2-propanediol (0.162 g 2.5 mmol) as the amine and without the addition of a second equivalent of N-methylmorpholine. After reverse phase HPLC purification, the organic extracts were concentrated under reduced pressure and dried in vacuo to afford the desired product (374.5 mg, 40%) as beige solid. 1H-NMR (CD3OD, 400 MHz) δ 8.32 (s, 1H), 7.92 (dd, 1H, J=2 Hz), 7.77 (d, 1H, J=2 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.4 Hz), 7.04 (m, 2H), 5.60 (q, 2H, J=12.4 Hz), 3.80 (m, 1H), 3.53 (m, 3H), 3.39 (m, 1H), 2.19 (s, 3H); ES-HRMS m/z 524.0649 (M+H C22H21BrF2N3O5 requires 524.0627).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].Cl.[O:7]1[CH:12]=[CH:11][CH2:10][CH2:9][CH2:8]1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:5][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][O:7]1)[CH2:2][C:3]#[CH:4]
Reactant: C1=COCCC1
Reactant: C#CCCO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Product: C#CCCOC1CCCCO1
Reaction time: 16 h

Procedure:
A solution of 3-butyn-1-ol (74.5 g, 1.06 mol) in carbon tetrachloride (225 ml) is cooled in an ice bath, and treated with concentrated hydrochloric acid (1 ml). Dihydropyran (157 g, 1.86 mol) is then added via a dropping funnel. After stirring 16 hours the reaction mixture is treated with solid sodium bicarbonate for 30 minutes and filtered. The reaction mixture is concentrated and the residue is distilled in vacuo to give the title compound.
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[O:15]1[CH2:16][CH2:17][N:12]([C:2]2[C:6]3[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=3[S:4][CH:3]=2)[CH2:13][CH2:14]1
Reactant: C1COCCN1
Reactant: O=c1[nH]ccc2scc(Br)c12
Product: O=c1[nH]ccc2scc(N3CCOCC3)c12
Yield: 42.7 %

Procedure:
3-Bromothieno[3,2-c]pyridin-4(5H)-one from Example 202.3 (411 mg, 1.786 mmol) and morpholine 81501 mg, 17.23 mmol) were stirred in a microwave for 3 h at 220° C. The mixture was poured onto water and extracted with DCM. The organic phase was concentrated and the residue was recrystallized from EA to give 180 mg (yield: 42.6%) of the title compound.
Reaction SMILES: Cl[CH2:2][N:3]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]1[Br:10].[O-:11][CH2:12][CH3:13].[Na+]>C(O)C>[CH2:12]([O:11][CH2:2][N:3]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[C:4]1[Br:10])[CH3:13]
Reactant: ClCn1c(Br)nc(Cl)c1Cl
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOCn1c(Br)nc(Cl)c1Cl
Yield: 22.8 %

Procedure:
A mixture of 1.06 g of 1-chloromethyl-2-bromo-4,5-dichloroimidazole, 0.54 g of sodium ethoxide and 40 ml of ethanol was heated under reflux for 10 hours. The reaction mixture was then concentrated under reduced pressure to obtain an oily product. This product was purified by column chromatography on silica gel to obtain 0.25 g of 1-ethoxymethyl-2-bromo-4,5-dichloroimidazole.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]2)[NH:11][C:10]3=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([N:17]2[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]2)[N:11]=[C:10]3[N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(N4CCCCC4)cc3c(=O)[nH]2)c1
Reactant: C1CCNC1
Product: O=C(O)c1cnn(-c2nc(N3CCCC3)c3cc(N4CCCCC4)ccc3n2)c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-(piperidin-1-yl)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and pyrrolidine in step E. MS (ESI/CI): predicted mass C21H24N6O2, 392.2.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]2.O.[NH2:20][NH2:21].CCOCC.O>N1C=CC=CC=1>[NH:20]([C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:5]2)[NH2:21]
Reactant: NN
Reactant: O=c1[nH]c2ccc(Cl)nc2cc1-c1ccccc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccncc1
Product: NNc1ccc2[nH]c(=O)c(-c3ccccc3)cc2n1
Temperature: 160 °C

Procedure:
A mixture of 6-chloro-3-phenyl-1,5-naphthyridin-2(1H)-one (7-1) (1.4 g, 5.61 mmol) and hydrazine hydrate (2 g, 40 mmol) in pyridine (18 mL) was heated under microwave irradiation at 160° C. for 1.5 hours. To the mixture was added Et2O and water, and the resulting solid was collected by filtration to give 6-hydrazino-3-phenyl-1,5-naphthyridin-2(1H)one (7-2) as orange solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[CH2:7][CH2:6][CH2:5]2.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC([N+](C(OCC)=O)=[N-])=O)C>ClCCCl>[OH:1][C:2]1[C:3]([C@@H:20]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[CH2:7][CH2:6][CH2:5]2
Reactant: COC(=O)CCCCC[C@H](O)c1ccc(F)cc1
Reactant: Cc1c(O)cc2c(c1C)CCC2
Agent: CCOC(=O)[N+](=[N-])C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCCl
Product: COC(=O)CCCCC[C@H](c1ccc(F)cc1)c1c(O)c(C)c(C)c2c1CCC2
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of 5-hydroxy-6,7-dimethylindan (0.96 g, 5.9 mmol), methyl (S)-7-(4-fluorophenyl)-7-hydroxyheptanoate (0.30 g, 1.2 mmol) and triphenylphosphine (0.46 g, 1.8 mmol) in 1,2-dichloroethane (15 ml) was added dropwise a solution of 95% diethyldiazodicarboxylate (DEAD) (0.33 ml) in 1,2-dichloroethane (3 ml) at 10° C. taking 30 minutes. The mixture was stirred for one hour at the same temperature range, then the solvent was distilled off under reduced pressure. The residue was subjected to a silica gel coluann chromatography to give 0.18 g of methyl (R)-7-(5-hydroxy-6,7-dimethylindan-4-yl)-7-(4-fluorophenyl)heptanoate. Likewise, Compound 1, 5-8 and 10-17 were prepared.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]([NH:5][C:6]1([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:41]=[CH:40][CH:39]=[CH:38][N:37]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:13][CH:12]=2)[CH2:9][C:8](=O)[CH2:7]1)=[O:4].[CH3:44][NH:45][CH3:46].CCOC(C)=O.C([O-])(O)=O.[Na+]>CO.[Cl-].[Na+].O>[CH3:44][N:45]([CH3:46])[CH:8]1[CH2:9][C:6]([NH:5][C:3](=[O:4])[C:2]([F:1])([F:43])[F:42])([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:26]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:25][C:24]4[C:23]5=[N:33][N:34]=[C:35]([C:36]6[N:37]=[CH:38][CH:39]=[CH:40][N:41]=6)[N:22]5[CH:21]=[CH:20][C:19]=4[N:18]=3)=[CH:15][CH:16]=2)[CH2:7]1
Reactant: CNC
Reactant: O=C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)C1CC(NC(=O)C(F)(F)F)(c2ccc(-c3nc4ccn5c(-c6ncccn6)nnc5c4cc3-c3ccccc3)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,2,2-trifluoro-N-(3-oxo-1-{4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)acetamide (4-2) (20 mg, 0.035 mmol) and dimethylamine (2M in THF, 0.052 mL, 0.104 mmol) in MeOH (0.3 mL) was added Zn(BH3CN)2 (0.3M in MeOH, 0.6 mL, 0.18 mmol), and the mixture was stirred at room temperature for overnight. To the mixture was added EtOAc, sat. NaHCO3, and brine. The resulting solid was collected by filtration to give N-(3-(dimethylamino)-1-{-4-[9-phenyl-3-(2-pyrimidinyl)[1,2,4]triazolo[3,4-f]-1,6-naphthyridin-8-yl]phenyl}cyclobutyl)-2,2,2-trifluoroacetamide (4-4) as colorless solid. HRMS (M+H)+: observed=609.2338, calculated=609.2342.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:23][CH2:24][C:25]1[N:29]([C:30]2[S:31][C:32]([CH2:44][CH3:45])=[CH:33][C:34]=2[C:35](=[O:43])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[Cl:42])[C:28]([CH3:46])=[N:27][N:26]=1.[CH:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][C:48]=1[C:57](O)=[O:58].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(N(CC)CC)C>[Cl:42][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[C:35]([C:34]1[CH:33]=[C:32]([CH2:44][CH3:45])[S:31][C:30]=1[N:29]1[C:28]([CH3:46])=[N:27][N:26]=[C:25]1[CH2:24][NH:23][C:57]([C:48]1[CH:49]=[CH:50][C:51]2[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=2)[CH:47]=1)=[O:58])=[O:43]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CN)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(C)nnc2CNC(=O)c2ccc3ccccc3c2)s1
Reaction time: 8 h
Yield: 19.6 %

Procedure:
3-Aminomethyl-4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazole di-p-toluenesulfonate (3.70 g) was dissolved in dimethylformamide (20 ml). Naphthalene-2-carboxylic acid (0.95 g) and diphenylphosphoryl azide (1.29 ml) were added under ice-cooling and dissolved in the solution. A solution of triethylamine (2.24 ml) in dimethylformamide was dropwise added, and the mixture was allowed to stand overnight at room temperature. Then, a 10% aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate to give 0.53 g of N-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethyl)naphthalene-2-caboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:20])=[C:9]([O:16][C:17](=O)[CH3:18])[C:10](=[O:15])[N:11]2[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:21](Br)C=C.CI>>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([OH:20])=[C:9]([O:16][CH2:17][CH:18]=[CH2:21])[C:10](=[O:15])[N:11]2[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)Oc1c(O)c2ccc([N+](=O)[O-])cc2n(C)c1=O
Reactant: C=CCBr
Solvent: CI
Product: C=CCOc1c(O)c2ccc([N+](=O)[O-])cc2n(C)c1=O

Procedure:
In accordance with EXAMPLE 15, using 7-nitro-3-acetoxy-4-hydroxy-1-methyl-2(1H)-quinolinone, allyl bromide was used as an alkylating agent instead of methyl iodide, 7-nitro-3-(2-propenyloxy)-4-hydroxy-1-methyl-2(1H)-quinolinone was provided. In the following, the spectrum data was shown.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][NH:14][CH2:15][CH:7]1[C:6](=[O:16])[NH:5]2.[N:17]1[CH:22]=[CH:21][C:20]([CH2:23]Cl)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][N:14]([CH2:23][C:20]3[CH:21]=[CH:22][N:17]=[CH:18][CH:19]=3)[CH2:15][CH:7]1[C:6](=[O:16])[NH:5]2
Reactant: O=C1Nc2cc(F)ccc2N2CCNCC12
Reactant: ClCc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C1Nc2cc(F)ccc2N2CCN(Cc3ccncc3)CC12

Procedure:
A solution of 2 g. (0.008 mole) of 8-fluoro-2,3,4,4a-tetrahydro-1H-pyrazino[1,2-a]quinoxalin-5(6H)-one and 1.6 g. (0.01 mole) of 4-picolyl chloride, 3.5 g. of potassium carbonate and 0.5 ml. of triethylamine was stirred and refluxed in 100 ml. of acetone for 48 hours, cooled and filtered. The solvent was removed under reduced pressure. The residue was dissolved in ethanol and treated with dry hydrogen chloride saturated ether. The product hydrochloride was filtered and recrystallized from ethanol-water to yield 1.25 g. of the title compound as the dihydrochloride, m.p. 269°-272° C.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([NH:6][C:7]([O:9]C2C=CC=CC=2)=O)=[CH:4][CH:3]=1.Cl.[NH2:19][N:20]1[CH2:25][CH:24]=[CH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:6][C:7]([NH:19][N:20]2[CH2:21][CH:22]=[CH:23][CH2:24][CH2:25]2)=[O:9])=[CH:16][CH:17]=1
Reactant: NN1CC=CCC1
Reactant: O=C(Nc1ccc(F)cc1)Oc1ccccc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)NN1CC=CCC1
Yield: 45.1 %

Procedure:
A solution of 4-fluoro-N-phenoxycarbonylaniline (2.29 g), N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (1.02 g) in chloroform (25 ml) was refluxed for 20 hours. After evaporation of chloroform, the residue was extracted with ethyl acetate (100 ml). The extract was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (20 g) using chloroform as an eluent to give N-[[(4-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (1.05 g). mp: 156°-157° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15](F)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>CS(C)=O.O.C(OC(C)C)(C)C>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:30]5[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:20])[C:6]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cn(C2CC2)c2nc3cc(F)c(F)cc3cc2c1=O
Solvent: CS(C)=O
Solvent: CC(C)OC(C)C
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2nc3cc(N4CCN(C)CC4)c(F)cc3cc2c1=O
Yield: 74.4 %

Procedure:
A suspension of 1.2 g of 1-cyclopropyl-3-ethoxycarbonyl-7,8-difluoro-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine in 1.4 g of 1-methylpiperazine and 20 cm3 of dimethyl sulphoxide is heated at a temperature close to 95° C. for 45 minutes. After cooling to a temperature close to 20° C., the reaction mixture is diluted with 100 cm3 of water and extracted with 3 times 30 cm3 of trichloromethane. The combined organic extracts are washed with 3 times 30 cm3 of water, dried over magnesium sulphate, filtered and concentrated under reduced pressure (20 kPa) at a temperature close to 50° C. The solid obtained is taken up in 20 cm3 of diisopropyl ether, drained, washed with 10 cm3 of the same solvent and recrystallized from 150 cm3 of ethyl acetate. 1.1 g of 1-cyclopropyl-3-ethoxycarbonyl-7-fluoro-8-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine are obtained in the form of a yellow solid melting at 223° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH:6]([CH3:8])[CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.[NH4+].[Cl-]>C(Cl)Cl>[CH2:5]([C@@H:2]1[CH2:3][O:4][C:17](=[O:19])[NH:1]1)[CH:6]([CH3:8])[CH3:7]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)C[C@@H](N)CO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@@H]1COC(=O)N1
Temperature: 4 °C
Reaction time: 0.25 h
Yield: 264.9 %

Procedure:
To a cooled (4° C.) solution of (R)-2-amino-4-methylpentan-1-ol (2.98 g, 25.4 mmol) and triethylamine (7.6 mL, 54 mmol, 2.1 equiv) in CH2Cl2 (80 mL) was added dropwise a solution of triphosgene (2.52 g, 8.49 mmol, 0.334 equiv) in 10 ml of CH2Cl2 over 30 min. The reaction mixture was stirred at 4° C. for 15 min, warmed up to room temperature and stirred for an additional 1 h. The mixture was treated with saturated NH4Cl (25 mL), followed by CH2Cl2 (50 mL) and the resulting mixture was stirred for 20 min. The layers were separated and the organic layer was washed with water. The combined aqueous layers were extracted with CH2Cl2 (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to give (R)-4-isobutyloxazolidin-2-one (3.22 g) in 88% yield. The crude product was used for the next reaction without purification. 1H NMR (400 MHz, CD3OD) δ 4.53-4.47 (m, 1H), 4.00-3.92 (m, 2H), 1.67 (ddq, J=13, 8.0, 6.5 Hz, 1H), 1.56-1.48 (m, 1H), 1.40-1.32 (m, 1H), 0.95 (d, J=6.1 Hz, 3H), 0.93 (d, J=6.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7](Cl)=[O:8].BrC1SC(C)=CC=1C(O)=O.S(Cl)(Cl)=O.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=1[OH:34]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[OH:34][C:27]1[CH:28]=[C:29]([O:32][CH3:33])[CH:30]=[CH:31][C:26]=1[NH:25][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[S:3][C:2]=1[Br:1])=[O:8]
Reactant: Cc1cc(C(=O)Cl)c(Br)s1
Reactant: COc1ccc(N)c(O)c1
Agent: Cc1cc(C(=O)O)c(Br)s1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)c2cc(C)sc2Br)c(O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.5 %

Procedure:
2-Bromo-5-methyl-3-thiophenecarbonyl chloride (2.6 g), prepared in the same manner as above from 2-bromo-5-methyl-3-thiophenecarboxylic acid and thionyl chloride, was suspended in toluene (20 ml). This toluene solution was added dropwise to a solution of 2-amino-5-methoxyphenol (2.0 g) in pyridine (50 ml) at 0° C. The mixture was stirred at room temperature for 2.5 hours and the solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration, and washed with diluted hydrochloric acid and diisopropyl ether to give N-(2-hydroxy-4-methoxyphenyl)-2-bromo-5-methyl-3-thiophenecarboxamide (2.1 g).
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[CH2:14][C:15]1[S:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.O>[CH3:30][C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[S:19][C:15]=1[CH2:14][S:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: O=C1CCCc2cc(S)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CSc1ccc2c(c1)CCCC2=O
Reaction time: 16 h

Procedure:
To a solution of 6-mercapto-3,4-dihydro-2H-naphthalen-1-one (3.5 g, 20 mmol) in acetonitrile (100 mL), under nitrogen atmosphere, was added %-chloromethyl-4-methyl-2-(4-trifluoromethylphenyl)thiazole (5.7 g, 20 mmol) followed by cesium carbonate (6.4 g, 20 mmol). The resulting mixture was stirred 16 h, diluted with water (100 mL). The precipitate was collected by filtration, dried, dissolved in EtOAc, and filtered through a plug of silica gel. The filtrate was concentrated under vacuum and the residue purified by recrystallization in iso-propanol to give 5.21 g (61%) of cream colored crystals. (mp 123–124° C.) Analyzed for C22H18F3NOS2: Calcd: C, 60.95%; H, 4.19%; N, 3.23%; Found: C, 60.79%; H, 4.09%; N, 3.09%.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[S:20][CH3:21])[CH3:11])=[O:9])[C:4](=[O:22])O1.[CH2:24]=O.[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:10]([CH3:11])[C:8]([C:7]2[CH2:24][N:26]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:4](=[O:22])[C:5]=2[OH:6])=[O:9])=[C:14]([S:20][CH3:21])[CH:15]=1
Reactant: CSc1cc(F)ccc1CN(C)C(=O)C=C1OC(C)(C)OC1=O
Reactant: C=O
Reactant: NCCCC(=O)O
Product: CSc1cc(F)ccc1CN(C)C(=O)C1=C(O)C(=O)N(CCCC(=O)O)C1
Yield: 49 %

Procedure:
2-(2,2-Dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(4-fluoro-2-methylsulfanyl-benzyl)-N-methyl-acetamide was reacted with paraformaldehyde and 4-amino-butyric acid as described in Method 44B to give the title compound as a white solid (0.05 g, 49% yield). 1HNMR (300 MHz, CDCl3) δ: 7.11 (1H, dd, J=8.42, 5.85 Hz), 6.91 (1H, dd, J=9.52, 2.57 Hz), 6.82 (1H, td, J=8.41, 2.56 Hz), 4.64 (2H, s), 4.15 (2H, s), 3.55 (2H, t, J=6.96 Hz), 2.98 (3H, s), 2.47 (3H, s), 2.38 (2H, t, J=6.95 Hz), 1.96–1.88 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CC(C)(C)C([O:13][C:14](=O)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=O.N1C=CC=CC=1>CN(C)C=O.O>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][C:14](=[O:13])[CH2:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)C(=O)OC(=O)Cc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1cccc(O)c1

Procedure:
Pyridine (14 g, 0.18 Mol) and 4-nitrophenylacetic acid (32 g, 0.18 Mol) were stirred in toluene (100 ml) whilst trimethylacetylchloride (21 g, 0.18 Mol) was added. The toluene was evaporated to yield 4-nitrophenylacetic-trimethylacetic anhydride. 3-Aminophenol (20 g, 0.18 Mol) was stirred in DMF (100 ml) and treated with the mixed anhydride and pyridine (14 g) in dimethylformamide (DMF) dropwise. The solution was diluted with water and the product isolated by filtration and dried (19 g, 39%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[O:8])[CH:2]=1.[C-]#N.[Na+].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].C(O)(=O)C>CN(C)C=O.O>[O:8]=[C:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH2:14][CH2:13][C:12]([O:16][CH3:17])=[O:15]
Reactant: O=Cc1cccnc1
Reactant: C=CC(=O)OC
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)CCC(=O)c1cccnc1
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
A solution of 3-pyridinecarboxaldehyde (10.7 g) in dimethyl formamide (DMF, 20 mL) was added over 10 min. to a stirred solution of sodium cyanide (2.45 g) in DMF (80 mL) at room temperature under dry nitrogen. The solution was stirred for 30 min. and methyl acrylate (18.6 g) in DMF (80 mL) was added dropwise over 50 min. The reaction mixture was stirred for 3 h. Acetic acid (6.6 mL) and water (30 mL) were added and stirring was continued for 5 minutes. The mixture was concentrated, dissolved in water (360 mL), and pH was adjusted to 7.5 with sodium bicarbonate. The aqueous layer was extracted with chloroform (3×300 mL). The chloroform layers were combined, washed with saturated sodium chloride solution (brine), dried (MgSO4), filtered, concentrated and purified by flash chromatography (SiO2, 30% ethyl acetate in hexanes) to yield 4.3 g (22%) of the title compound; ESMS (M+1)+194.