Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH:4]([CH:7]=O)[CH:3]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][OH:16].[CH2:17]([CH:19]([CH2:42][CH2:43][CH2:44][CH3:45])[C:20]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])[CH3:18]>O1CCCC1>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[CH:4]([CH:7]=[CH:22][C:20](=[O:21])[CH:19]([CH2:17][CH3:18])[CH2:42][CH2:43][CH2:44][CH3:45])[CH2:5][CH2:6][CH:2]1[OH:1]
Reactant: CCCCC(CC)C(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCC(O)C1CCCCCCCO
Solvent: C1CCOC1
Product: CCCCC(CC)C(=O)C=CC1CCC(O)C1CCCCCCCO
Temperature: 0 °C

Procedure:
A mixture of 3-hydroxy-2-(7-hydroxyheptyl)-cyclopentanecarbaldehyde (6 g.) [prepared as described in Example 1]and 2-ethylhexanoylmethylenetriphenylphosphorane (9g.) in dry tetrahydrofuran (70 ml.) was heated under refux under nitrogen for 6 hours. The solvent was removed in vacuo and the residue was triturated with petrol (b.p. 40°-α°C.) with cooling to 0°C. and filtered to remove triphenylphosphine oxide. Evaporation of the filtrate then gave crude 2-(7-hydroxyheptyl)-3-(4-ethyl-3-oxo-1-octenyl)cyclopentanol (4.4 g.), ν max 1620 cm-1, 1655 cm-1 (liquid film), which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=O)[C:6]2[S:7][CH2:8][C:9](=[O:14])[N:10]([CH3:13])[C:11]=2[N:12]=1)[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:5]1[C:6]2[S:7][CH2:8][C:9](=[O:14])[N:10]([CH3:13])[C:11]=2[N:12]=[C:3]([CH2:1][CH3:2])[N:4]=1
Reactant: CCc1nc2c(c(=O)[nH]1)SCC(=O)N2C
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1nc(Cl)c2c(n1)N(C)C(=O)CS2
Yield: 83 %

Procedure:
The 6,7-dihydro-2-ethyl-8-methyl-3H-pyrimido- ]5,4-b][1,4]thiazine-4,7-dione of Example 115 (2.7 g, 12.04 mmole) was suspended in approximately 150 ml of phosphorus oxychloride and refluxed for about 20 hours. The solution was concentrated in vacuo and the excess phosphorus oxychloride was decomposed with the careful addition of ice and water. The aqueous solution was neutralized with the cautious addition of concentrated ammonium hydroxide, followed by the addition of sodium bicarbonate. The aqueous solution was extracted numerous times with chloroform; the extracts were combined, washed well with water, then brine, dried over magnesium sulfate, filtered and evaporated in vacuo to provide 2.4 g (83%) of an off-white solid. The structural assignment was confirmed by infrared and nuclear magnetic resonance spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:10]([C:19](OC(C)(C)C)=O)[NH:11][C:12](OC(C)(C)C)=O)=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:26]OC(OC)CC(OC)OC.CCO.OS(O)(=O)=O>CCOC(C)=O>[Cl:1][C:2]1[C:3]([N:10]2[CH:19]=[CH:26][CH:12]=[N:11]2)=[C:4]([F:9])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: COC(CC(OC)OC)OC
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1c(Cl)cnc(F)c1F
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1ncc(Cl)c(-n2cccn2)c1F
Temperature: 45 °C
Reaction time: 0.75 h
Yield: 74.2 %

Procedure:
To a stirred mixture of di-tert-butyl 1-(5-chloro-2,3-difluoropyridin-4-yl)hydrazine-1,2-dicarboxylate (4.0 g, 0.010 mol, 1.0 equiv) and 1,1,3,3-tetramethoxypropane (17 mL, 0.10 mol, 10 equiv) was added a mixture of EtOH (100 mL) and concentrated H2SO4 (28 mL). The vessel was then sealed and heated to 45° C. After stirring for 45 minutes, the mixture was diluted with EtOAc (300 mL) and washed with water (300 mL), dried over Na2SO4 and concentrated under vacuum. The residue was purified over silica gel using 100% dichloromethane as eluent to give the desired product (1.6 g, 70%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:6]([O:15][CH3:16])[CH:5]=1)([O-])=O>[Pd].CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:6]([O:15][CH3:16])[CH:5]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cnco1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1-c1cnco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.6 %

Procedure:
In a 2 L hydrogenation flask was placed 1C (130.0 g, 0.6131 mol), Pd/C (10%, 26.2 g) and absolute EtOH (1280 mL). The mixture was hydrogenated at 35-45 psi H2 until the reaction was complete. The mixture was filtered over a pad of celite (20 g) and the cake was washed with EtOH (3×100 mL). The filtrate was concentrated to a volume of 350 mL. Heptane (500 mL) was added to the resulting slurry. After stirring for 2 hours at room temperature, the slurry was filtered. The cake was washed with heptane (3×100 mL) and air-dried to give 80.0 g of 1D. Another 30.2 g of product was recovered from the mother liquor affording a total yield of 95%. 1H NMR (CDCl3) d 7.88 (s, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.41 (s, 1H), 6.41 (dd, J=8.4, 2.1 Hz, 1H), 3.34 (d, J=2.1 Hz, 1H), 3.98 (bs, 2H), 3.94 (s, 3H).
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][NH:13][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=2)=[O:22])=[CH:19][CH:18]=1>COCCOC>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][N:13]3[C:7]4[N:6]=[CH:5][N:4]([CH2:1][CH2:2][CH3:3])[C:9](=[O:10])[C:8]=4[CH:11]=[CH:12]3)=[CH:25][CH:24]=2)=[O:22])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: CCCn1cnc2[nH]ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCn1cnc2c(ccn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1=O
Yield: 88.9 %

Procedure:
Under argon gas, 3-propyl-7H-pyrrolo[2,3-d]pyrimidin-4-one (249 mg) was dissolved in anhydrous DME (6 ml) and, under ice-cooling and stirring, 60% sodium hydride-oil (62 mg) was added. The mixture was stirred for 30 minutes, after which a solution of 4-(4-chlorobenzoyl)benzyl bromide (564 mg) in anhydrous DME (2 ml) was added. The mixture was further stirred at room temperature for 2 hours. The solvent was then distilled off under reduced pressure and the residue was dissolved in ethyl acetate, washed with saturated aqueous NaCl solution, and dried over anhydrous sodium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by flash column chromatography (silica gel, 21 g; hexane: ethyl acetate =4:1-3:2) to provide the title compound as colorless powder (507 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[H-].[Na+].Cl[CH2:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]=1>O1CCCC1>[CH3:1][N:2]([CH2:12][C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Cn1c(CCl)nc2ccccc21
Reactant: CNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(Cc1nc2ccccc2n1C)c1ccccn1

Procedure:
To a flask were added 0.6 g 2-(methylamino)pyridine and 20 ml tetrahydrofuran, and the mixture was cooled to 5 C. To this mixture were added 0.26 g of 60% sodium hydride in mineral oil in small portions, and after stirring at 5-10 C for ten minutes, 1.0 g of 2-(chloromethyl)-1-methyl-1H-benzimidazole was added. The reaction mixture was heated to 45 C for 16 hours, then cooled to 22 C and quenched with 40 ml water. The product was extracted with 40 ml ethyl acetate and following removal of the solvent, the product was purified by silica gel chromatography using 63% ethyl acetate, 25% hexane and 12% methanol resulting in 0.55 g of a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4].C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>C(Cl)Cl>[Cl:16][CH2:17][C:18]([NH:1][C@H:2]([CH2:7][OH:8])[C@H:3]([CH2:5][CH3:6])[CH3:4])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: CC[C@H](C)[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H](CO)NC(=O)CCl
Temperature: -20 °C

Procedure:
To a stirred solution of L-isoleucinol (20 g, 0.17 mol) and triethylamine (28.56 ml, 0.204 mol) in CH2Cl2 (500 ml) at -78° C. was added chloroacetyl chloride (16.3 ml, 0.204 mol) over 5 minutes. The cooling bath was removed and the solution allowed to warm to -20° C. The mixture was diluted with EtOAc and washed sequentially with 1M HCl, and brine and dried (Na2SO4). Evaporation in vacuo afforded the title compound Rf=0.3 CH2Cl2 :MeOH (95:5);
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1/[CH:12]=[CH:13]/N(C)C.C([OH:19])C>>[Cl:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[CH2:12][CH:13]=[O:19]
Reactant: CCO
Reactant: CN(C)/C=C/c1ccc([N+](=O)[O-])cc1Cl
Agent: Cl
Product: O=CCc1ccc([N+](=O)[O-])cc1Cl

Procedure:
50 mL of 1N hydrochloric acid is added dropwise to a solution of 10 g (30.88 mmol) of [(E)-2-(2-chloro-4-nitrophenyl)vinyl]dimethylamine in 200 mL of ethanol and the reaction mixture is then refluxed for 1 hour. Then the reaction mixture is evaporated down, diluted with water, and twice extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate. The purification is carried out by column chromatography on silica gel (eluant: petroleum ether/ethyl acetate (3:1)). Yield: 4.5 g (73% of theory); C8H6ClNO3 (M=199.59); Rf value: 0.62 (silica gel, petroleum ether/ethyl acetate (1:1)).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.I[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[K+].CN(C=O)C>[Cu]I.C(OCC)(=O)C>[C:11]1([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: c1ccc2ocnc2c1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: c1ccc(-c2nc3ccccc3o2)cc1
Yield: 61 %

Procedure:
Copper(I) iodide (19.1 mg, 0.1 mmol), benzoxazole (119 mg, 1.0 mmol), iodobenzene (612 mg, 3.0 mmol), t-BuOK (224 mg, 2.0 mmol), and DMF (1.0 mL). After column chromatography (hexanes, then 10% ethyl acetate in hexanes) and preparative HPLC (5% ethyl acetate in hexanes) 119 mg (61%) of 2-phenylbenzoxazole is obtained. Table I, entry 3.
Reaction SMILES: [N:1]1([C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:13]([C:25]([O:27]CC)=[O:26])=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[N:1]1([C:10]2[N:15]=[C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:13]([C:25]([OH:27])=[O:26])=[CH:12][N:11]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cnc(N2CCc3ccccc32)nc1OCc1ccc(F)cc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a suspension of ethyl 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-fluorobenzyl)oxy]-5-pyrimidinecarboxylate (5.0 g, 13 mmol) in ethanol (25 mL) were added 10% aqueous sodium hydroxide solution (15 mL) and tetrahydrofuran (15 mL) and the mixture was heated under reflux for 30 min. The reaction mixture was allowed to cool to room temperature and 1N hydrochloric acid was added to adjust the reaction mixture to pH 5. The precipitated crystals were collected by filtration, washed several times with water, dried with heating under vacuum to give 2-(2,3-dihydro-1H-indol-1-yl)-4-[(4-fluorobenzyl)oxy]-5-pyrimidinecarboxylic acid (4.8 g, 100%) as crystals. To the obtained suspension of the obtained carboxylic acid (183 mg, 0.5 mmol), t-butyl glycine (89 mg, 0.53 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (102 mg, 0.53 mmol) in dichloromethane (2 mL) was added triethylamine (0.21 mL, 1.5 mmol) and the mixture was stirred at room temperature for 18 h. Water and ethyl acetate were added to the reaction mixture and the organic layer was concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography and eluted with ethyl acetate to give the title compound (210 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:33])([C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br.[CH2:38](Cl)Cl>>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:33])([C:27]2[N:28]([CH3:32])[CH:29]=[N:30][CH:31]=2)[C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:38])[C:13](=[O:18])[CH:12]=[C:11]3[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)=[CH:4][CH:3]=1
Reactant: COc1cccc(-c2cc(=O)[nH]c3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Reactant: ClCCl
Agent: BrB(Br)Br
Product: Cn1cncc1C(O)(c1ccc2c(c1)c(-c1cccc(O)c1)cc(=O)n2C)c1ccc(Cl)s1
Yield: 66 %

Procedure:
Following the same procedure as that described in Example 34A, the title compound of example 31 (100 mg, 0.203 mmol) was treated with BBr3 in CH2Cl2 (1M, 1.02 ml, 1.02 mmol) to give the title compound (64 mg, 67% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.[CH2:22]1[O:24][CH2:23]1.[CH3:25][S:26]([OH:29])(=[O:28])=[O:27]>CO>[CH3:25][S:26]([OH:29])(=[O:28])=[O:27].[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[C:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][OH:24])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(=C1CCNCC1)c1ccccc1O2
Reactant: C1CO1
Agent: CS(=O)(=O)O
Solvent: CO
Product: OCCN1CCC(=C2c3ccccc3Oc3ccc(Cl)cc32)CC1
Temperature: 40 °C

Procedure:
A solution of 4-(2-chloro-9-xanthenylidene)piperidine (1.5 g., 5 mmol) in 50 ml. of methanol at 0° C. is treated with ethylene oxide (5 ml.). The solution is allowed to come to 23° C., then heated to 40° C. for one hour and the solvent evaporated. The residue is dissolved in acetonitrile and treated with one equivalent of methanesulfonic acid to give 4-(2-chloro-9-xanthenylidene)-1-(β-hydroxyethyl)-piperidine methanesulfonate, m.p. 242°-244° C.
Reaction SMILES: S(=O)(=O)(O)O.N([O-])=[O:7].[Na+].[Br:10][C:11]1[CH:24]=[CH:23][C:14]2[C:15]3[CH:21]=[CH:20][C:19](N)=[CH:18][C:16]=3[S:17][C:13]=2[CH:12]=1>O>[Br:10][C:11]1[CH:24]=[CH:23][C:14]2[C:15]3[CH:21]=[CH:20][C:19]([OH:7])=[CH:18][C:16]=3[S:17][C:13]=2[CH:12]=1
Reactant: O=N[O-]
Reactant: Nc1ccc2c(c1)sc1cc(Br)ccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Oc1ccc2c(c1)sc1cc(Br)ccc12
Temperature: 2 °C
Reaction time: 3 h

Procedure:
A flask equipped with a stirrer and a thermometer was charged with 209.3 g of concentrated sulfuric acid and 8.93 g of NaNO2 in a nitrogen atmosphere, and cooled to 2° C. Then 24.0 g of the intermediate 7-bromodibenzothiophene-3-yl-amine prepared in Example 1-3 was added, and stirred at 2 to 4° C. for 3 hours. The resulting mixture together with 99.8 g of water was poured into 348.7 g of 65 wt % sulfuric acid preheated to 80° C., stirred at 80 to 85° C. for 5 hours, and cooled to room temperature. The reactant was filtered, extracted six times with 300 ml of ethyl acetate, and vacuum concentrated. The concentrate was purified by silica gel chromatography using chloroform as an eluting solvent to obtain 7.11 g of objective 7-bromodibenzothiophene-3-ol. The 1H-NMR spectrum data and the results of elemental analysis of the product are shown below:
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:8]([C:19]([F:22])([F:21])[F:20])[CH:7]=1)=O.CO.C([O-])([O-])=O.[K+].[K+]>O>[F:22][C:19]([F:20])([F:21])[C:8]1[CH:7]=[C:6]([NH2:5])[CH:11]=[CH:10][C:9]=1[CH2:12][N:13]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=C(Nc1ccc(CN2CCCCC2)c(C(F)(F)F)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1ccc(CN2CCCCC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,2,2-trifluoro-N-(4-piperidin-1-ylmethyl-3-trifluoromethyl-phenyl)-acetamide (Stage 128.2; 1.427 g, 4.03 mmol) in boiling methanol (42 ml), 20 ml of a 1 N solution of K2CO3 in water are added dropwise. After 2 h stirring, the reaction mixture is cooled to rt, concentrated in vacuo and the residue re-dissolved in AcOEt and water. The aqueous layer is separated off and extracted twice with AcOEt. The organic phases are washed with water and brine, dried (Na2SO4) and concentrated to yield the title compound: MS: [M+1]+=259; 1H-NMR (DMSO-d6): 7.28 (d, 1H), 6.82 (d, 1H), 7.73 (dd, 1H), 5.40 (s, H2N), 3.32 (s, 2H), 2.27 (sb, 4H), 1.46 (m, 4H), 1.39 (m, 2H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 51 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-hexyl chloroformate. Yield: 51% of theory, C34H41N7O5 (627.8); Rf value: 0.53 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=628; (M+H+Na)++=325.7; (M+2H)++=314.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.Cl.[CH3:38][NH:39][CH3:40].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:38][N:39]([CH3:40])[CH2:30][CH2:29][CH2:28][NH:27][C:26]1[C:6]2[C:7](=[O:25])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:21])([CH3:22])[CH3:20])=[C:13]([F:24])[CH:12]=3)[O:10][C:5]=2[C:4]([F:36])=[CH:3][C:2]=1[F:1]
Reactant: CNC
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Temperature: 50 °C
Reaction time: 39 h
Yield: 69.2 %

Procedure:
709 mg (1.35mmol) of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one obtained in Example 129 (2) was dissolved in 30 mL of dimethylformamide under argon atmosphere, 1.10 g (13.5 mmol) of dimethylamine hydrochloride and 1.86 g (13.5 mmol) of potassium carbonate were added and the mixture was stirred at 50° C. for 39 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to give 444 mg of 5-(3-dimethylaminopropylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 69%).
Reaction SMILES: [ClH:1].C(O[C:7]([N:9](C)[C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C:18](=[O:20])[CH3:19])=[C:12]([CH3:21])[C:11]=1[CH3:22])=O)(C)(C)C>O1CCOCC1>[ClH:1].[CH3:7][NH:9][C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([O:17][C:18](=[O:20])[CH3:19])=[C:12]([CH3:21])[C:11]=1[CH3:22]
Reactant: CC(=O)Oc1c(C)cc(N(C)C(=O)OC(C)(C)C)c(C)c1C
Agent: Cl
Solvent: C1COCCO1
Product: CNc1cc(C)c(OC(C)=O)c(C)c1C
Reaction time: 3 h

Procedure:
A mixture prepared by adding 100 ml of a 4N solution of hydrogen chloride in 1,4-dioxane to 5.45 g of N-t-butoxycarbonyl-N-methyl-4-acetoxy-2,3,5-trimethyl-aniline [prepared as described in step (g) above] at room temperature was stirred for 3 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting residue was triturated with diisopropyl ether. The crystals thus obtained were collected by filtration, after which they were washed with diisopropyl ether to give 4.36 g of the title compound, melting at 172°-176° C.
Reaction SMILES: [C:1]1([CH2:7][CH:8]2[CH2:10][O:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH4+:11].[OH-]>>[NH2:11][CH2:10][CH:8]([OH:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [NH4+]
Reactant: c1ccc(CC2CO2)cc1
Agent: [OH-]
Product: NCC(O)Cc1ccccc1
Reaction time: 12 h

Procedure:
A solution of 2-(phenylmethyl)oxirane (7.5 g, 56.3 mmol) in NH4OH (100 mL) was stirred at 25° C. in a sealed tube. After 12 h, the solution was concentrated and used directly: LCMS (ES) m/e 152 (M+H)+.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH:26]([CH3:28])[CH3:27])(=[O:25])=[O:24])=[CH:19][CH:18]=3)[N:15]=2)[N:10]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH:9]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[CH:26]([S:23]([C:20]1[CH:19]=[CH:18][C:17]([C:14]2[N:15]=[C:16]3[C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:9][N:10]([S:29]([C:32]4[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=4)(=[O:30])=[O:31])[C:11]3=[N:12][CH:13]=2)=[CH:22][CH:21]=1)(=[O:24])=[O:25])([CH3:28])[CH3:27]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(C#C[Si](C)(C)C)c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc32)cc1
Temperature: 25 °C
Yield: 56.5 %

Procedure:
(Trimethylsilyl)acetylene (168.1 mg, 241.9 μL, 1.711 mmol) was added dropwise to a stirred solution of 7-iodo-2-(4-isopropylsulfonylphenyl)-5-(p-tolylsulfonyl)pyrrolo[2,3-b]pyrazine (765 mg, 1.316 mmol), triethylamine (665.8 mg, 917.1 μL, 6.580 mmol), copper(I) iodide (30.07 mg, 0.1579 mmol) and Pd(PPh3)4 (76.04 mg, 0.06580 mmol) in DMF (7 mL) at 0° C. and the resulting solution allowed to warm to ambient temperature over 64 hours. The solution was added dropwise to a mixture of EtOAc/ice water and the layers separated. The organic layer was washed with brine (×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 40 g column, eluting with 2 to 20% EtOAc/DCM, loaded in DCM) to give the sub-title product as a beige solid (410.4 mg, 56% Yield). 1H NMR (400.0 MHz, DMSO) δ 0.17 (t, 9H), 1.07 (d, 6H), 2.38 (qn, 3H), 3.45-3.50 (m, 1H), 7.36 (d, 2H), 7.90 (d, 2H), 7.96 (d, 2H), 8.27 (d, 2H), 8.60 (s, 1H) and 9.08 (s, 1H) ppm; MS (ES+) 552.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24]([OH:26])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][NH:28]1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24]([N:28]2[CH2:29][C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:27]2)=[O:26])=[CH:12][N:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: c1ccc2c(c1)CNC2
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N3Cc4ccccc4C3)c2c1

Procedure:
As described in example 1E, 76 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with 2,3-dihydro-1H-isoindole to give 75 mg of [4-(1,3-dihydro-isoindole-2-carbonyl)-6,8-dimethoxy-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C26H29N3O5+H 464.5; found 464.0.