Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2Cl)=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35]C1C=CC(CO)=CC=1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([F:18])[C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:19]1[C:20]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:35][CH3:34])=[CH:29][CH:28]=2)=[N:21][CH:22]=[CH:23][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3ccccc3)c2cc1F
Reactant: COc1ccc(CO)cc1
Product: COc1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2ccccc2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate c, from 1-benzyl-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 6, intermediate) and (4-methoxy-phenyl)-methanol (CAS Reg. No. 105-13-5). Colorless solid (72%). MS (Turbo Spray): m/z=458.1 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2].Cl[Si](C)(C)[CH3:19]>CO>[C:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16][CH3:19])=[O:15])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cc(C(=O)O)c2ccccc2n1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)nc2ccccc12
Reaction time: 8 h

Procedure:
To a mixture of 2,4-dicarboxyquinoline (1.085 g, 5 mmol) in methanol (40 mL) was added chlorotrimethylsilane (TMSCl) (1.41 mL), and the reaction mixture was stirred overnight. The reaction mixture turned into a clear solution. The solvents were evaporated to yield a crude product, 2-carboxy-4-methoxycarbonylquinoline. To a solution of 2-carboxy-4-methoxycarbonylquinoline (151 mg, 0.65 mmol) in THF (10 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (181 mg, 1.05 eq.), EDCl (161 mg, 1.2 eq. ), and HOBt (75 mg, 1.1 eq.), and the resulting reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2 afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]-aminocarbonyl-4-(methoxycarbonyl)quinoline (146 mg) which was treated with trifluoroacetic acid (TFA) and CH2Cl2 (TFA/CH2Cl2, 1:1, 1.5 mL) and the resulting reaction mixture was stirred at ambient temperture for 1 hour. Evaporation of the solvents gave 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-(methoxycarbonyl)quinoline (74 mg). To this was added a mixture of THF:H2O (2:1, 2 mL) and LiOH (4 eq.). The resulting mixture was stirred at ambient temperature for 1.5 hours. The pH value was adjusted to between pH 3 and pH 4 with 1N HCl solution. Extraction of the organic layers with ethyl acetate was followed by evaporation of the solvents to yield 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-4-carboxyquinoline (39 mg); NMR (CD3OD) 1.25 (t, 3), 1.99 (m, 1), 2.2 (m, 1), 2.5 (m, 2 ), 3.4–3.9 (m, 8), 4.16 (q, 2), 5.25 (m, 1), 7.75 (m, 1 ), 7.86 (m, 1), 8.25 (m, 3) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([OH:12])[N:8]=[CH:9]2)=[CH:4][N:3]=1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH2:24])(=[O:23])=[O:22])=[CH:19][CH:20]=1)[C:7](=[O:12])[CH:6]=2
Reactant: Oc1cc2cnc(Br)cc2cn1
Reactant: NS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Cn2cc3cc(Br)ncc3cc2=O)cc1

Procedure:
The alkylation of 7-bromo-3-hydroxy-6-azaisoquinoline (1.00 g, 4.40 mmol) using 4-bromomethyl-benzene sulfonamide (1.67 g, 6.69 mmol) and cesium carbonate (2.18 g, 6.69 mmol) in dimethyl-formamide is carried out as previously described in Example 1, Step (1). Purification on a silica gel column eluted with hexanes/ethyl acetate 3:1, followed by trituration with hexanes/ethyl acetate 4:1 will afford the desired product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[CH:9]([O:8][C:5]1[N:6]=[CH:7][C:2]([C:22]3[CH:23]=[C:18]([CH:19]=[CH:20][CH:21]=3)[NH2:17])=[CH:3][CH:4]=1)[CH2:10]2
Reactant: Brc1ccc(OC2CN3CCC2CC3)nc1
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(-c2ccc(OC3CN4CCC3CC4)nc2)c1

Procedure:
The product of Example 12A (283 mg, 1 mmol) was treated with 3-amino-phenylboronic acid (Lancaster, 274 mg, 2.0 mmol) according to the procedure of Example 1B. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.10) as solid (180 mg, yield, 61%). 1H NMR (MeOH-d4, 300 MHz) δ 1.42-1.56 (m, 1H), 1.62-1.88 (m, 2H), 1.99-2.12 (m, 1H), 2.16-2.28 (m, 1H), 2.73-3.04 (m, 5H), 3.40-3.50 (m, 1H), 5.01-5.10 (m, 1H), 6.70 (ddd, J=7.8, 2.7, 0.7 Hz, 1H), 6.84-6.94 (m, 3H), 7.16 (t, J=7.8 Hz, 1H), 7.88 (dd, J=8.5, 2.4 Hz, 1H), 8.29 (d, J=2.6 Hz, 1H) ppm. MS (DCl/NH3) m/z 296 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]([NH:9][C:10]1[C:19]([I:20])=[CH:18][CH:17]=[CH:16][C:11]=1[C:12](OC)=[O:13])=O)[CH2:2][CH3:3].O.C([NH2:28])=O>>[CH2:1]([O:4][C:5]1[CH:24]=[CH:23][CH:22]=[CH:21][C:6]=1[C:7]1[NH:28][C:12](=[O:13])[C:11]2[C:10](=[C:19]([I:20])[CH:18]=[CH:17][CH:16]=2)[N:9]=1)[CH2:2][CH3:3]
Reactant: NC=O
Reactant: CCCOc1ccccc1C(=O)Nc1c(I)cccc1C(=O)OC
Solvent: O
Product: CCCOc1ccccc1-c1nc2c(I)cccc2c(=O)[nH]1

Procedure:
19.4 g (44.17 mmoles) of the compound from Example I is stirred for 10 hours at 180° C. in 216 ml of formamide. After cooling, 500 ml of water is added and extracted 4 times with 300-ml portions of CH2Cl2. The combined organic phases are dried over MgSO4, the solvent is evaporated under vacuum, and the residue is stirred in a mixture of 100 ml of diethyl ether and 50 ml of petroleum ether. The product (17.8 g) is filtered off by suction and recrystallized from 250 ml of absolute ethanol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[N:3][CH:2]=1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[N:1]1[CH:6]=[CH:5][C:4]([O:7][CH:8]2[CH2:13][CH2:12][CH:11]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:10][CH2:9]2)=[N:3][CH:2]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(Oc2ccncn2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3ccncn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(pyrimidin-4-yloxy)-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[C:7]([O:10][CH3:11])[CH:6]=[C:5]([CH:12]=[O:13])[CH:4]=1.S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>C1C=CC=CC=1.O>[CH3:11][O:10][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:18])[CH:12]=[O:13]
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(C=O)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(C=O)cc(OC)c1OC
Temperature: 75 °C
Reaction time: 1 h

Procedure:
25.0g syringealdehyde (0.137 mol), 26.6g of dimethyl sulfate (0.211 mol), and 27.7 g. of potassium carbonate (0.201 mol) were heated with stirring as in Example 1. When the temperature reached 45° C the mixture became fluid and carbon dioxide was given off. The temperature was slowly increased to 75° C and held at this value for 1 hour. Addition of water, acidification, and benzene extraction gave a quantitative yield of 3,4,5-trimethoxybenzaldehyde which contained no detectable syringealdehyde or other impurities as determined by g.l.c. analysis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH:5]=[C:6]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2].C(OC(=O)CC(C1C=CC=C2C=1C(C#N)=CN2)C1C=CC=CC=1)C>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]([C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1)[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C=C(c1cccnc1)c1ccc2cc[nH]c2c1
Agent: CCOC(=O)CC(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Product: CCOC(=O)CC(c1cccnc1)c1ccc2cc[nH]c2c1

Procedure:
3-(1H-Indol-6-yl)-3-pyridin-3-yl-propionic acid ethyl ester CLVIII was prepared from 3-(1H-indol-6-yl)-3-pyridin-3-yl-acrylic acid ethyl ester using the procedure described above for preparation of 3-(3-Cyano-1H-Indol-4-yl)-3-phenyl-propionic acid ethyl ester LIX (Example 14).
Reaction SMILES: [C:1](=[O:16])([O:14][CH3:15])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[CH3:13]>C(O)C.[Pt](=O)=O>[F:12][C:6]1[CH:5]=[C:4]([CH3:13])[C:3]([O:2][C:1]([O:14][CH3:15])=[O:16])=[CH:8][C:7]=1[NH2:9]
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C
Agent: O=[Pt]=O
Solvent: CCO
Product: COC(=O)Oc1cc(N)c(F)cc1C
Reaction time: 1 h

Procedure:
A solution of (4-fluoro-2-methyl-5-nitrophenyl) methyl carbonate (3 g, 13 mmol), (prepared as described in EP 0307777 A2), in ethanol (60 ml) containing platinum(IV)oxide (300 mg) was stirred under hydrogen at 0.3 atmosphere for 1 hour. After filtration and evaporation of the solvent, 2-fluoro-5-methoxycarbonyloxy-4-methylaniline was isolated as a solid (2.6 g, 100%).
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(N[C@H]2CC[C@H](C)CC2)CCCC1.NC1SC=NC=1.C([O:51][C:52](=[O:56])C(S)C)C>>[CH:24]1([N:16]([C@H:17]2[CH2:22][CH2:21][C@H:20]([CH3:23])[CH2:19][CH2:18]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:52]([OH:56])=[O:51])=[CH:9][N:10]=2)[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CCOC(=O)C(C)S
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCCC2)[C@H]2CC[C@H](C)CC2)s1
Agent: C[C@H]1CC[C@H](NC2CCCC2)CC1
Agent: Nc1cncs1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(SCCC(=O)O)s2)C2CCCC2)CC1

Procedure:
{2-[3-Cyclopentyl-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid ethyl ester prepared as described in general procedure (A) using cyclopentyl-(trans-4-methyl-cyclohexyl)-amine and 5-aminothiazole-2-mercaptopropionic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[CH3:30][N:31]([CH2:33][C:34](Cl)=[O:35])[CH3:32]>>[CH3:30][N:31]([CH2:33][C:34]([N:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:23])=[CH:19][CH:18]=1)[CH3:22])=[O:35])[CH3:32]
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Reactant: CN(C)CC(=O)Cl
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(=O)CN(C)C)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide and dimethylamino-acetyl chloride, the title compound was prepared as light yellow crystals (46% yield). MS: m/e=498(M+H+).
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].S(O[CH2:38][CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:41][CH2:40]1)(C1C=CC(C)=CC=1)(=O)=O>>[C:15]([O:14][C:13]([NH:12][CH2:11][CH2:10][C@H:9]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:38][CH:39]1[CH2:44][CH2:43][N:42]([C:45]([O:47][C:48]([CH3:49])([CH3:51])[CH3:50])=[O:46])[CH2:41][CH2:40]1)[OH:8])=[O:19])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
Alkylation of phenol (7, Intermediate I) with tert-butyl 4-((tosyloxy)methyl)piperidine-1-carboxylate following the method used in Example 11 gave (R)-tert-butyl 4-((3-(3-((tert-butoxycarbonyl)amino)-1-hydroxypropyl)phenoxy)methyl)piperidine-1-carboxylate as a colorless oil. Yield (0.70 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-])=O)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8]>CO.[C].[Pd]>[NH2:13][C:3]1[C:2]([NH2:1])=[CH:10][C:6]([C:7]([NH2:9])=[O:8])=[C:5]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc([N+](=O)[O-])c(N)cc1C(N)=O
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(N)cc1C(N)=O
Temperature: 60 °C

Procedure:
A suspension of 3.04 g of 5-amino-2-methoxy-4-nitrobenzamide and 110 mg of 10 % palladium carbon in 300 ml of methanol was stirred at 60° C. under a hydrogen atmosphere. After absorption of hydrogen was completed, the catalyst was removed by filtration, and the filtrate was concentrated to give the title compound, m.p. 181°-183° C., yield of 2.18 g.
Reaction SMILES: [Cl:1][C:2]1[C:24]([OH:25])=[CH:23][C:5]2[C:6]([C:9]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)=[O:10])=[CH:7][O:8][C:4]=2[C:3]=1[Cl:26].[N+]([O-])(O)=[O:28].O.C(Cl)(Cl)Cl.CO>C(O)(=O)C>[Cl:1][C:2]1[C:24](=[O:25])[C:23](=[O:28])[C:5]2[C:6]([C:9](=[O:10])[C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)=[CH:7][O:8][C:4]=2[C:3]=1[Cl:26]
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)c2coc3c(Cl)c(Cl)c(O)cc23)cc(OC)c1OC
Solvent: O
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)c2coc3c2C(=O)C(=O)C(Cl)=C3Cl)cc(OC)c1OC
Temperature: 60 °C

Procedure:
To a suspension of compound 22 (100 mg, 0.25 mmol) in glacial acetic acid (2 mL) at room temperature was added nitric acid (0.1 mL, d 1.35) dropwise with vigorous stirring. The mixture was heated at 60° C. for 3 h, left to cool for 30 min, and poured into cold water. The resulting precipitate was filtered and recrystallized to afford compound SKC-BF-11 (50 mg, 49%) as an orange solid. TLC Rf=0.6 (CHCl3-MeOH, 9:1); 1H NMR (CDCl3) δ 7.90 (s, 1H), 7.13 (s, 2H), 3.95 (s, 3H), 3.88 (s, 6H); MS (ES) m/z 411 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH:16]=O)[CH:5]=1)[CH3:2].Cl.Cl.[CH2:20]([NH:22][C:23](=[O:37])[C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[C:26]([CH3:36])[CH:25]=1)[CH3:21]>>[CH2:1]([O:3][C:4]1[C:9]2[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=2[CH:7]=[C:6]([CH2:16][N:33]2[CH2:32][CH2:31][N:30]([C:27]3[CH:28]=[CH:29][C:24]([C:23]([NH:22][CH2:20][CH3:21])=[O:37])=[CH:25][C:26]=3[CH3:36])[CH2:35][CH2:34]2)[CH:5]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Reactant: CCOc1cc(C=O)cc2c1OC(C)C(=O)N2
Agent: Cl
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc4c(c(OCC)c3)OC(C)C(=O)N4)CC2)c(C)c1

Procedure:
Using 398B and N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide-2HCl in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.07 Hz, 3H) 1.32 (t, J=6.95 Hz, 3H) 1.40 (d, J=6.57 Hz, 3H) 2.26 (s, 3H) 2.51-2.59 (m, 4H) 2.88 (br. s., 4H) 3.19-3.29 (m, 2H) 3.42 (s, 2H) 3.98-4.09 (m, 2H) 4.55-4.64 (m, 1H) 6.51 (d, J=1.52 Hz, 1H) 6.63 (d, J=1.52 Hz, 1H) 7.02 (d, J=8.34 Hz, 1H) 7.55-7.69 (m, 2H) 8.26 (t, J=5.56 Hz, 1H) 10.57 (s, 1H). ESI-MS: m/z 467.4 (M+H)+. mp 199.8-199.9° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]=[C:35]([Cl:37])[Cl:36])[CH:29]=[C:28]([Cl:38])[C:22]=1[O:23][CH2:24][CH2:25][CH2:26][OH:27].[C:39]([O:43][C:44](=[O:53])[NH:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1)([CH3:42])([CH3:41])[CH3:40]>C1COCC1>[C:39]([O:43][C:44](=[O:53])[NH:45][C:46]1[CH:47]=[CH:48][C:49]([O:27][CH2:26][CH2:25][CH2:24][O:23][C:22]2[C:21]([Cl:20])=[CH:31][C:30]([O:32][CH2:33][CH:34]=[C:35]([Cl:37])[Cl:36])=[CH:29][C:28]=2[Cl:38])=[CH:50][CH:51]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.69 g of azadicarboxylic acid diisopropyl ester are added dropwise at 0-5° C. to a solution of 1.97 g of triphenylphosphine in 60 ml of THF. After 30 minutes at 0-5° C., 2.5 g of 3-[2,6-dichloro-4-(3,3-dichloroallyloxy)-phenoxy]-propan-1-ol and 1.5 g of (4-hydroxy-phenyl)-carbamic acid tert-butyl ester dissolved in 30 ml of tetrahydrofuran are added dropwise. After being stirred for 24 hours at room temperature, the reaction mixture is concentrated and then purified over silica gel. (4-{3-[2,6-Dichloro-4-(3,3-dichloroallyloxy)-phenoxy]-propoxy}-phenyl)-carbamic acid tert-butyl ester (compound 1.6) is obtained.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[C:26]2[CH3:33].Cl>C(O)(C)C>[CH2:15]([O:14][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[NH:28][C:27]([CH3:32])=[C:26]4[CH3:33])=[N:3][CH:4]=[N:5]2)=[CH:10][C:9]=1[O:12][CH3:13])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Cc1[nH]c2ccc(N)cc2c1C
Agent: Cl
Solvent: CC(C)O
Product: COc1cc2c(Nc3ccc4[nH]c(C)c(C)c4c3)ncnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.5 %

Procedure:
A solution of 4-chloro-6-methoxy-7-benzyloxyquinazoline (7 g, 23 mmol), (prepared as described for the starting material in Example 1), and 5-amino-2,3-dimethylindole (4.5 g, 28 mmol) in isopropanol (90 ml) containing 6.2 N hydrogen chloride in isopropanol (380 μl) was heated at relux for 3 hours and stirred overnight at ambient temperature. The mixture was triturated with ether and the solid was filtered, washed with ether and dried under vacuum to give 7-benzyloxy-4-(2,3-dimethylindol-5-ylamino)-6-methoxyquinazoline (10.5 g, quant.).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([CH2:7][NH:8][C:9]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]3[O:19][CH:18]=[CH:17][C:16]=13)=[O:10])[NH:2]2.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:28]([C:33]([N:2]2[C@H:3]([CH2:7][NH:8][C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[O:19][CH:18]=[CH:17][C:16]=34)=[O:10])[CH2:4][C@H:5]3[C@@H:1]2[CH2:6]3)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1F
Reactant: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1)c1cccc2occc12
Product: O=C(NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1ccccc1-c1ccccc1F)c1cccc2occc12

Procedure:
prepared by reaction of benzofuran-4-carboxylic acid [(1S,3S,5S)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide with 2′-fluoro-biphenyl-2-carboxylic acid. LC-MS (basic): tR=1.43 min; [M+H]+=455.1.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=O)[CH3:2].[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O>[CH3:2][C:1]1[O:8][C:6](=[O:7])[C:5](=[CH:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][C:10]([F:9])([F:20])[F:21])=[CH:13][CH:14]=2)[N:4]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: CC(=O)NCC(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: CC1=NC(=Cc2ccc(OC(F)(F)F)cc2)C(=O)O1
Temperature: 120 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
A mixture of N-acetylglycine (5.00 g, 42.7 mmol), 4-trifluoromethoxybenzaldehyde (9.30 g, 47.0 mmol), sodium acetate (4.55 g, 55.5 mmol), and acetic anhydride (20 mL, 213 mmol) was stirred at 120° C. for 1 hour, and then was cooled to room temperature. After further ice-cooling, the precipitated yellow solid was suspended in water. The insoluble substance was collected by filtration, washed with water, and dried by heating under reduced pressure to give 10.7 g of the title compound (yellowish brown crystal, yield: 92%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:14])[C:12]#[CH:13].[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:14][CH2:11][C:12]#[CH:13])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C#CCN
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C#CCNc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 48.9 %

Procedure:
A mixture of 26.6 g (189 mmol) of 4-fluoronitrobenzene, 20.8 g (377 mmol) of propargylamine, 11 g (189 mmol) of potassium fluoride, and 26 g (188 mmol) of potassium carbonate in 600 ml of dimethylsulfoxide is stirred at room temperature under a nitrogen atmosphere for twenty hours. The reaction mixture is poured into 1.5 l of water and stirred at room temperature for two hours. The yellow solid is filtered, rinsed with water, and then isopropyl alcohol. The product is dried in vacuo at 50° C. for two days to give 16.27 g (49%) 4-nitro-N-2-propynylbenzenamine; mp 150°-153° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.[C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1)#[N:22].C([O-])([O-])=O.[K+].[K+].C([O-])(O)=O.[Na+]>CC#N>[CH3:1][O:2][C:3](=[O:20])[CH:4]([O:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=2)=[CH:34][CH:33]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCCCCCCCCCCC(Oc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)OC
Temperature: 82 °C
Reaction time: 17 h
Yield: 83.8 %

Procedure:
A mixture of 16-bromohexadecanoic acid methyl ester (4.86 g, 13.9 mmol), MeCN (20 ml), 4-cyano-4′-hydroxybiphenyl (3.16 g, 16.2 mmol), and K2CO3 (2.45 g, 17.7 mmol) was stirred at 82° C. After 17 h satd aqueous NaHCO3 (150 ml) was added, and the product was filtered, washed with water, and recrystallized from boiling MeCN (approx 80 ml). Filtration and drying under reduced pressure yielded 5.40 g (84%) of (4′-cyanobiphenyl-4-yloxy)hexadecanoic acid methyl ester colorless needles.