Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:10][CH2:9][C:8]2[N:7]=[C:6]([CH3:12])[CH:5]=[CH:4][C:3]1=2.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C(C)C)C=CC=CC=1>[Pd].Cl>[C:13]1([C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]3)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Cc1ccc2c(n1)CCCC2(O)c1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)c1ccccc1
Product: Cc1ccc2c(-c3ccccc3)cccc2n1

Procedure:
A mixture of 20 g (0.084 mole) of 5-hydroxy-5-phenyl-5,6,7,8-tetrahydroquinaldine, 10 g of 10% palladium on carbon, 2.3 g of para-toluenesulfonic acid and 200 ml of cumene was heated at its reflux temperature for 24 hours. The mixture was filtered hot, and then the filtrate was evaporated to provide a residue. This residue was dissolved in dilute hydrochloric acid. This solution was extracted with diethyl ether and the acid layer was then neutralized with 50% aqueous sodium hydroxide solution. The product was extracted into diethyl ether. The organic layer was dried and then evaporated to provide a solid residue. Recrystallization from methanol provided white crystals of 5-phenylquinaldine. Analysis: Calculated for C16H13N.H2O: %C, 81.0; %H, 6.4; %N, 5.8; Found: %C, 81.4; %H, 6.6; %N, 5.5. The structure assignment was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH:17]=[N+:18]([CH3:20])[CH3:19].COC1C=C(C=CC=1OC)C=O.CNC>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]([N:18]([CH3:20])[CH3:19])[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:2]([CH3:1])[CH:3]=2)[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: Cn1ccc2ccccc21
Reactant: COc1ccc(C=[N+](C)C)cc1OC
Agent: CNC
Agent: COc1ccc(C=O)cc1OC
Agent: [Cl-]
Product: COc1ccc(C(c2cn(C)c3ccccc23)N(C)C)cc1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-indole and (3,4-dimethoxy-benzylidene)-dimethylammonium chloride, which had been prepared in accordance with example 44 from 3,4-dimethoxy-benzaldehyde and dimethylamine.
Reaction SMILES: [C:1]([CH:8]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:37][CH3:38])=[CH:12][C:11]=1[CH2:39][CH2:40][CH3:41])([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:8]([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[C:21]3=[N:22][C:23]([C:27]([O:29][CH2:30][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:28])=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]=[C:18]2[CH2:37][CH3:38])=[CH:12][C:11]=1[CH2:39][CH2:40][CH3:41])([OH:3])=[O:2]
Reactant: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)OCc4ccccc4)nc32)ccc1OC(C(=O)OC(C)(C)C)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cc(Cn2c(CC)nc3c(C)cc(C(=O)OCc4ccccc4)nc32)ccc1OC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47 %

Procedure:
To a solution of the product of Step A (9 mg, 0.014 mmol) CH2Cl2 (1 mL) was added TFA (0.4 mL) at rt dropwise. The solution was stirred at rt for 2.5 hours. After evaporation of the solvent the crude mixture was purified by flash chromatography eluted with CHCl3 /MeOH/NH4OH (80:15:1), to give 3.8 mg of the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6]1)=[O:4].[Cl:28][C:29]1[C:34](O)=[C:33]([Cl:36])[CH:32]=[C:31]([CH3:37])[CH:30]=1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH:5]1[CH:10]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:34]3[C:29]([Cl:28])=[CH:30][C:31]([CH3:37])=[CH:32][C:33]=3[Cl:36])=[CH:13][CH:12]=2)[CH2:9][CH2:8][N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:6]1)=[O:4]
Reactant: Cc1cc(Cl)c(O)c(Cl)c1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCO)cc1
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1
Temperature: 50 °C
Yield: 90.4 %

Procedure:
A mixture of compound 4-[4-(2-Hydroxyethoxy)phenyl]piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (5.50 g, 15 mmol), 2,6-dichloro-p-cresol (3.08 g, 18 mmol), azodicarboxylic dipiperidine (7.31 g, 29 mmol) and PBu3 (14 mL, 58 mmol) in toluene (150 mL) was heated to 50° C. for 16 h. The mixture was allowed to cool to rt, filtered, and the precipitate was washed with toluene. The filtrate was diluted with EtOAc, and washed with water (2×) and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (EtOAc/heptane 0:1→1:9→2:8) yielded the compound as a colorless oil (7.3 g, 90%). LC-MS: tR=1.18 min, ES+=538.34.
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]([C:21]3[N:26]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:25](=[O:34])[C:24]4=[CH:35][CH:36]=[C:37]([Cl:38])[N:23]4[N:22]=3)[CH2:19][CH3:20])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CN(C=O)C.CCOC(C)=O>[NH2:17][CH:18]([C:21]1[N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:25](=[O:34])[C:24]2=[CH:35][CH:36]=[C:37]([Cl:38])[N:23]2[N:22]=1)[CH2:19][CH3:20]
Reactant: CCC(NC(=O)OCC1c2ccccc2-c2ccccc21)c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: CCC(N)c1nn2c(Cl)ccc2c(=O)n1Cc1ccccc1
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
A solution of (±)-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-propyl]-carbamic acid 9H-fluoren-9-ylmethyl ester (0.92 g, 1.7 mmol) and piperidine (0.5 mL) in DMF (10 mL) was allowed to stand at rt for 30 min. The reaction mixture was diluted with EtOAc to 100 mL, washed with 10% LiCl solution (2×50 mL) and dried over MgSO4. Concentration and purification of the crude product by flash column chromatography (SiO2, EtOAc/hexane 1:1) gave the title compound as colorless oil (0.462 g, 85.5%): 1H NMR (CDCl3) δ 7.26 (m, 2H), 7.20 (m, 1H), 7.10 (d, 2H, J=7.15 Hz), 7.00 (d, 1H, J=4.4 Hz), 6.42 (d, 1H, J=4.4 Hz), 5.43 (d, 1H, J=16.5 Hz), 5.23 (d, 1H, J=16.5 Hz), 3.67 (t, 1H, J=6.62 Hz), 1.83 (m, 1H), 1.57 (m, 1H), 0.83 (t, 3H, J=7.15 Hz); 13C NMR (CDCl3) δ 154.6, 136.3, 129.0, 127.8, 126.3, 117.7, 117.2, 110.0, 108.4, 53.6, 44.4, 29.7, 10.5; MS (ESI+), 316.99, 319.31 (M++H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2.[CH3:16][C:17]1[C:21]([C:22]([N:24]2[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]2)=[O:23])=[C:20]([CH3:31])[NH:19][C:18]=1[CH:32]=O>>[CH3:16][C:17]1[C:21]([C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]2)=[O:23])=[C:20]([CH3:31])[NH:19][C:18]=1[CH:32]=[C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[CH:14][C:6]=2[C:2]2[S:1][CH:5]=[CH:4][N:3]=2)[NH:10][C:9]1=[O:15]
Reactant: O=C1Cc2c(cccc2-c2nccs2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1CCN(C)CC1
Product: Cc1[nH]c(C=C2C(=O)Nc3cccc(-c4nccs4)c32)c(C)c1C(=O)N1CCN(C)CC1

Procedure:
4-Thiazol-2-yl-1,3dihydro-indol-2-one (54 mg, 0.25 mmol) was condensed with 3,5-dimethyl-4-(4-methylpiperazine-1-carbonyl)-1H-pyrrole-2-carbaldehyde (69 mg, 0.275 mmol) to give the title compound.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:18][C:19]3[C:24]([N:25]=2)=[CH:23][C:22]([C:26]([O:28]C)=[O:27])=[CH:21][CH:20]=3)=[CH:12][CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CI>C1COCC1>[C:3]([O:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([C:16]2[C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:18][C:19]3[C:24]([N:25]=2)=[CH:23][C:22]([C:26]([OH:28])=[O:27])=[CH:21][CH:20]=3)=[CH:14][CH:15]=1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3ccc(C(=O)OC(C)(C)C)cc3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Reaction time: 1 h
Yield: 119.2 %

Procedure:
Sodium hydride (60 mg, 2.50 mmol, 5.60 equiv) was added to a solution of methyl 3-(4-(t-butoxycarbonyl)phenyl)-2-phenylquinoxaline-6-carboxylate (200 mg, 0.42 mmol, 1.00 equiv, 95%) in THF (10 mL) at 0° C. under an inert atmosphere and stirred for 1 h. A solution of CH3I (125 mg, 0.88 mmol, 2.00 equiv) in THF (1 mL) was added dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was quenched by the addition of water. The pH value of the solution was adjusted to 3-4 with 1N HCl. The resulting mixture was concentrated under vacuum, yielding 213.5 mg (crude) of 3-(4-(t-butoxycarbonyl)phenyl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Cl.Cl.C([O:5][C:6]([C@@H:8]([NH:19][C@H:20]1[CH2:26][CH2:25][C@H:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23][N:22]([CH2:33][C:34]([OH:36])=[O:35])[C:21]1=[O:37])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:7])C.[OH-].[Na+].Cl>>[C:6]([C@@H:8]([NH:19][C@H:20]1[CH2:26][CH2:25][C@H:24]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:23][N:22]([CH2:33][C:34]([OH:36])=[O:35])[C:21]1=[O:37])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)([OH:7])=[O:5]
Reactant: CCOC(=O)[C@H](CCCCC1CCNCC1)N[C@H]1CC[C@H](c2ccccc2)CN(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CN1C[C@@H](c2ccccc2)CC[C@H](N[C@@H](CCCCC2CCNCC2)C(=O)O)C1=O
Yield: 90.7 %

Procedure:
A solution of 300 mg of rel-α-{3(S)-[1(S)ethoxycarbonyl-5-(4-piperidyl)pentylamino]-2-oxo-6(R)-phenylperhydroazepin-1-yl}acetic acid dihydrochloride (prepared as described in Example 22) in 3.2 ml of a 1N aqueous solution of sodium hydroxide was stirred for 16 hours at room temperature, and then its pH value was adjusted to a value of 4.5 by adding 1N aqueous hydrochloric acid. The resulting precipitate was collected by filtration and dissolved again in water containing a small amount of acetic acid. The resulting solution together with the filtrate was poured onto a column pached with a porous resin HP-20 (Mitsubishi Kasei Kogyo Co., Ltd.) and eluted first with water and then with 20% v/v aqueous acetone. The fractions first eluted with water contained sodium chloride and acetic acid, whilst the fractions eluted next with 20% v/v aqueous acetone contained the title compound. The latter fractions were concentrated by evaporation under reduced pressure to give 223 mg of the title compound as a powdery substance.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[O:29]1[C:33]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][NH:31][C:30]1=[O:39].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:36]2[CH2:35][CH2:34][C:33]3([O:29][C:30](=[O:39])[NH:31][CH2:32]3)[CH2:38][CH2:37]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=C1NCC2(CCNCC2)O1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC4(CC3)CNC(=O)O4)n(C)c2n1
Reaction time: 18 h
Yield: 55.1 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (100 mg, 0.27 mmol) and 1-oxa-3,8-diazaspiro[4.5]decan-2-one (50 mg, 0.32 mmol) in DCE (3 mL) was stirred at ambient temperature for 90 min. Sodium triacetoxyborohydride (86 mg, 0.41 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; 100:0 to 95:5 to 90:10 to 85:15) to afford 327 as a white solid (77 mg, 56%). LCMS (Method G): RT=5.35 min, M+H+=518. 1H NMR (CDCl3, 400 MHz) δ 8.9 (m, 1 H); 7.72 (m, 1 H); 7.29 (m, 2 H); 4.99 (bs, 1 H); 4.35 (m, 4H); 3.90-3.83 (m, 7 H); 3.80 (s, 2 H); 3.36 (s, 2 H); 2.95 (s, 3 H); 2.76-2.65 (m, 4 H); 2.03 (m, 2 H) and 1.82 (m, 2 H)
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14](O)[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.P(Cl)(Cl)([Cl:19])=O.C(Cl)Cl.C([O-])(O)=O.[Na+]>C(OCC)C>[Cl:19][C:14]1[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=[C:2]([CH3:1])[CH:15]=1
Reactant: Cc1cc(O)c2ccc3cccnc3c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc(Cl)c2ccc3cccnc3c2n1
Temperature: 25 °C

Procedure:
To a 500 mL round-bottomed flask equipped with a reflux condenser containing 2-methyl-[1,10]phenathrolin-4-ol, (10.20 g, 48.5 mmol), was slowly added phosphorus oxychloride (200 mL) and the mixture was refluxed for 3 hours. The reaction flask was allowed to cool down to room temperature and the solvent was removed in a rotary evaporator. The solid obtained was treated with methylene chloride (200 mL) and saturated NaHCO3 (200 mL) and transferred to a separatory funnel. The aqueous layer was further extracted with methylene chloride (200 mL) and the combined organic layers were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated. The residue obtained was treated with ethyl ether (100 mL), filtered and dried yielding a light brown solid (9.00 g). A second crop of 0.60 g of material was obtained from the mother liquors as a light yellow solid, with an overall yield of 9.60 g (87% yield).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])=[CH:11][CH:10]=4)=[O:20])[CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cc1
Yield: 44 %

Procedure:
A solution of 2,2,2-trichloroethyl [4-(propionylamino)phenyl]carbamate (200 mg, 0.589 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (145 mg, 0.589 mmol), diisopropylethylamine (0.206 ml, 1.18 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 113 mg (44.0%) of the desired product as a solid.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:17]=1[O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)C>[Cl:15][C:16]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:17]=1[O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:25]
Reactant: OC1CCCCC1
Reactant: O=C(Cl)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: O=C(OC1CCCCC1)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
To a stirred solution of cyclohexanol (1.05g., 0.0105 mole) and triethylamine (1.10g., 0.011 mole) in toluene (30 ml.) was added 5-(2',4'-dichlorophenoxy)-2-nitrobenzoyl chloride (3.47g., 0.01 mole). A precipitate of triethylamine hydrochloride occurred immediately. The reaction solution was heated to reflux for one hour, cooled and diluted with diethyl ether (150 ml.). After filtering the triethylamine hydrochloride, the solvent was evaporated to give 4.1g. of a brown oil. A small amount of additional precipitate was filtered off. The ether was again stripped to yield 3.5g. of brown oil.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:13]/[CH2:14][OH:15])=[CH:8][CH:7]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[CH3:54][O:55][C:56](=[O:67])[CH2:57][O:58][C:59]1[CH:64]=[CH:63][C:62](O)=[CH:61][C:60]=1[CH3:66]>O1CCCC1>[CH3:54][O:55][C:56](=[O:67])[CH2:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([O:15][CH2:14]/[CH:13]=[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([C:5]#[C:4][CH2:3][N:2]([CH3:1])[CH3:22])=[CH:7][CH:8]=2)\[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:61][C:60]=1[CH3:66]
Reactant: COC(=O)COc1ccc(O)cc1C
Reactant: CN(C)CC#Cc1ccc(/C(=C/CO)c2ccccc2)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccccc2)c2ccc(C#CCN(C)C)cc2)cc1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of the above alcohol (407 mg, 1.397 mmol) in dry tetrahydrofuran (40 mL) was added tributylphosphine (0.50 ml, 2.79 mmol). To the mixture was cooled to 0° C. and added 1,1′-(azodicarbonyl)dipiperidine (703 mg, 2.79 mmol) and after 10 min. (4-hydroxy-2-methyl-phenoxy)-acetic acid methyl ester (301 mg, 1.536 mmol) was added. After stirring for 1.5 hr at 0° C. the mixture was allowed to warm up to ambient temperature and stirred overnight. The reaction mixture was added silica gel Fluka 60 (10 g) and evaporated in vacuo. The residue was purified by ISCO combiflash 16 (silica gel, hexane/ethyl acetate 85:15) giving (4-{(E)-3-[4-(3-dimethylamino-prop-1-ynyl)-phenyl]-3-phenyl-allyloxy}-2-methylphenoxy)-acetic acid methyl ester as an oil.
Reaction SMILES: [CH:1]1([NH:7][CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:21](O)C>O>[CH:1]1([N:7]2[CH2:8][C:9](=[O:10])[N:11]([C:12]3[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=3)[CH2:21]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCO
Reactant: O=C(CNC1CCCCC1)Nc1ccc([N+](=O)[O-])cc1
Solvent: O
Product: O=C1CN(C2CCCCC2)CN1c1ccc([N+](=O)[O-])cc1

Procedure:
2-Cyclohexylamino-N-(4-nitrophenyl)-acetamide (3.5g) were added to ethanol (85 ml). p-Formaldehyde (0.8g) in water (110 ml) was added and the mixture was refluxed 4 hours, cooled and filtered to yield 3.1 g, m.p. 132°-133°C
Reaction SMILES: [C:1]([O:4][C@H:5]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](Cl)=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2].[F:27][C:28]1[C:36]([OH:37])=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[C:31]([CH3:38])[NH:32]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:4][C@H:5]([CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([O:37][C:36]3[C:28]([F:27])=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][C:31]([CH3:38])=[CH:30]4)=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:19][CH3:20])(=[O:3])[CH3:2]
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OC[C@@H](CN1CCCC1)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H](CN1CCCC1)OC(C)=O
Temperature: 90 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
A suspension of (2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)4-chloro-6-methoxyquinazoline (530 mg, 1.4 mmol) and 4-fluoro-5-hydroxy-2-methylindole (277 mg, 1.68 mmol), (prepared as described for the starting material in Example 237), in DMF (8 ml) containing potassium carbonate (290 mg, 2.1 mmol) was stirred at 90° C. for 2 hours. After cooling, the volatiles were removed under vacuum and the residue was purified by column chromatography eluting with methylene chloride/methanol (95/5) to give (2R)-7-(2-acetoxy-3-(pyrrolidin-1-yl)propoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxyquinazoline (580 mg, 81%).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][CH:6]=1.[Li+].[OH-].Cl.CCOC(C)=O>O1CCOCC1.O>[CH3:15][S:12]([O:11][C:8]1[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:16])=[O:2])=[CH:10][CH:9]=1)(=[O:14])=[O:13]
Reactant: COC(=O)Cc1ccc(OS(C)(=O)=O)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(4-Methanesulfonyloxy-phenyl)-acetic acid methyl ester (615 mg, 2.51 mmol) was dissolved in a 1:1 mixture of dioxane and water (6 mL) and an aq. solution of LiOH (2 eq., 5.05 mL, 1N) was added and the mixture was stirred at ambient temperature for 15 min. After the addition of aq. HCl (3N) and EtOAc, the phases were separated and the organic layer was dried (MgSO4), filtered and evaporated under reduced pressure. The title compound was obtained without further purification as a solid (497 mg, 85.7%). 1H NMR (400 MHz, CDCl3): δ 7.35-7.38 (d, 2H), 7.25-7.29 (d, 2H), 3.64 (s, 2H), 3.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([OH:26])=O)=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.CN.C[CH2:33][N:34]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:24]([NH:34][CH3:33])=[O:26])=[C:21]([CH3:23])[N:22]=3)[CH2:14][C@H:13]2[O:27][CH3:28])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)O)s3)C[C@H]2OC)nc1Cl
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc(C)c(C(=O)NC)s3)C[C@H]2OC)nc1Cl
Yield: 75.6 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-4-methyl-1,3-thiazole-5-carboxylic acid obtained in Example (14a) (40 mg, 0.09 mmol), methylamine hydrochloride (7 mg, 0.11 mmol), WSC hydrochloride (59 mg, 0.31 mmol), HOBT (21 mg, 0.15 mmol), diisopropylethylamine (0.020 mL, 0.11 mmol), dichloromethane (0.75 mL) and DMA (0.75 mL), to obtain 30 mg of the title compound as a white solid (73%).
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH3:22][C:23]1[O:27][C:26]([CH2:28][NH2:29])=[CH:25][CH:24]=1>>[CH3:22][C:23]1[O:27][C:26]([CH2:28][NH:29][C:20]2[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=2)=[CH:25][CH:24]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNC2=Nc3ccc([N+](=O)[O-])cc3CO2)o1
Yield: 79.1 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (2.0 g, 6.16 mmol; HPLC: 4.446 min) and 5-methyl-2-furanmethanamine (CAS 14003-16-8) (0.685 g, 6.163 mmol) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (1.40 g, 79%, HPLC 1.624 min), MS (ISP) m/e=326.2 [(M+H)+].