Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=3[C:24](=[O:26])[CH3:25])=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:28][O:27][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([CH3:23])=[CH:18][C:17]=1[C:24](=[O:26])[CH3:25]
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCN1CCOCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
1-{2-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone (compound 315) (52 mg), morpholine (34 mg), and potassium carbonate (90 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (18 mg, 31%).
Reaction SMILES: C([O:5][C:6]([CH2:8][CH2:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:7][C:6]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:14]#[N:15])=[CH:16][CH:17]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)CCc1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 100 %

Procedure:
A 2.31 g portion of 4-(2-t-butoxycarbonylethyl)-benzonitrile was admixed with 3 ml of trifluoroacetic acid and 30 ml of methylene chloride. The mixture was stirred at room temperature for 13 hours and concentrated. The resulting concentrate was subjected to azeotropic distillation with use of toluene, giving 1.75 g (yield 100%) of crude 4-(2-hydroxycarbonylethyl)benzonitrile. This compound was used for the subsequent reaction without purification.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)[N:10]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[N:10][C:11]([NH:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1)=[CH:12]2
Reactant: Oc1ccccc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(Oc3ccccc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 10 was used, starting from phenol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (6-methoxy-1-phenoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([C:11]1[C:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[N:13][N:14]([CH3:16])[CH:15]=1)[N:5]=2.[CH2:24]([NH2:27])[CH2:25][CH3:26]>O1CCOCC1.C(Cl)Cl>[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:12]1[C:11]([C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:27][CH2:24][CH2:25][CH3:26])=[N:10][C:9]3=[CH:8][CH:7]=2)=[CH:15][N:14]([CH3:16])[N:13]=1
Reactant: CCCN
Reactant: Cn1cc(-c2ccc3nc(Br)sc3n2)c(-c2ccccc2F)n1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCNc1nc2ccc(-c3cn(C)nc3-c3ccccc3F)nc2s1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A solution of 2-bromo-5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)thiazolo[5,4-b]pyridine (0.0294 g, 0.0755 mmol, 1.0 eq.) and n-propylamine (0.1 mL, 1.22 mmol, 16.1 eq.) in 1,4-dioxane (1.5 mL) was heated at 75° C. for 3 h. After cooling to room temperature, the reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-4-yl)-N-propylthiazolo[5,4-b]pyridine-2-amine as a light tan solid (0.0270 g, 97% yield). LC/MS (MH)= 368.16.
Reaction SMILES: [C:1]([CH:4]([C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:5]#[N:6])(=O)[CH3:2].Cl.[NH2:21][NH:22]C(N)=O.CO>O>[NH2:6][C:5]1[C:4]([C:7]2[CH:12]=[CH:11][C:10]([S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)=[C:1]([CH3:2])[NH:22][N:21]=1
Reactant: CC(=O)C(C#N)c1ccc(Sc2ccccc2)cc1
Reactant: NNC(N)=O
Agent: Cl
Solvent: CO
Solvent: O
Product: Cc1[nH]nc(N)c1-c1ccc(Sc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91.4 %

Procedure:
A mixture of 520 mg of α-acetyl-4-phenylthiophenylacetonitrile, 217 mg of semicarbazide hydrochloride, 15 ml of methanol and 3 ml of water was stirred at 0° C. for 10 minutes. Removing the ice bath, 40 hours later, the mixture was stirred at room temperature for 1 hour while keeping the pH at 9 to 10 by using aqueous solution of 2N sodium hydroxide. Adding 50 ml of water, the mixture was stirred for 30 minutes in ice-cooling, and the precipitate was filtered. It was directly added to the mixed solution of 5 ml of aqueous solution of 2N sodium hydroxide and 50 ml of methanol, and the mixture was stirred for 4 hours at room temperature, and then 80 ml of water was added, and the mixture was stirred for 30 minutes in ice-cooling, then the precipitate was filtered, Washed in water and dried, thereby obtaining 500 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:32]=[CH:31][C:30]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[CH:35][CH:34]=3)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2ncc3c(I)n[nH]c3n2)c1Cl
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: COc1cc(OC)c(Cl)c(-c2ncc3c(-c4ccc(N5CCN(C)CC5)cc4)n[nH]c3n2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine (Alfa Aesar, Cat. No. H51659). LCMS (M+H)+=499.1/501.1. 1H NMR (300 MHz, DMSO-d6) δ: 9.61 (s, 1H), 7.91 (d, J=8.8 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 6.98 (s, 1H), 3.92 (s, 6H), 3.30-3.14 (m, 8H), 2.17 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([S:43][CH3:44])[N:22](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:23]=2)=[O:18])=[C:11]([F:45])[C:10]=1[O:46][C:47]1[CH:52]=[C:51]([C:53]#[N:54])[CH:50]=[C:49]([Cl:55])[CH:48]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[N:20]=[C:21]([S:43][CH3:44])[NH:22][CH:23]=2)=[O:18])=[C:11]([F:45])[C:10]=1[O:46][C:47]1[CH:52]=[C:51]([C:53]#[N:54])[CH:50]=[C:49]([Cl:55])[CH:48]=1
Reactant: CSc1nc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)c[nH]1
Yield: 75.2 %

Procedure:
N-({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)-2-(methylthio)-1-(triphenylmethyl)-1H-imidazole-4-carboxamide trifluoroacetate (0.030 g, 0.04 mmol) was dissolved in CH2Cl2 (2 mL) and trifluoroacetic acid (2 mL) and stirred for 2 h. The solvent was evaporated. Purification was accomplished by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were lyophilized to afford the title compound (0.017 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 8.57 (t, 1H), 7.79 (s, 1H), 7.68 (s, 1H), 7.43-7.52 (m, 3H), 7.30 (t, 1H), 4.45 (d, 2H), 2.55 (s, 3H). MS: m/z 451.0 (M+1).
Reaction SMILES: [CH2:1]([S:8][C:9]1[S:18][C:12]2=[N:13][CH:14]=[CH:15][C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:19]Cl.[Cl-].[Na+]>[Cl-].[Zn+2].[Cl-].C(O)(=O)C>[CH2:1]([S:8][C:9]1[S:18][C:12]2=[N:13][CH:14]=[C:15]([I:19])[C:16](=[O:17])[N:11]2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccnc2sc(SCc3ccccc3)nn12
Reactant: ClI
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: O=c1c(I)cnc2sc(SCc3ccccc3)nn12
Reaction time: 1 h
Yield: 18 %

Procedure:
Five (5) grams of the thus obtained 2-benzylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one, 5 g of zinc chloride were added to 50 ml of acetic acid. Six (6) grams of iodine monochloride was added to the mixture, and the mixture was stirred at 70°-80° C. for 1 hour. After the reaction was finished, the reaction mixture was cooled and a sodium chloride solution was added. The deposited crystals were collected by filtration, washed with water and isopropyl ether and thus 1.3 g of 2-benzylthio-6-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained. Yield 18%.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:6][N:5]([CH2:4][C:3]2[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=2[CH3:1])[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1ccc(C)c(CNN)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(C)c(Cn2[nH]c(N)cc2=O)c1
Reaction time: 8 h

Procedure:
26.6 g of 2,5-dimethylbenzylhydrazine were added dropwise to a solution of 28.2 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1 g of p-toluenesulphonic acid in 130 ml of ethanol, in the course of which the temperature rose from 25 to 35°C. After stirring overnight, the compound identified above separated out, and was filtered off and recrystallised from ethanol. Melting point: 124°, 20 g (52%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[O:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1.[CH3:23][CH2:24][O-:25].[Na+]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([O:25][CH2:24][CH3:23])[C:5]2[O:10][C:9]3[N:11]=[C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([CH3:15])[C:8]=3[C:6]=2[N:7]=1
Reactant: Cc1cc(-c2ccccc2)nc2oc3c(Cl)nc(Cl)nc3c12
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(Cl)nc2c1oc1nc(-c3ccccc3)cc(C)c12
Yield: 46.1 %

Procedure:
0.2 g (0.6 mmol) 2,4-dichloro-9-methyl-7-phenyl-pyrido[3′,2′:4,5]furo-[3,2-d]pyrimidine and 0.12 g (1.8 mmol) sodium ethylate are added by stirring into 50 ml absolute ethanol at room temperature for 24 h. Then, the precipitate is sucked off, washed with about 40 ml water and dried. Following flash chromatography, 94 mg (46%) 2-chloro-4-ethoxy-9-methyl-7-phenyl-pyrido[3′,2′:4,5]furo[3,2-d]pyrimidine is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([NH2:27])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:13])[F:12])[CH:7]=1.[O:28]=[C:29]1[NH:33][CH2:32][C@@H:31]([C:34](O)=[O:35])[CH2:30]1.CCN=C=NCCCN(C)C.Cl.O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:19]=[C:18]([NH:27][C:34]([C@H:31]3[CH2:30][C:29](=[O:28])[NH:33][CH2:32]3)=[O:35])[CH:17]=2)[CH:5]=[C:6]([CH2:8][O:9][C@H:10]([CH3:15])[C:11]([F:14])([F:12])[F:13])[CH:7]=1
Reactant: O=C1C[C@H](C(=O)O)CN1
Reactant: C[C@@H](OCc1cc(Cl)cc(-c2cc(N)nn2-c2ccccc2)c1)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: C[C@@H](OCc1cc(Cl)cc(-c2cc(NC(=O)[C@@H]3CNC(=O)C3)nn2-c2ccccc2)c1)C(F)(F)F
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of 5-[3-chloro-5-((R)-2,2,2-trifluoro-1-methylethoxymethyl)phenyl]-1-phenyl-1H-pyrazol-3-ylamine (79 mg) in N,N-dimethylacetamide (1.0 ml) were sequentially added (S)-5-oxopyrrolidine-3-carboxylic acid (31 mg) prepared according to the same procedures as Preparation 14 and WSC.HCl (47 mg) at room temperature, and the mixture was stirred overnight. To this reaction mixture was added water, and then the precipitated solid was collected by filtration. This solid was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1). To the resulting solid were added water and a small amount of methanol, and the mixture was stirred. A solid was collected from this suspension by filtration and was dried under reduced pressure to give the titled compound (60 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[NH:13][C:12]2=[O:22])[N:4]=1.CN1C=CN=C1.[F:29][CH:30]([F:35])[S:31](Cl)(=[O:33])=[O:32].O>ClCCl>[F:29][CH:30]([F:35])[S:31]([N:13]1[C:14]2[C:19](=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:11]([C:5]2[N:4]=[C:3]([O:2][CH3:1])[N:8]=[C:7]([O:9][CH3:10])[N:6]=2)[C:12]1=[O:22])(=[O:33])=[O:32]
Reactant: COc1ccc2c(c1)C(c1nc(OC)nc(OC)n1)C(=O)N2
Reactant: O=S(=O)(Cl)C(F)F
Agent: Cn1ccnc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)C(c1nc(OC)nc(OC)n1)C(=O)N2S(=O)(=O)C(F)F
Temperature: -10 °C

Procedure:
3-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-5-methoxy-1,3-dihydro-2H-indol-2-one (1.0 g) and 1-methyl-1H-imidazole (0.51 g) are introduced as initial charge in 8 ml of dichloromethane and cooled to −10° C. under nitrogen. With stirring, difluoromethanesulfonyl chloride (0.66 g) is added dropwise in two portions and the mixture is stirred for 2.5 hours at −5 to −10° C. For the work-up, water is added and the mixture is stirred, and the solid is filtered off, washed with dilute hydrochloric acid and water and dried. This gives the title compound as a solid in an HPLC purity of 99% (0.91 g, 70% of theory). The UV absorption (maximum at 360 nm) verifies the N-sulfonylation of the product.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[NH2:10])=[CH:14][N:13]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: NNc1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: NN(Cc1ccc(Cl)nc1)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of (4-fluorophenyl)hydrazine hydrochloride (2.52 g, 20 mmol; Aldrich) and 2-chloro-5-(chloromethyl)pyridine (3.24 g, 20.00 mmol; Aldrich) in ethanol (120 mL) was treated with triethylamine (9.76 mL, 70.0 mmol; Aldrich), and the mixture was heated at 80° C. with stirring for 16 hours. The solvent was removed and the residue was purified by flash chromatography (silica gel, 10:1 CH2Cl2—CH3OH) to afford the title compound: 1H NMR (300 MHz, methanol-d4) δ ppm 4.53 (s, 2H), 6.93-6.99 (m, 2H), 7.02-7.10 (m, 2H), 7.40 (d, J=8 Hz, 1H), 7.77 (dd, J=8, 3 Hz, 1H), 8.30 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 252 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:14]=[C:13](O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].P(Cl)(Cl)([Cl:22])=O>C(Cl)Cl>[CH2:1]([C:5]1[N:14]=[C:13]([Cl:22])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(O)c2cc(C(F)(F)F)ccc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCc1nc(Cl)c2cc(C(F)(F)F)ccc2n1
Yield: 121.7 %

Procedure:
Preparation D11, Step 2: 2-butyl-6-(trifluoromethyl)-quinazolin-4-ol (100 mg, 0.37 mmol, 1 eq) and phosphorus oxychloride (3.00 mL, 3.22 mmol, 87 eq) were mixed at room temperature under nitrogen then refluxed for 3 hours. The reaction was stripped 3 times from methylene chloride. The residue was dissolved in methylene chloride (25 mL) and rinsed 3 times with saturated sodium bicarbonate (25 mL), 1× with water (25 mL). The organic layer was dried (sodium sulfate) and stripped to give 2-butyl-4-chloro-6-(trifluoromethyl)quinazoline (130 mg) as a tan solid. LCMS of a an analytical sample prepared in MeOH detects (M-Cl+OMe)+=285.24.
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][CH:3]=1.[OH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN1CCCC1=O>[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:13]3=[C:14]4[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]3)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]4=[CH:4][CH:3]=2)[CH2:23][CH2:22]1
Reactant: CC1CCc2c(Cl)ccc3c(=O)c(C(=O)O)cn1c23
Reactant: OC1CCNCC1
Solvent: CN1CCCC1=O
Product: CC1CCc2c(N3CCC(O)CC3)ccc3c(=O)c(C(=O)O)cn1c23
Reaction time: 6 h
Yield: 23.9 %

Procedure:
In a 100 ml flask were placed 6.1 g of 8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.5 g of 4-hydroxypiperidine and 60 ml of N-methylpyrrolidone and the mixture was stirred at 150° C. in an argon gas atmosphere. After 6 hours, N-methylpyrrolidone and excessive 4-hydroxypiperidine were removed under reduced pressure. To the residue were added dimethylformamide, ethanol and water and allowed to stand overnight to give 2.3 g of crude crystals which were recrystallized from ethanol-water to give 1.8 g of 8-(4-hydroxy-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 238°-240° C.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=2)[O:9][C:10]2[CH:24]=[CH:23][C:13]3[N:14]4[CH2:22][CH2:21][CH2:20][CH:15]4[NH:16][S:17](=[O:19])(=[O:18])[C:12]=3[CH:11]=2)=[N:4][N:3]=[N:2]1.[CH2:28](O)C>>[CH3:28][N:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=2)[O:9][C:10]2[CH:24]=[CH:23][C:13]3[N:14]4[CH2:22][CH2:21][CH2:20][C:15]4=[N:16][S:17](=[O:19])(=[O:18])[C:12]=3[CH:11]=2)=[N:4][NH:3][NH:2]1
Reactant: O=S1(=O)NC2CCCN2c2ccc(Oc3cccc(-c4nnn[nH]4)c3)cc21
Reactant: CCO
Product: CN1NNN=C1c1cccc(Oc2ccc3c(c2)S(=O)(=O)N=C2CCCN23)c1
Reaction time: 8 h

Procedure:
200 μl (0.39 mmol) of bis(tri-n-butyl)tin oxide are added to a suspension of the product obtained in Example 1 (300 mg, 0.78 mmol) in 20 ml of anhydrous ethanol and the solution is refluxed for 10 minutes. The ethanol is evaporated off, 1 ml of methyl iodide is added and stirring is carried out at ambient temperature overnight. The precipitate is filtered off to yield a mixture of the 1- and 2-methyl-2H-tetrazol isomers which is purified to yield the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])O[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(S(C(N)C2[N:46](C)[C:45](C(O)=O)=C(OCC3C=CC=CC=3)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:46]([CH3:45])[C:10]=1[C:28]([OH:30])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)o2)cc1
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)cc1
Yield: 70.51 %

Procedure:
3-Benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-06) (1.6 g, 70.51%) was synthesized as a white solid from 3-benzyloxy-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-4H-pyran-2-carboxylic acid (12-06) (2.2 g, 5.13 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-01).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[Mg].CN([CH:15]=[O:16])C.Cl>C1COCC1.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:9])[C:7]=1[F:8])[CH:15]=[O:16]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: CN(C)C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cc(F)c(F)c(F)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
In a nitrogen atmosphere, a solution prepared by dissolving 50 g of 3,4,5-trifluorobromobenzene in 50 mL of THF was added dropwise at a rate that caused gentle reflux to a mixed solution of 6.34 g of magnesium and 60 mL of THF. After dropwise addition, the mixture was stirred at 40° C. for 1 hour. Then, a solution prepared by dissolving 34.64 g of DMF in 60 mL of THF was added dropwise under ice cooling at such a rate that the inside temperature did not exceed 20° C., followed by stirring at room temperature for 1 hour. Then, 10% hydrochloric acid was added until the reaction system became acidic, and the mixture was stirred at room temperature for 1 hour. Then, hexane was added to the mixture to separate an organic layer, and an aqueous layer was subjected to extraction with hexane. The hexane extract was combined with the organic layer and washed with a saturated aqueous sodium bicarbonate solution and saturated brine. The resultant mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure to yield 37.91 g of 3,4,5-trifluorobenzaldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH2:16])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][C:9]=1[NH:16][C:23](=[O:22])[CH2:24][C:25](=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:27]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: COc1ccc(N)c(NC(=O)OC(C)(C)C)c1
Product: COc1ccc(NC(=O)CC(=O)c2cccc(-c3cccnc3)c2)c(NC(=O)OC(C)(C)C)c1

Procedure:
The title compound was prepared from (2-Amino-5-methoxy-phenyl)-carbamic acid tert-butyl ester (Example J12) (179 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown foam (256 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:15]([O:17]CC)=[O:16])[C:7]([C:10]([O:12]CC)=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+:21]>O>[N+:1]([C:4]1[CH:5]=[C:6]([C:15]([O-:17])=[O:16])[C:7]([C:10]([O-:12])=[O:11])=[N:8][CH:9]=1)([O-:3])=[O:2].[Na+:21].[Na+:21]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])cnc1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])c1cc([N+](=O)[O-])cnc1C(=O)[O-]
Yield: 98.6 %

Procedure:
45 g (0.168 mol) of diethyl 5-nitropyridine-2,3-dicarboxylate were added in the course of 10 minutes with stirring to a mixture of 13.4 g (0.336 mol) of sodium hydroxide in 65 ml of water and washed in with 6.5 ml of ethanol. The mixture was brought to reflux, diluted with a further 30 ml of water and cooled again after heating for 1 hour. The precipitate deposited after the addition of 500 ml of acetone was filtered off with suction, washed and dried, 42.4 g (98.6% of theory) of sodium 5-nitropyridine-2,3-dicarboxylate of m.p.>260° C. being obtained.