Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23]([C:25]3[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=3)[C:28]([O:30][CH3:31])=[O:29])=O)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:21][C:20]1[N:22]=[C:23]([C:25]2[CH:26]=[C:27]([CH:32]=[CH:33][CH:34]=2)[C:28]([O:30][CH3:31])=[O:29])[N:16]2[C:17]=1[CH:18]=[N:19][C:14]([NH:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[N:15]2
Reactant: COC(=O)c1cccc(C(=O)NC(C)c2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn2)c1
Agent: c1nc[nH]n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1cccc(-c2nc(C)c3cnc(Nc4cc(OC)c(OC)c(OC)c4)nn23)c1
Yield: 63.6 %

Procedure:
In a similar manner as described for Example 9, methyl 3-{[(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)amino]carbonyl}benzoate (Intermediate 21) (0.26 g, 0.56 mmol) and 1,2,4-triazole (240 mg, 3.4 mmol) in pyridine (4 mL) and phosphorus oxychloride (0.16 mL, 1.7 mmol) gave methyl 3-{5-methyl-2-[(3,4,5-trimethoxyphenyl)amino]imidazo[5,1-f][1,2,4]triazin-7-yl}benzoate (0.16 g) as a yellow solid. 1H NMR (DMSO-d6): δ9.66 (s, 1H), 9.28 (s, 1H), 8.94 (dd, J=1.7, 1.3 Hz, 1H), 8.74 (ddd, J=8.5, 1.9, 1.2 Hz, 1H), 8.01 (ddd, J=7.7, 1.8, 1.2 Hz, 1H), 7.65 (dd, J=8.3, 7.9 Hz, 1H), 7.08 (s, 2H), 3.84 (s, 3H), 3.68 (s, 6H), 3.65 (s, 3H), 2.55 (s, 3H). MS m/z 450 (M+1).
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[C:15]([O:17][CH2:18][CH2:19][CH2:20][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[O:16])=[S:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=NC1CCCCC1
Reactant: O=C(OCCCc1cccnc1)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCCCc1cccnc1)[C@@H]1CCCN1C(=S)NC1CCCCC1
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A mixture of cyclohexylisothiocyanate (120 mg; 0.9 mmol), 3-(3-pyridyl)-1-propyl (2S)-pyrrolidine-2-carboxylate (200 mg; 0.9 mmol) triethylamine (90 mg; 0.9 mmol) in 20 mL of methylene chloride was stirred for 1 hour and then partitioned between water and a 1:1 mixture of ethyl acetate and hexane. The organic phase was dried, concentrated and purified by column chromatography (50% ethyl acetate/hexane) to obtain 160 mg (47%) of the compound of Example 3 (Compound 3, Table I). 1H NMR (CDCl3, 300 MHz) δ1.16-1.40 (m, 6H); 1.50-1.71 (m, 4H); 1.95-2.08 (m,7H); 2.70-2.75 (t, 2H); 3.40-3.60 (m, 2H); 4.17-4.26 (m, 2H); 4.95-4.98 (d, 1H); 5.26-5.29 (d, 1H); 7.17-7.25 (m, 1H). Analysis calculated for C20H29N3O2S: C, 63.97; H, 7.78; N, 11.19. Found: C, 63.25; H, 7.80; N, 11.07.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[CH:20][N:19]=[C:18]([O:22]C3C=CC(NC(=O)CC(NC4C=CC(F)=CC=4)=O)=CC=3F)[CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C=CC(CC(N=C=O)=O)=CC=1.COC1C=CC(CNC2N=CN=C(O[C:72]3[CH:77]=[CH:76][C:75]([NH:78][C:79]([NH:81][C:82](=[O:91])[CH2:83][C:84]4[CH:89]=[CH:88][C:87]([F:90])=[CH:86][CH:85]=4)=[O:80])=[CH:74][C:73]=3[F:92])C=2)=CC=1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[CH:20][N:19]=[C:18]([O:22][C:72]3[CH:77]=[CH:76][C:75]([NH:78][C:79]([NH:81][C:82](=[O:91])[CH2:83][C:84]4[CH:89]=[CH:88][C:87]([F:90])=[CH:86][CH:85]=4)=[O:80])=[CH:74][C:73]=3[F:92])[CH:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Reactant: O=C(CC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1)Nc1ccc(F)cc1
Agent: O=C=NC(=O)Cc1ccc(F)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2cc(Nc3ccc(OCc4ccccc4)cc3)ncn2)c(F)c1
Yield: 90.7 %

Procedure:
The title compound was prepared from 6-(4-amino-2-fluorophenoxy)-N-(4-(benzyloxy)phenyl)pyrimidin-4-amine (Compound B of Example 29, 45 mg, 0.11 mmol) and a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example 11, 0.13 mmol) in THF using a similar procedure described for the preparation of Compound E of Example 11. The crude product was triturated with isopropyl ether to give the title compound (58 mg, 90%) as a pink solid. 1H NMR (DMSO-d6) δ 11.02 (s, 1H), 10.54 (s, 1H), 9.46 (s, 1H), 8.24 (s, 1H), 7.70 (dd, 1H, J=12.7, 2.4 Hz), 7.46-7.26 (m, 9H), 7.18 (dd, 2H, J=9.6, 8.3 Hz), 7.00 (d, 2H, J=9.6 Hz), 6.11 (s, 1H), 5.09 (s, 2H), 3.75 (s, 2H); MS(ESI+) m/z 582.3 (M+H)+.
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].N(CNC(N)=O)=O.[O:11]([C:18]1[CH:19]=[C:20]([C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][N:26]=1)[C:21](Cl)=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCOCC>[O:11]([C:18]1[CH:19]=[C:20]([C:21](=[O:22])[CH:3]=[N+:1]=[N-:2])[C:24]([CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][N:26]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=[N+]=[N-]
Reactant: CCOC(=O)CCc1cnc(Oc2ccccc2)cc1C(=O)Cl
Agent: NC(=O)NCN=O
Solvent: CCOCC
Product: CCOC(=O)CCc1cnc(Oc2ccccc2)cc1C(=O)C=[N+]=[N-]

Procedure:
To an ethereal solution of diazomethane prepared from nitrosomethylurea (2.0 g) and ether (25 ml), a solution of the said 2-phenoxy-5-ethoxycarbonylethylisonicotinoyl chloride (1.05 g) in anhydrous ether (10 ml) is added dropwise at 0° to 3° C, and the resultant mixture is stirred at 10° to 15° C for 1 hour. The reaction mixture is evaporated under reduced pressure to remove the ether. The residue is chromatographed on a column of neutral alumina/50 % benzene-n-hexane, whereby 2-phenoxy-4-diazoacetyl-5-ethoxycarbonylethylpyridine (830 mg) is obtained. This substance is recrystallized from ether/n-hexane to give crystals melting at 77° to 79° C (decomp.). IR (CCl4): 2120, 1745 cm-1.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=3[Cl:28])=[N:14][CH:15]=[N:16]2)=[C:11]([O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH:10]=1)C1C=CC=CC=1.C(O)C.C1COCC1.[H][H]>[Pd].CN(C=O)C>[Cl:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[CH:10][C:11]=2[O:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)[N:16]=[CH:15][N:14]=1
Reactant: [H][H]
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OCc4ccccc4)cc(OCCCN4CCOCC4)c23)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ccc(Cl)c(Nc2ncnc3cc(O)cc(OCCCN4CCOCC4)c23)c1
Yield: 29.3 %

Procedure:
A mixture of 7-benzyloxy-4-(2-chloro-5-methoxyanilino)-5-(3-morpholinopropoxy)quinazoline (0.185 g), 10% palladium on charcoal catalyst (0.018 g), ethanol (2.5 ml), THF (2.5 ml) and DMF (1 ml) was stirred under an atmosphere pressure of hydrogen for 16 hours. The mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography on silica using a 9:1 mixture of methylene chloride and a saturated methanolic ammonia solution as eluent. There was thus obtained the title compound (0.045 g); NMR Spectrum: (DMSOd6) 2.05 (m, 2H), 2.35 (br s, 4H), 2.45 (t, 2H), 3.55 (t, 4H), 3.8 (s, 3H), 4.42 (t, 2H), 6.7 (d, 2H), 7.45 (d, 1H), 8.3 (s, 1H), 8.45 (s, 1H), 10.05 (s, 1H); Mass Spectrum: M+H+ 445.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.[Cl:20][C:21]1[CH:26]=[C:25]([N:27]=C=O)[CH:24]=[C:23]([Cl:30])[CH:22]=1.[N:31]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[NH2:42])[CH:35]=[CH:34][CH:33]=[CH:32]1>>[Cl:20][C:21]1[CH:26]=[C:25]([NH:27][C:6]([N:8]2[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]2[C:17]([NH:42][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[N:31]2[CH:35]=[CH:34][CH:33]=[CH:32]2)=[O:19])=[O:7])[CH:24]=[C:23]([Cl:30])[CH:22]=1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: Nc1ccccc1-n1cccc1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Product: CCON=C1C[C@@H](C(=O)Nc2ccccc2-n2cccc2)N(C(=O)Nc2cc(Cl)cc(Cl)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, 1,3-dichloro-5-isocyanatobenzene, and 2-(1H-pyrrol-1-yl)phenylamine the title compound was obtained in 54% purity by LC/MS. MS(ESI+): m/z=500.6.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=1.[F:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[C:19]([F:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:17]2[CH:16]=[C:15]([F:14])[CH:20]=[C:19]([F:21])[CH:18]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cnccc2c1Cl
Reactant: OB(O)c1cc(F)cc(F)c1
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: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(F)c2)nc2cnccc2c1Cl

Procedure:
Prepared according to procedure F using 2,4-dichloro-3-methyl-1,7-naphthyridine (0.18 g, 0.845 mmol), 3,5-difluorophenylboronic acid (0.147 g, 0.929 mmol), Pd(PPh3)4 (0.098 g, 0.084 mmol), potassium carbonate (0.519 g, 3.75 mmol) in toluene (6 mL) at 95° C. for 18 h. Purification by column chromatography (silica gel; 0-25% EtOAc in hexanes) gave 4-chloro-2-(3,5-difluorophenyl)-3-methyl-1,7-naphthyridine as a yellow amorphous solid. Mass Spectrum (ESI) m/e=291.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]#[C:12][C:13]2[C:21]3[C:16](=[N:17][CH:18]=[N:19][C:20]=3[NH2:22])[N:15]([CH2:23][CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[N:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.NC1N=CN=C2N([CH2:52][CH:53]3C[CH2:57][N:56]([C:59](=O)C=C)[CH2:55][CH2:54]3)N=C(C#CC3C=C(OC)C=C(OC)C=3)C=12.C[O:64]C1C=C(C#CC2C3C(=NC=NC=3N)N([C@H]3CCNC3)N=2)C=C(OC)C=1>>[NH2:22][C:20]1[N:19]=[CH:18][N:17]=[C:16]2[N:15]([CH2:23][CH:24]3[CH2:29][CH2:28][N:27]([C:52](=[O:64])[CH:53]=[CH:54][CH2:55][N:56]([CH3:59])[CH3:57])[CH2:26][CH2:25]3)[N:14]=[C:13]([C:12]#[C:11][C:5]3[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[C:21]=12
Reactant: COc1cc(C#Cc2nn([C@H]3CCNC3)c3ncnc(N)c23)cc(OC)c1
Reactant: C=CC(=O)N1CCC(Cn2nc(C#Cc3cc(OC)cc(OC)c3)c3c(N)ncnc32)CC1
Reactant: COc1cc(C#Cc2nn(CC3CCNCC3)c3ncnc(N)c23)cc(OC)c1
Product: COc1cc(C#Cc2nn(CC3CCN(C(=O)C=CCN(C)C)CC3)c3ncnc(N)c23)cc(OC)c1

Procedure:
In accordance with Example 4, except that 3-((3,5-dimethoxyphenyl)ethynyl)-1-(piperidin-4-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (i.e., the intermediate obtained in Example 33) was used in place of (S)-3-((3,5-dimethoxyphenyl)ethynyl)-1-(pyrrolidin-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine, the title compound was obtained as a light-yellow, amorphous substance. Table 1 shows the physical properties thereof.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][S:10][C:11]=2[C:12](=[S:14])[NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][C:17](=O)[C:18]([O:20][CH3:21])=[O:19].C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[C:1]1([C:7]2[N:8]=[N:9][S:10][C:11]=2[C:12]2[S:14][CH:16]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[N:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=S)c1snnc1-c1ccccc1
Reactant: COC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Clc1ccccc1
Product: COC(=O)c1csc(-c2snnc2-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.8 %

Procedure:
In 20 ml of chlorobenzene were dissolved 1.1 g (5.0 mmol) of 4-phenyl-1,2,3-thiadiazole-5-carbothioamide and 0.92 g (5.0 mmol) of methyl bromopyruvate. The solution thus obtained was stirred for 3 hours with heating under reflux. After the reaction was completed, the reaction mixture was cooled to room temperature, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, and the objective product was extracted with ethyl acetate. The solvent was distilled off from the extract solution under a reduced pressure, and the residue was purified by silica gel column chromatography using 3:1 mixture of n-hexane and ethyl acetate. Thus, 0.74 g of the objective compound was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:10]2([NH:13][CH2:12][C:11]2([F:15])[F:14])[CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.Cl.CO>C(OCC)(=O)C>[F:14][C:11]1([F:15])[C:10]2([CH2:16][CH2:17][NH:8][CH2:9]2)[NH:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC2(C1)NCC2(F)F
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CCOC(C)=O
Product: FC1(F)CNC12CCNC2
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 129.5 %

Procedure:
To an optically-active compound of 3,3-difluoro-1,6-diazaspiro[3,4]octane-6-carboxylic acid tert-butyl ester (211 mg) were added 4M hydrochloric acid-1,4-dioxane (2.1 ml) and 2M hydrochloric acid-methanol (2.1 ml), and the mixture was stirred at room temperature for 45 minutes. To the reaction mixture was added ethyl acetate, and the mixture was filtered to give the titled compound (163 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[N:5]([CH3:13])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[CH3:31][O:32][C:33]1[CH:56]=[CH:55][C:36]([CH2:37][N:38]2[CH2:44][C:43]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51]([OH:53])=O)[CH:47]=[N:48][C:42]=3[NH:41][C:40](=[O:54])[CH2:39]2)=[CH:35][CH:34]=1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][N:38]2[CH2:44][C:43]3[CH:45]=[C:46](/[CH:49]=[CH:50]/[C:51]([N:2]([CH3:1])[CH2:3][C:4]4[N:5]([CH3:13])[C:6]5[C:11]([CH:12]=4)=[CH:10][CH:9]=[CH:8][CH:7]=5)=[O:53])[CH:47]=[N:48][C:42]=3[NH:41][C:40](=[O:54])[CH2:39]2)=[CH:55][CH:56]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)O)cc3C2)cc1
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: COc1ccc(CN2CC(=O)Nc3ncc(/C=C/C(=O)N(C)Cc4cc5ccccc5n4C)cc3C2)cc1
Yield: 83 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(1-methyl-1H-indol-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[4-(4-methoxy-benzyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.20 g, 83%) was prepared as a tan powder: 1H NMR (300 MHz, DMSO-d6) δ 12.07 (br s, 1H), 11.23-11.21 (m, 1H), 8.78 (s, 1H), 8.27-8.20 (m, 1H), 7.64-6.99 (m, 10H), 6.42-6.18 (m, 1H), 5.06-4.86 (m, 2H), 4.32-4.20 (m, 4H), 3.77-3.68 (m, 8H), 3.12-3.00 (m, 3H); MS (ESI) m/e 510 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:19])[C:12]3[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccccc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A solution of p-chlorophenyl isocyanate (15.3 g, 0.10 mol) in toluene (50 ml) is metered at room temperature into a solution of methyl anthranilate (15.1 g, 0.10 mol) in toluene (100 ml). After addition is complete, the mixture is stirred at 90° C. for 2 hours. 1.80 ml of a 30% strength solution of methanolic sodium methoxide (0.010 mol) are metered in and the mixture is stirred at 90° C. for a further 1 hour, methanol being distilled off. After cooling, the product is filtered off with suction and washed with 3×20 ml of toluene. The toluene-moist precipitate is treated with dilute sulfuric acid and the residual toluene is removed by azeotropic distillation. The product is then filtered off with suction, washed with water and dried. 26.8 g of 3-(4-chlorophenyl)-2,4(1H,3H)-quinazolinedione (yield: 98.3% of theory) of melting point 290° to 292° C. are obtained.
Reaction SMILES: C(N(CC)CC)C.I[C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]#[CH:23])[CH:17]=1>C(OCC)(=O)C.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[ClH:15].[Cl:15][C:16]1[CH:17]=[C:18]([C:22]#[C:23][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: C#Cc1cccc(Cl)c1
Reactant: Ic1cccnc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cl
Product: Clc1cccc(C#Cc2cccnc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
Add triethylamine (0.55 mL, 3.92 mmol), copper (I) iodide (19 mg, 0.098 mmol) and bis(triphenylphosphine)palladium (II) dichloride (35 mg, 0.049 mmol) to a solution of 3-iodopyridine (200 mg, 0.97 mmol) and 1-chloro-3-ethynylbenzene, (prepared essentially as described in PREPARATION 12), (133.7 mg, 0.98 mmol) in ethyl acetate (1 mL). Stir under nitrogen at room temperature for 18 h, filter through diatomaceous earth, wash with ethyl acetate and dichloromethane, and concentrate. Purify the residue by silica gel chromatography, eluting with 100:0 to 0:100 hexanes:dichloromethane. Treat with a 2 M solution of hydrogen chloride in diethyl ether to give the title compound (202 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[CH:17]([S:20](Cl)(=[O:22])=[O:21])([CH3:19])[CH3:18].N1C=CC=CC=1>O>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:20]([CH:17]([CH3:19])[CH3:18])(=[O:22])=[O:21])=[CH:3][C:4]=2[F:16])=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1F
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)S(=O)(=O)Nc1ccc(-c2ccc(C#N)n2C)c(F)c1
Temperature: 100 °C
Yield: 19.4 %

Procedure:
5-(4-amino-2-fluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (200 mg, 0.93 mmol) was dissolved in isopropyl sulfonyl chloride (0.50 mL, 2.8 mmol), pyridine (0.2 mL) was added and the mixture was heated to 100° C. for 6 hours. The mixture was then cooled and diluted with water and extracted with ethyl acetate. The organics were combined, washed with water, brine, dried over MgSO4, and concentrated. Flash chromatography (0%-100% ethyl acetate in hexane) afforded N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-3-fluorophenyl]propane-2-sulfonamide (58 mg).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C:7]1=[CH:6][CH2:5][C@@H:4]2[OH:21])[CH3:2].C.[H][H]>C1C=CC=CC=1>[CH2:1]([C@:3]12[CH2:11][CH2:10][C:9]3[C:12]4[CH:13]=[CH:14][C:15]([OH:20])=[CH:16][C:17]=4[CH2:18][CH2:19][C:8]=3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:21])[CH3:2]
Reactant: [H][H]
Reactant: CC[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CC[C@@H]2O
Solvent: c1ccccc1
Product: CC[C@]12CCC3=C(CCc4cc(O)ccc43)[C@@H]1CC[C@@H]2O

Procedure:
Shake 13β-ethylgona-1,3,5-(10),8,14-pentaene-3,17β-diol (0.28 g.) in benzene (35 cc.) with 10% palladised charcoal (300 mg.) in an atmosphere of hydrogen until 25 cc. of hydrogen has been absorbed. Filter off the catalyst, evaporate the solvent and recrystallize the residue from methanol to obtain the title product, m.p. 234°-8°; ultraviolet absorption peak at 280 mμ (ε 41,200).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])=[CH:4][C:3]=1[CH:21]=[O:22].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:21]([C:3]1[CH:4]=[C:5]([O:6][C:7]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:8]=2[C:9]#[N:10])[CH:19]=[CH:20][C:2]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:22]
Reactant: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(Br)c(C=O)c1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: COCCOC
Product: N#Cc1ccc(C(F)(F)F)cc1Oc1ccc(-c2ccccc2)c(C=O)c1
Yield: 98.9 %

Procedure:
To a mixture of 2-(4-bromo-3-formyl-phenoxy)-4-trifluoromethyl-benzonitrile (1.76 g, 4.76 mmol) and Pd(dba)3 (21.8 mg, 5 mole %) in dimethoxyethane (15 ml) was added a solution of phenylboronic acid (609 mg, 5 mmol), triphenylphosphine (15 mg, 12 mole %) and sodium carbonate (530 mg, 5 mmol) in water (10 ml). The mixture was refluxed for 3 h. The solvent was evaporated off and the aqueous layer was extracted with dichloromethane. The extracts were dried with MgSO4 and filtered through silica. Evaporation yielded a brown solid (1.73 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.[CH2:21](O)[CH:22]1[O:26][CH2:25][CH2:24][CH2:23]1.C(C1C=C(C(C)C)C=C(C(C)C)C=1S(Cl)(=O)=O)(C)C.CN1C=CN=C1.Cl>O1CCCC1.C(Cl)(Cl)Cl>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([O:16][CH2:21][CH:22]2[O:26][CH2:25][CH2:24][CH2:23]2)=[O:15])[N:6]=1
Reactant: COc1cc(OC)nc(Oc2ccccc2C(=O)O)n1
Reactant: OCC1CCCO1
Agent: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Agent: Cl
Agent: Cn1ccnc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)OCC2CCCO2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.55 Gram of 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoic acid, 0.21 g of tetrahydrofurfuryl alcohol and 0.85 g of 2,4,6-triisopropylbenzenesulfonyl chloride were dissolved in 5 ml of tetrahydrofuran. Subsequently, 0.45 g of 1-methylimidazole was added to the mixture. After stirring the resulting solution at room temperature for 1 hour in order to carry out the reaction, the reaction solution was poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (mfd. by Merck & Co., Inc., solvent: chloroform) to obtain 0.30 g of tetrahydrofurfuryl 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoate [present compound (III-g)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]#[C:11][C:12]([OH:14])=O.[Cl:15][C:16]1[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:17]=1[O:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23].ClCCl.CO.N>>[ClH:1].[Cl:15][C:16]1[CH:29]=[C:28]([NH:30][C:12](=[O:14])[C:11]#[C:10][C:3]2[C:4]([Cl:9])=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:27]=[CH:26][C:17]=1[O:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23]
Reactant: O=C(O)C#Cc1c(Cl)cc(Cl)cc1Cl
Reactant: CCN(CC)CCOc1ccc(N)cc1Cl
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCN(CC)CCOc1ccc(NC(=O)C#Cc2c(Cl)cc(Cl)cc2Cl)cc1Cl
Product: Cl

Procedure:
Prepared analogously to Example 2.3.f. from (2,4,6-trichlorophenyl)propynoic acid and [2-(2-chloro-4-aminophenoxy)ethyl]diethylamine. Yield: 0.72 g (82.9% of theory); melting point: 188° C.-191° C.; C21H20Cl4N2O2*HCl (M=510.67); calc.: molecular ion peak (M+H)+: 473/475/477/479/481; found: molecular ion peak (M+H)+: 473/475/477/479/481; Rf value: 0.4 (silica gel, dichloromethane/methanol/ammonia (90:10:0.1)).