Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:27]=2[C:28]([NH:30][CH2:31][C:32]#[CH:33])=[O:29])[C:22]([Cl:39])=[CH:21][N:20]=1>>[Cl:39][C:22]1[C:23]([NH:25][C:26]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:27]=2[C:28]([NH:30][CH2:31][C:32]#[CH:33])=[O:29])=[N:24][C:19]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][C:8](=[O:14])[N:7]([CH2:15][CH3:16])[C:6]=3[CH:17]=2)=[N:20][CH:21]=1
Reactant: CCN1C(=O)CCC(C)(C)c2ccc(N)cc21
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)N(CC)C(=O)CCC3(C)C)ncc1Cl

Procedure:
2-[5-Chloro-2-(1-ethyl-5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-prop-2-ynyl-benzamide was prepared from 8-amino-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow solid (93 mg, 43%). m.p.=237-241° C.; LCMS (m/e) 535 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.57 (s, 1H), 8.12 (s, 1H), 7.49 (s, 1H), 7.40 (d, 1H, J=7.4 Hz), 7.36-7.25 (m, 2H), 7.21 (d, 1H, J=8.9 Hz), 7.13 (d, 1H, J=8.3 Hz), 6.89 (s, 1H), 6.34-6.27 (m, 1H), 4.19-4.15 (m, 2H), 3.77-3.65 (m, 2H), 2.34-2.21 (m, 3H), 2.10-1.93 (m, 2H), 1.33 (s, 6H), 1.20 (t, 3H, J=7.4 Hz).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][CH2:7][S:6](=[O:10])(=[O:9])[NH:5]1)([CH3:3])[CH3:2].Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=3[CH3:33])[CH2:22][CH2:21]2)=[O:19])=[C:14]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:13]=1>>[CH3:33][C:27]1[CH:28]=[C:29]([CH3:32])[CH:30]=[CH:31][C:26]=1[N:23]1[CH2:22][CH2:21][N:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([N:5]3[C@H:4]([CH:1]([CH3:3])[CH3:2])[CH2:8][CH2:7][S:6]3(=[O:10])=[O:9])=[CH:13][C:14]=2[S:34]([CH3:37])(=[O:36])=[O:35])=[O:19])[CH2:25][CH2:24]1
Reactant: CC(C)[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](C(C)C)CCS4(=O)=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 24.4 %

Procedure:
Using (S)-3-isopropylisothiazolidine 1,1-dioxide (320 mg) described in Preparation Example 6 and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 4, the title compound (130 mg) was obtained.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8][C:9]#[N:10])=[O:7].CCN(CC)CC.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(COC)OC>[O:7]=[C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)[CH:8]([C:26](=[O:27])[NH:25][C:22]1[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=1)[C:9]#[N:10]
Reactant: N#CCC(=O)c1ccc[nH]1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: N#CC(C(=O)Nc1ccc(Cl)cc1)C(=O)c1ccc[nH]1
Reaction time: 8 h

Procedure:
To the solution of 6.7 g of 2-pyrroloylacetonitrile in 25 ml of glyme and 5.5 g of Et3N is added a solution of 8.6 g of 4-chlorophenyl isocyanate in 25 ml of glyme. After the exothermic reaction, the mixture is let stand overnight. Part of the solvent is evaporated and the cooled residue is poured into a solution of 10 ml of 6N HCl in 250 ml of water. After the addition of some methanol, the crude material is collected. It is dissolved in dilute NaOH solution, the solution is treated with charcoal, filtered, and acidified with 6N HCl. The reprecipitated product is collected, washed with water, and triturated with methanol to give solid, m.p. 219°-221°. Recrystallization from methanol gives β-oxo-α-(4-chlorophenyl carbamoyl)-β-(2-pyrrolyl)propionitrile, m.p. 223°-5°.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]([CH2:13][C:14](=O)[CH3:15])[CH:11]=O)=[CH:4][CH:3]=1.C(O)(=O)C.C([O-])(=O)C.[NH4+:25].N>C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([N:10]2[CH:13]=[C:14]([CH3:15])[N:25]=[CH:11]2)=[CH:4][CH:3]=1
Reactant: COc1nc(Cl)ccc1N(C=O)CC(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1nc(Cl)ccc1-n1cnc(C)c1
Temperature: 130 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A mixture of N-(6-chloro-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (4.71 g), acetic acid (11.1 mL) and ammonium acetate (7.48 g) was stirred at 130° C. for one hour. The reaction solution was left to cool to room temperature. Ice water, ethyl acetate and aqueous ammonia were added and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 2.42 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: I[C:2]1[C:6](=[O:7])[S:5][C:4]2=[C:8](I)[C:9](=[O:11])[S:10][C:3]=12.C([Sn](CCCC)(CCCC)[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])CCC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I.C1(C)C=CC=CC=1>[CH2:23]([C:22]1[CH:21]=[CH:20][S:19][C:18]=1[C:2]1[C:6](=[O:7])[S:5][C:4]2=[C:8]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:9](=[O:11])[S:10][C:3]=12)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: O=C1SC2=C(I)C(=O)SC2=C1I
Reactant: CCCCCCCCc1ccsc1[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: Cc1ccccc1
Product: CCCCCCCCc1ccsc1C1=C2SC(=O)C(c3sccc3CCCCCCCC)=C2SC1=O
Temperature: 90 °C
Yield: 46.2 %

Procedure:
The 3,6-diiodo-thieno[3,2-b]thiophene-2,5-dione (1.000 g; 2.370 mmol), tributyl-(3-octyl-thiophen-2-yl)-stannane (Bras, Jérôme; Guillerez, Stéphane; Pépin-Donat, Brigitte. Chem. Mater. 2000, 12, 2372-2384) (2.977 g; 5.213 mmol), PdCl2(PPh3)2 (166 mg; 0.237 mmol), copper Iodide (45 mg; 0.237 mmol) and toluene (100 cm3) is added in a 250 cm3 flask. The resulting mixture is carefully degassed for 30 minutes, and then heated at 90° C. for 16 h under nitrogen protection. Silica is added and the solvent removed in vacuo. The crude product is purified by column chromatography (eluent: petroleum ether 40-60:DCM; 70:30 ratio) to recover the pure product as a red powder (612 mg, Yield: 46%). NMR (1H, 300 MHz, CDCl3): δ 7.47 (d, J=5.1 Hz, 2H); 7.02 (d, J=5.1 Hz, 2H); 2.57 (t, J=7.8 Hz, 4H); 1.61 (m, 4H); 1.26 (m, 20H); 0.86 (t, J=6.7 Hz, 6H). NMR (13C, 75 MHz, CDCl3): δ 186.92; 154.77; 145.82; 129.91; 192.26; 129.05; 123.79; 32.01; 30.70; 30.06; 29.61; 29.52; 29.37; 22.81; 14.27.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[F:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:35][CH:32]2[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]2)[N:3]=1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 90 was used, starting from (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone, Example 103, and 1-methanesulfonyl-piperidin-4-ylamine (with trifluoro-acetic acid), Example 162, to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(2,3-difluoro-6-methoxy-phenyl)-methanone. MS (M+H)+, 442.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([O:11]CC)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1nc(Cl)c(CC)[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)O)nc1Cl
Temperature: 70 °C
Reaction time: 0.67 h
Yield: 107.4 %

Procedure:
Ethyl 4-chloro-5-ethyl-1H-imidazole-2-carboxylate obtained in Example (1c) (0.52 g, 2.56 mmol) was dissolved in methanol (8 mL) and dichloromethane (2 mL), and the solution was slowly added dropwise to a 3 N aqueous lithium hydroxide solution (3.5 mL, 10.5 mmol) heated to 70° C. Following stirring at that temperature for 40 minutes, the reaction solution was concentrated under reduced pressure and 1 N hydrochloric acid was added dropwise until the pH was 7. Thereafter, purification by reverse phase silica gel column chromatography (elution solvent: distilled water) gave 0.48 g of the title compound as a white solid (100%).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:26]=1)[O:19][CH2:20][C:21](=O)[CH3:22].[CH2:31]([NH2:34])[CH2:32][CH3:33].C(O)(=O)C>ClCCCl>[F:15][C:16]1[CH:17]=[C:18]([CH:24]=[C:25]([S:27]([CH3:30])(=[O:29])=[O:28])[CH:26]=1)[O:19][CH2:20][CH:21]([NH:34][CH2:31][CH2:32][CH3:33])[CH3:22]
Reactant: CC(=O)COc1cc(F)cc(S(C)(=O)=O)c1
Reactant: CCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCCNC(C)COc1cc(F)cc(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Sodium triacetoxyborohydride (1.16 g, 5.51 mmol) was added to a stirred mixture of 1-(3-fluoro-5-methylsulfonyl-phenoxy)propan-2-one (0.905 g, 3.67 mmol), propylamine (0.24 g, 4.04 mmol), acetic acid (0.5 g, 8.33 mmol) and molecular sieves (2 g, 4 Å, 4-8 mesh) in dry 1,2-dichloroethane (20 ml) the mixture was stirred at ambient temperature for 24 h, the suspension was filtrated and sodium carbonate (100 ml, 10% aqueous solution) was added. The aqueous phase was extracted with dichloromethane (3×50 ml). The combined organic phase was dried with Na2SO4 and evaporated. Purification on flash chromatography (ethyl acetate:methanol 1:0 to 4:1). 0.3 g, 28%. MS m/z (relative intensity, 70 eV) 289 (M+, 1), 260 (9), 152 (4), 87 (6), 86 (bp).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11](O)=[O:12])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:47]([N:54]([C:56]([NH:58][CH2:59][CH3:60])=[O:57])[NH2:55])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.C(N(C(C)C)CC)(C)C>ClCCl>[CH2:47]([N:54]([C:56]([NH:58][CH2:59][CH3:60])=[O:57])[NH:55][C:11](=[O:12])[C@H:10]([N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH3:9])[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CCNC(=O)N(N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)N(Cc1ccccc1)NC(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
##STR188## To a solution of (2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (2.6 g, 7.9 mmol) in dichloromethane (20 ml) was added 1-hydroxy-7-azabenzotriazole (1.1 g, 8.0 mmol) and 1-ethyl-3-dimethylaminopropyl carbodiimide hydrochloride (1.6 g, 8.6 mmol) and the mixture was stirred at 30 min at room temperature. Then 2-benzyl-4-ethylsemicarbazide (1.3 g, 6.6 mmol) and diisopropylethylamine (1.5 ml, 8.6 mmol) in dichloromethane (20 ml) were added and the mixture was stirred overnight. The mixture was washed with saturated sodium bicarbonate (2×50 ml), dried (magnesium sulfate) and concentrated in vacuo. The obtained product was chromatographed on silica (100 g) with petrol ether/ethyl acetate 1:1 to give 3.0 g (90%) of 2-benzyl-1-[(2R)-2-(N-(tert-butoxycarbonyl)-N-methylamino)-3-(2-naphtyl)propionyl]-4-ethylsemicarbazide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:17]O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][N:13]=[N:12]2)=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(-n2cnnn2)ccc1Cl
Agent: Cl
Product: COC(=O)c1cc(-n2cnnn2)ccc1Cl
Reaction time: 20 h

Procedure:
A solution of 1.0 g of 2-chloro-5-(1-tetrazolyl)benzoic acid from Step A in 25 mL of methanol was saturated with HCl (gas) and stirred for 20 h. The solution was concentrated in vacuo, diluted with water and extracted twice with ether. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated to afford 1.0 g of title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[N:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])SC)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:37][O:38][NH2:39]>C(#N)C.[N+]([O-])([O-])=O.[Ag+]>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:39][O:38][CH3:37])=[N:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CON
Reactant: CSC(=NC(=O)OC(C)(C)C)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Agent: [Ag+]
Agent: Cl
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CONC(=NC(=O)OC(C)(C)C)Nc1ccc(CCNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39.6 %

Procedure:
To a mixture of the compound (190 mg) obtained in Example 289, triethylamine (0.14 ml), O-methylhydroxylamine hydrochloride (84 mg) and acetonitrile (5 ml), a solution of silver nitrate (90 mg) in acetonitrile (2 ml) was added and stirred at 0° C. for 15 min. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent, chloroform:ethyl acetate=3:1) to give the 75 mg of titled compound (yield, 38%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:4]=O.C[O-].[Na+].Br[CH2:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[C:18]#[N:19]>CN(C=O)C.C(O)C>[CH3:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:15]([C:16]3[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[CH:4][C:3]=2[CH:6]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Cc1ccc(O)c(C=O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1ccc2oc(-c3ccccc3C#N)cc2c1
Temperature: 75 °C
Reaction time: 0.33 h
Yield: 68.9 %

Procedure:
A solution of the product of step (a) (130 g) in dry DMF (400 ml) was added dropwise to a solution of sodium methoxide (56.2 g) in ethanol (400 ml) mechanically stirred under nitrogen. After a further 20 mins, a solution of 2-(bromomethyl)benzonitrile (182.2 g) in dry DMF (400 ml) was added dropwise. The mixture was then heated to 75° C. for 30min. The solution was allowed to cool for 1 h. A slurry of sodium methoxide (56.2 g) in dry DMF (100 ml) was added and the mixture heated at reflux for 1.5 h. The mixture was concentrated in vacuo and then poured into iced water. The solid was collected, and then triturated with methanol to give the title compound (Intermediate 7) as a beige solid (149.4 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:28]=[CH:27][C:10]2[C:11]3[N:12]([CH:16]=[C:17]([C:19]4[N:23]([CH:24]([CH3:26])[CH3:25])[N:22]=[CH:21][N:20]=4)[N:18]=3)[CH2:13][CH2:14][O:15][C:9]=2[CH:8]=1)(=O)=O.[CH3:31][NH:32][C:33]([C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)=[O:34]>>[CH:24]([N:23]1[C:19]([C:17]2[N:18]=[C:11]3[C:10]4[CH:27]=[N:28][C:7]([N:36]5[CH2:37][CH2:38][CH2:39][C@H:35]5[C:33]([NH:32][CH3:31])=[O:34])=[CH:8][C:9]=4[O:15][CH2:14][CH2:13][N:12]3[CH:16]=2)=[N:20][CH:21]=[N:22]1)([CH3:25])[CH3:26]
Reactant: CNC(=O)[C@@H]1CCCN1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cnc(OS(=O)(=O)C(F)(F)F)cc1OCC2
Product: CNC(=O)[C@@H]1CCCN1c1cc2c(cn1)-c1nc(-c3ncnn3C(C)C)cn1CCO2

Procedure:
Following the procedures of Example 388, 2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d]pyrido[3,4-f][1,4]oxazepin-9-yl trifluoromethanesulfonate and (S)—N-methylpyrrolidine-2-carboxamide were reacted to give 405. M/z 423.2, calc. 422.22. 1H NMR (400 MHz, DMSO) δ 9.06 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.74 (d, J=4.3, 1H), 5.95 (p, J=6.7, 2H), 4.58-4.41 (m, 4H), 4.35 (d, J=8.5, 1H), 3.67-3.57 (m, 1H), 3.41-3.33 (m, 1H), 2.57 (d, J=4.6, 3H), 2.15 (dd, J=10.8, 7.7, 1H), 1.94 (d, J=6.6, 3H), 1.47 (dd, J=6.6, 2.4, 6H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:26](=[O:40])[CH2:27][C:28]2[CH:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:31]=[CH:32][CH:33]=2)[CH:20]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(O)(C)(C)C>[C:30]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:31]=[CH:32][CH:33]=[C:28]([C:27]2[C:26](=[O:40])[C:25]([C:21]3[CH:20]=[C:19]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:24]=[CH:23][CH:22]=3)=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:10]=2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH:29]=1
Reactant: O=C(C(=O)c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: O=C(Cc1cccc(-c2ccccc2)c1)Cc1cccc(-c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=C1C(c2cccc(-c3ccccc3)c2)=C(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)=C1c1cccc(-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 76.6 %

Procedure:
To a degassed solution of 940 mg of 4,4′-dichlorobenzil (3.37 mmol) and 1.22 g of 1,3-di(biphenyl-3-yl)propan-2-one (7, 3.37 mmol) in 20 ml of tert-butanol was added, at 80° C., a methanolic tetrabutylammonium hydroxide solution (1M, 1.7 ml, 1.7 mmol). The reaction solution was stirred at 80° C. for 20 minutes, and the reaction then stopped by adding water. The mixture was extracted three times with dichloromethane and the collected organic phases were washed with saturated sodium chloride solution and dried over magnesium sulfate, before the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (silica gel, eluent: hexane with 20% DCM) and gave 1.56 g of the tetraarylcyclopentadienone 8b as a pale violet solid (77%, 2.58 mmol). Elemental analysis measured: C 81.3; H 3.3% (calculated for C41H26Cl2O: C, 81.3; H, 4.3%); 1H NMR (700 MHz, d8-THF) δ=7.52 (s, 2H, CH), 7.50 (d, J=7.8 Hz, 2H, CH), 7.42 (d, J=7.2 Hz, 4H, CH), 7.36 (t, J=7.7 Hz, 4H, CH), 7.32 (m, 6H, CH), 7.27 (t, J=7.3 Hz, 2H, CH), 7.23 (d, J=7.8 Hz, 2H, CH), 7.06 (d, J=8.5 Hz, 4H, CH); 13C NMR (175 MHz, d8-THF) δ=199.86, 154.28, 141.91, 141.82, 135.61, 133.14, 132.14, 132.10, 129.98, 129.90, 129.70, 129.69, 129.52, 128.27, 127.78, 127.20, 126.73; MS (MALDI-TOF): m/z (%): 604.6 (100) [M+] (calculated for C41H26Cl2: 604.1); Rf (hexane with 10% ethyl acetate)=0.47.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][CH:14]=2)[CH2:4][CH2:3]1.C(Cl)(Cl)Cl.[I:33]N1C(=O)CCC1=O>C(#N)C>[OH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]2[N:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:26])=[O:27])[CH:20]=3)[C:12]([C:15]([NH2:17])=[O:16])=[N:13][C:14]=2[I:33])[CH2:6][CH2:7]1
Reactant: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)cnc2C(N)=O)c1
Reactant: O=C1CCC(=O)N1I
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@H]3CC[C@H](O)CC3)c(I)nc2C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-[(trans-4-hydroxycyclohexyl)amino]-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (Example 111) (150 mg), chloroform (40 mL) and acetonitrile (20 mL), N-iodosuccinimide (87 mg) was added and stirred at room temperature for 2 hours. To the reaction liquid, silica gel was added, and the solvent was distilled off, followed by purification by silica gel column chromatography (eluent; chloroform:methanol=10:0 to 10:1). The resulting crude product was solidified with ethyl acetate and washed with ethyl acetate to give 5-[(trans-4-hydroxycyclohexyl)amino]-6-iodo-3-{[3-(methylsulfonyl)phenyl]amino}pyrazine-2-carboxamide (153 mg) as a light yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].[CH2:28]([O:30][C:31](=[O:34])[CH2:32][NH2:33])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[CH2:28]([O:30][C:31]([CH2:32][NH:33][C:1]([C:4]1[CH:5]=[C:6]([NH:10]/[C:11](=[C:18]2\[C:19](=[O:27])[NH:20][C:21]3[C:26]\2=[CH:25][CH:24]=[CH:23][CH:22]=3)/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)=[O:2])=[O:34])[CH3:29]
Reactant: CCOC(=O)CN
Reactant: O=C1Nc2ccccc2/C1=C(/Nc1cccc(C(=O)O)c1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)c1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 21 from (Z)-3-[1-(3-carboxyphenylamino)-1-phenyl-methylidene]-2-indolinone, glycine ethyl ester, TBTU, HOBt and triethylamine in DMF.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]2[C:6]3[CH2:20][CH2:19][C:18](=[O:21])[C:7]=3[N:8](C(OC(C)(C)C)=O)[C:9]=2[CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([Cl:22])=[CH:4][C:5]2[C:6]3[CH2:20][CH2:19][C:18](=[O:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)n1c2c(c3cc(Cl)c(Cl)cc31)CCC2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCc2c1[nH]c1cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.3 %

Procedure:
To a solution of tert-butyl 6,7-dichloro-3-oxo-2,3-dihydrocyclopenta[b]indole-4(1H)-carboxylate (0.34 g, 1.0 mmol) in CH2Cl2 (10 mL), cooled to 0° C., TFA (1 mL) was added. The reaction mixture was slowly warmed to room temperature and stirred for 90 min., quenched with saturated NaHCO3 (pH-8) and extracted with DCM (3×100 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by washing with 5% EtOAc-hexane (3×20 mL) to provide the title compound (200 mg, 83%). 1H NMR (500 MHz, DMSO-d6, δ in ppm) 11.96 (s, 1H), 8.06 (s, 1H), 7.65 (s, 1H), 3.03 (t, J=3.5 Hz, 2H), 2.92 (t, J=4.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[S:8]([NH:17][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[Cl:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Cl
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)cc1
Product: O=S(=O)(/C=C/c1ccc(Cl)cc1)Nc1ccccc1Cl
Yield: 57.8 %

Procedure:
A solution of (E)-4-chlorostyrylsulfonyl chloride (10 mmol) and 2-chloroaniline (10 mmol) was subjected to General Procedure 1, part B. The title compound, melting point 107-109° C., was obtained in 57.8% yield.