Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([N:8]([C:18](=O)[C:19]2[CH:24]=[CH:23]C(Cl)=CC=2Cl)C2SC(C)=C(C(O)=O)N=2)=CC=1.[Cl:28][C:29]1[CH:56]=[C:55]([Cl:57])[CH:54]=[CH:53][C:30]=1[C:31]([N:33]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH3:52])[CH:44]=1)[C:34]1[S:35][C:36]([CH3:42])=[C:37]([C:39](O)=[O:40])[N:38]=1)=[O:32]>CCN(CC)CC>[Cl:28][C:29]1[CH:56]=[C:55]([Cl:57])[CH:54]=[CH:53][C:30]=1[C:31]([N:33]([C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH3:52])[CH:44]=1)[C:34]1[S:35][C:36]([CH3:42])=[C:37]([C:39]([N:8]2[CH2:18][CH2:19][CH2:24][CH2:23]2)=[O:40])[N:38]=1)=[O:32]
Reactant: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)c(C)s2)cc1OC
Reactant: Cc1sc(N(C(=O)c2ccc(Cl)cc2Cl)c2ccc(Cl)cc2)nc1C(=O)O
Solvent: CCN(CC)CC
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)N3CCCC3)c(C)s2)cc1OC

Procedure:
According to the procedure described fort he synthesis of Example 96 further derivatives have been synthesised from 2-[(4-Chloro-phenyl)-(2,4-dichloro-benzoyl)-amino]-5-methyl-thiazole-4-carboxylic acid or 2-[(2,4-Dichloro-benzoyl)-(3,4-dimethoxy-phenyl)-amino]-5-methyl-thiazole-4-carboxylic acid and various commercially available amines and comprise Examples 97-Example 124 below. In cases of Example 102 and 118 additionally 2 eq. NEt3 were added to the reaction mixture as amine hydrochlorides were used as starting materials.
Reaction SMILES: [F:1][CH:2]([F:37])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[CH:21][N:20](COCC[Si](C)(C)C)[C:17]2=[N:18][CH:19]=1.C(O)(C(F)(F)F)=O>ClCCl>[F:37][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:25][CH:26]([CH3:27])[CH3:28])=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(OC(F)F)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(OC(F)F)cc34)nc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.8 %

Procedure:
To a pale yellow solution of 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (32.5 mg, 61.2 μmol) in dichloromethane (1.44 mL) was added TFA (426 mg, 288 μL, 3.73 mmol) and stirred at 25° C. for 15 h. The mixture was concentrated then re-dissolved in 5 mL of a solution of dichloromethane/MeOH/ammonium hydroxide (60:10:1) and stirred at 25° C. for 3 h, then evaporated to an off-white solid which was purified by chromatography (spherical silica 20-45 μm, 23 g, Versaflash Supelco, 0 to 5% MeOH containing 10% ammonium hydroxide in dichloromethane). The pure product was dissolved in dichloromethane/MeOH and dichloromethane evaporated to allow solid formation, then the solid was collected by filtration and dried to give 2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (23 mg, 57.4 μmol, 94%) as a light yellow solid. MS (M+H)+=401; 1H NMR (DMSO-d6) δ: 12.83 (br. s., 1H), 9.10 (s, 1H), 8.41 (s, 1H), 8.20 (d, J=2.3 Hz, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.86 (d, J=9.4 Hz, 1H), 7.42 (dd, J=9.1, 1.9 Hz, 1H), 7.21 (t, J=74.4 Hz, 1H), 4.12-4.33 (m, 4H), 2.49 (s, 9H), 1.30 (d, J=6.4 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[C:3](F)=[CH:4][C:5]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[F:1][C:2]1[C:3]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[CH:4][C:5]2[N:14]3[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]3)=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: CCOC(=O)c1c(=O)c2cc(F)c(F)cc2n2ccccc12
Reactant: CN1CCNCC1
Product: CCOC(=O)c1c(=O)c2cc(F)c(N3CCN(C)CC3)cc2n2ccccc12
Temperature: 110 °C
Yield: 79.1 %

Procedure:
A mixture of 2.0 g of ethyl 8,9-difluoro-6-oxo-6H-benzo[c]quinolizine-5-carboxylate and 3.3 g of N-methylpiperazine was heated at 110° C. for 2 hours. The solvent was evaporated and the residue partitioned between water and dichloromethane. The organic layer was dried and the solvent removed giving 2.0 g of the desired product, mp 167°-170° C.
Reaction SMILES: [CH3:1]/[C:2](=[C:7](\[CH3:12])/[C:8]([O:10][CH3:11])=[O:9])/[C:3]([O:5][CH3:6])=[O:4].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:13][CH2:12]/[C:7](=[C:2](\[CH3:1])/[C:3]([O:5][CH3:6])=[O:4])/[C:8]([O:10][CH3:11])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)/C(C)=C(/C)C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C(C)=C(/CBr)C(=O)OC
Reaction time: 4 h
Yield: 26.2 %

Procedure:
To a solution of dimethyl 2,3-dimethylmaleate (500 mg, 2.90 mmol) in carbon tetrachloride (11 mL) were added N-bromosuccinimide (803 mg, 4.51 mmol) and 2,2′-azobisisobutyronitrile (3.2 mg, 0.019 mmol) at room temperature, and the mixture was heated under reflux with stirring for 4 h. The reaction mixture was directly filtrated, and the filtrate was washed with water and brine. The residue obtained by concentrating the organic layer under reduced pressure was subjected to silica gel column chromatography (hexane-ethyl acetate 20:1→8:1) to give 191 mg of dimethyl 2-bromomethyl-3-methylmaleate (yield: 26%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:11][S:12](O)(=[O:14])=[O:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)c1ccccc1Cl
Product: O=C(O)c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 100 °C
Reaction time: 24 h

Procedure:
To a solution of 2-chlorobenzoic acid (5.0 g, 31.93 mmol) was slowly added chlorosulphonic acid (25 mL). The reaction mixture was heated at 100° C. for 5-6 h, followed by stirring at RT for 24 h. The reaction mass was quenched in ice cold water slowly and the solid obtained was filtered off, washed with water and dried to afford 4.0 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 7.50 (d, J=7.8 Hz, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.96 (d, J=1.5 Hz, 1H), 12.69-12.94 (br s, 1H).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[O:8]1[CH:13]=[CH:12][CH2:11][CH2:10][CH2:9]1>C1(C)C=CC(S(=O)=O)=CC=1.C(Cl)(Cl)Cl>[OH:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:7][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13][O:8]1
Reactant: OCCCCCO
Reactant: C1=COCCC1
Agent: Cc1ccc([SH](=O)=O)cc1
Solvent: ClC(Cl)Cl
Product: OCCCCCOC1CCCCO1
Reaction time: 0.33 h
Yield: 31.9 %

Procedure:
To 31.2 g of 1.5-pentanediol was added 380 mg of p-toluenesulfonic acid monohydride and dropwise 8.4 g of dihydropyran with ice-cooling and stirring over 20 minutes, and the mixture was stirred at a room temperature for 3.5 hours. After adding 300 ml of chloroform, the mixture was washed with 2% sodium bicarbonate aqueous solution, water and a saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with hexane/ethyl acetate (3:1) to obtain 6.0 g of 2-(5-hydroxypentyloxy)tetrahydropyran as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][N:6]=1)=[O:4].[CH:12]1(B(O)O)[CH2:14][CH2:13]1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:12]2[CH2:14][CH2:13]2)=[CH:7][N:6]=1)=[O:4]
Reactant: OB(O)C1CC1
Reactant: COC(=O)c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(C2CC2)cn1
Temperature: 110 °C
Reaction time: 12 h
Yield: 45.1 %

Procedure:
5-Bromo-pyridine-2-carboxylic acid methyl ester (CAN 29682-15-3, 2.16 g, 0.01 mol), cyclopropylboronic acid (CAN 411235-57-9, 0.9 g, 0.01 mol), tris(dibenzylideneacetone)dipalladium (CAN 52409-22-0, 0.2 g), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (CAN 161265-03-8, 0.3 g) and cesium carbonate (CAN 534-17-8, 3.3 g, 0.01 mol) was added into 1,4-dioxane (40 mL). The mixture was stirred for 12 h at 110° C. under nitrogen atmosphere. Subsequently, the mixture was filtered and concentrated. The residue was poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated to give crude product. The crude product was purified by a flash column chromatography (silica gel, 50 g, eluting with 20% ethyl acetate in petroleum ether) to give product (0.8 g, 45%); MS (EI): m/e 178.1 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][S:5][CH:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])=[CH:11][CH:10]=1)[CH2:7][CH3:8].[OH-].[K+].C1CCCCC1.C(OCC)(=O)C>C(O)C.O>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[CH:13]=[CH:14][C:9]([CH:6]([S:5][CH2:4][C:3]([OH:22])=[O:2])[CH2:7][CH3:8])=[CH:10][CH:11]=1
Reactant: CCC(SCC(=O)OC)c1ccc(-c2ccccc2F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCC(SCC(=O)O)c1ccc(-c2ccccc2F)cc1
Reaction time: 1 h

Procedure:
220 gm of the methyl ester obtained in Example B were hydrolized with 58.2 gm of potassium hydroxide in 900 ml of ethanol by boiling for one hour. Subsequently, the mixture was diluted with 1800 ml of water, the neutral components were extracted with ether, and the free acid was precipitated from the alkaline phase. By extraction with ether, and washing, drying and evaporating the ethereal extract, the reaction product was isolated. Yield: 130 gm (62% of theory); oil, Rf -value: 0.7 (cyclohexane-ethyl acetate=1:1 on silicagel-polygram-plates).
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br>CN(C)C=O>[Br:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1Br
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccccc1COc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
1.2 g of sodium hydride (at 50% in suspension in oil) are added at 5° C., in portions, to 20.2 g of phenol in solution in 150 ml of dimethylformamide. The mixture is stirred at room temperature and 37.2 g of 2-bromobenzyl bromide in solution in 15 ml of dimethylformamide are introduced at 5° C. After 2 hours at 20° C., the reaction medium is poured over ice-cold water and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulphate and concentrated to give 36 g of oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14](C(=O)C)[C:13](=[O:21])[C:12]23[CH2:23][CH2:22]2)[CH:5]=[C:4]([F:24])[C:3]=1[C:25]([F:28])([F:27])[F:26].OS(O)(=O)=O>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:21])[C:12]23[CH2:22][CH2:23]2)[CH:5]=[C:4]([F:24])[C:3]=1[C:25]([F:28])([F:27])[F:26]
Reactant: CC(=O)N1C(=O)C2(CC2)c2cc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)ccc21
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc(Oc3cc(F)c(C(F)(F)F)c(Cl)c3)cc2C12CC2

Procedure:
A mixture of 5'-[(2-chloro-α,α,α,6-tetrafluoro-p-tolyl)oxy]-1'-acetyl-spiro[cyclopropane -1,3'-indolin]-2'-one (0.60 g, 1.95 mmol), 5 mL of 1 N H2SO4 and tetrahydrafuran is heated at reflux for about 24 hours (until reaction is complete by gas chromatographic analysis). The reaction mixture is diluted with ethyl acetate and water and the phases are separated. The organic phase is dried (MgSO4) and concentrated in vacuo to give a residue. The residue is chromatographed using silica gel and ethyl acetate/hexane 25/75 to give the title product as a white solid, 0.41 g, (76%), mp 168°-170° C. identified by H1NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Zn+]>C1COCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=2)[CH:7]=1
Reactant: [Zn+]c1ccccn1
Reactant: Brc1cncc(Br)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cncc(-c2ccccn2)c1
Temperature: 25 °C

Procedure:
A solution of 3,5-dibromopyridine (2.5 g, 10.5 mmol), PPh3 (210 mg, 0.8 mmol) in degassed THF (2 mL) was treated with Pd2(dba)3 (Tris(dibenzylideneacetone)dipalladium (0), 91.5 mg, 0.1 mmol) at 25° C. under N2. A solution of 2-pyridinyl zinc chloride (21 mL, 0.5 M in THF, Aldrich) in THF was added and the resulting solution was warmed to reflux for 16 h. The solution was allowed to cool to room temperature, diluted with EtOAc (200 mL), washed with water (2×100 mL), dried (MgSO4), filtered and was concentrated in vacuo. Purification by flash chromatography (EtOAc) afforded the title compound as a white solid. MS 236 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:41])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH3:40])[C:12](=[O:39])[NH:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)OCC4C=CC=CC=4)=[C:23]([F:38])[CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:7][CH2:6]1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:18]2[CH:17]=[CH:16][N:15]=[C:14]([NH:13][C:12](=[O:39])[N:11]([CH:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[CH3:41])[CH2:10][CH2:9]3)[CH3:40])[CH:19]=2)=[CH:22][C:23]=1[F:38]
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)OCc4ccccc4)c(F)c3)ccn2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
After adding 20% palladium hydroxide-carbon (20 mg) to a solution of benzyl [4-(2-{3-[1-(2-dimethylaminoethyl)piperidin-4-yl]-3-methylureido}pyridin-4-yloxy)-2-fluorophenyl]carbamate (51.3 mg) in tetrahydrofuran (5.0 ml), the mixture was stirred for 6 hours at room temperature under a hydrogen atmosphere. The catalyst was then filtered. The filtrate was concentrated to provide 3-[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (ESI-MS (m/z): 431[M+H]+) as a pale yellow oil. This was dissolved in ethanol (0.68 ml), and then (1S)-(+)-10-camphorsulfonic acid (40.1 mg) was added thereto and the mixture was stirred for 5 minutes at room temperature. After adding 2-(4-fluorophenyl)acetyl isothiocyanate (0.2 M solution in toluene, 0.682 ml) thereto, the mixture was stirred at room temperature for 1 hour. After further adding 2-(4-fluorophenyl)acetyl isothiocyanate (0.2 M solution in toluene, 1.24 ml), the mixture was further stirred at room temperature for 1 hour. After still further adding 2-(4-fluorophenyl)acetyl isothiocyanate (0.2 M solution in toluene, 0.205 ml), stirring was continued at room temperature for 1 hour. Finally, additional 2-(4-fluorophenyl)acetyl isothiocyanate (0.2 M solution in toluene, 0.205 ml) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by LC-MS (eluent; acetonitrile-water-trifluoroacetic acid system). Fractions containing the target compound were concentrated, and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Hexane:ethyl acetate=5:1 was added to the resultant residue to precipitate a solid. The solid was filtered and washed with hexane, and then dried to provide the title compound (8.5 mg, 14.9%) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:20]=1[F:26])=[O:18].Cl[CH2:28][C:29]([NH:31][CH3:32])=[O:30].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=2[CH3:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([CH:22]=[CH:21][C:20]=1[F:26])[O:25][CH2:28][C:29]([NH:31][CH3:32])=[O:30])=[O:18]
Reactant: CNC(=O)CCl
Reactant: Cc1cc(Cl)ccc1Nc1ccc(C(=O)c2cc(O)ccc2F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CNC(=O)COc1ccc(F)c(C(=O)c2ccc(Nc3ccc(Cl)cc3C)cc2Cl)c1
Temperature: 130 °C
Reaction time: 0.75 h

Procedure:
Compound 513 (36 mg, 0.09 mmol) was dissolved in acetonitrile (2 mL) in a reaction vial. 2-Chloro-N-methyl-acetamide (30 mg, 0.28 mmol), K2CO3 (38 mg, 0.28 mmol) were added. The reaction vial was flushed with argon, closed and then stirred at 130° C. for 45 min. in a microwave oven. The reaction mixture was poured into a mixture of EtOAc:H2O (1:1, 10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3×5 mL). The combined organic layers were dried (MgSO4), filtered, concentrated in vacuo and purified by continuously gradient flash chromatography using EtOAc/petroleum ether (40-60)(v:v=1:3 to 100:0) as the eluent, affording the title compound as a yellow oil. 13C NMR (CDCl3) δ 190.1, 168.2, 155.7 (d), 153.2 (d), 149.2, 136.6, 135.0, 134.5, 133.4, 131.2, 130.5, 128.7 (d), 128.1, 127.1, 125.3, 119.6 (d), 117.4 (d), 116.1 (d), 115.6, 112.4, 68.0, 25.8, 17.9
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:39][C:40]#[N:41]>CN(C=O)C.[Cl-].[Na+].O>[C:40]([CH2:39][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][N:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:20][CH:19]=2)=[CH:4][CH:3]=1)#[N:41]
Reactant: Oc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1ccc(-c2sc3ccccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2-(4-hydroxyphenyl)-3-[4-[2-(1-pyrrolidinyl)ethoxy]benzyl]benzo[b]thiophene (102 mg) and cesium carbonate (386 mg) in DMF (3.0 mL) was treated with bromoacetonitrile (20 μL) while stirring at ambient temperature. Stirring was continued for 2 h and the reaction mixture was diluted with brine (30 mL) and extracted with EtOAc (20 mL×3). The combined organic layers were dried with sodium sulfate and concentrated under reduced pressure. Chromatography with Et3N-EtOAc (0-5%) afforded the product (98 mg).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH3:4].[C:12](Cl)([Cl:14])=[O:13]>C1C=CC=CC=1>[Cl:14][C:12]([O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:13]
Reactant: CCCCOCCOCCO
Reactant: O=C(Cl)Cl
Solvent: c1ccccc1
Product: CCCCOCCOCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
24.3 G. (150 mmoles) of 2-(2-n-butoxyethoxy)ethanol is added dropwise with stirring to 250 ml. (290 mmoles) of a 12.5% phosgene solution in benzene, cooled in an ice bath and protected from moisture. The addition is carried out over a period of approximately 1 1/2 hours and stirring is continued in an ice bath for 2 hours. The solution is allowed to warm to room temperature and stirred overnight. Nitrogen is passed through the solution for several hours to remove excess phosgene and excess HCl. The solvent is removed in vacuo affording 32.9 g. of a colorless oil. The infrared spectrum revealed a strong carbonyl absorption and no hydroxy absorption. The oil is used without any further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[NH2:21])[C:5]([NH:7][C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1)=[O:6].[CH2:22]([O:24][P:25]([CH2:30][O:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([CH:39]=O)=[C:34]([Cl:41])[CH:33]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]>>[CH2:22]([O:24][P:25]([CH2:30][O:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([C:39]2[NH:1][C:2]3[CH:3]=[C:4]([C:5](=[O:6])[NH:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)[CH:18]=[CH:19][C:20]=3[N:21]=2)=[C:34]([Cl:41])[CH:33]=1)(=[O:29])[O:26][CH2:27][CH3:28])[CH3:23]
Reactant: CCOP(=O)(COc1cc(Cl)c(C=O)c(Cl)c1)OCC
Reactant: Nc1ccc(C(=O)Nc2ccc3ccccc3n2)cc1N
Product: CCOP(=O)(COc1cc(Cl)c(-c2nc3ccc(C(=O)Nc4ccc5ccccc5n4)cc3[nH]2)c(Cl)c1)OCC

Procedure:
The title compound was prepared from 3,4-diamino-N-quinolin-2-yl-benzamide (from Example 6-17) and (3,5-dichloro-4-formylphenoxymethyl)-phosphonic acid diethyl ester analogous to Example 6-17. 1H NMR (Methanol-d4, 400 MHz): δ 8.77 (d, 1H), 8.54 (d, 1H), 8.17 (t, 1H), 8.16 (t, 1H), 8.12 (d, 1H), 8.07 (d, 1H), 7.99 (m, 1H), 7.86 (d, 1H), 7.77 (m, 1H), 7.38 (s, 2H), 4.62 (d, 2H), 4.30 (m, 4H), 1.42 (t, 6H). MS (m/z) 599.5 (M+1); Retention time: 1.40 min (Method 10).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCl>[N:33]1([C:8]([C@@H:5]2[CH2:4][CH2:3][C@H:2]([OH:1])[CH2:7][CH2:6]2)=[O:10])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: O=C(O)[C@H]1CC[C@@H](O)CC1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: O=C([C@H]1CC[C@@H](O)CC1)N1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of cis-4-hydroxycyclohexanecarboxylic acid (720 mg, 0.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.33 g, 6 mmol) and 1-hydroxy-7-azabenzotriazole (816 mg, 6 mmol) in dichloromethane (6 ml) was treated with morpholine 1.3 ml, 15 mmol). After stirring at room temperature for 18 hours, the crude reaction was applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo, and the resulting residue was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (D55); MS (ES+) m/e 214 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][CH3:34])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:35](Cl)(=[O:37])[CH3:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH2:28][CH2:29][N:30]([CH2:31][CH2:32][O:33][CH3:34])[C:35](=[O:37])[CH3:36])[N:20]=[CH:19][N:18]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CC(=O)Cl
Reactant: COCCNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: COCCN(CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12)C(C)=O
Yield: 30 %

Procedure:
The procedure described in Example 5 was repeated using N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-{2-[(2-methoxyethyl)amino]ethoxy}quinazolin-4-amine and acetyl chloride to give the title compound in 30% yield; NMR spectrum (DMSO-d6) 1.99 (s, 3H), 3.24 (s, 3H), 3.46-3.51 (m, 2H), 3.52-3.57 (m, 2H), 3.88-3.98 (m, 2H), 4.37-4.43 (m, 2H), 5.31 (s, 2H), 7.17 (d, 1H), 7.26 (d, 1H), 7.34 (d, 1H), 7.35-7.40 (m, 1H), 7.55-7.63 (m, 2H), 7.71-7.78 (m, 1H), 7.86-7.92 (m, 1H), 7.94 (d, 1H), 8.46 (s, 1H), 8.61 (d, 1H), 9.86 (s, 1H); Mass spectrum MH+ 522.