Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:40])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6]>C(#N)C>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:39])[C@@H:24]([NH:31][C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@@:14]2([OH:40])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:58])[C:5]([C@@:7]1([CH3:57])[C@H:12]([C@@H:13]2[O:41][C:42]([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[O:43])[C@:11]2([O:52][C:53]([CH3:55])=[O:54])[CH2:50][O:51][C@@H:10]2[CH2:9][C@@H:8]1[OH:56])=[O:6].[OH2:6].[OH2:6].[OH2:6]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Solvent: CC#N
Product: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c4ccccc4)C[C@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Product: O
Yield: 338.2 %

Procedure:
Docetaxel (460 gm obtained from step 2b) is dissolved in filtered acetonitrile (13.8 L) at 68° C. under stirring. To this solution purified water (41.4 L) is added slowly and then the mixture is stirred further at 15-20° C. for 3h. The precipitated material is filtered and then dried at 36° C. under 650 mm mercury vacuum for 36h to obtain docetaxel trihydrate (415 gm, C.P. 99.59%, assay 99.2% on dry basis, water content 6.8%).
Reaction SMILES: [N+]1([O-])C=CC=CC=1.Br[C:9]1[C:10]([C:15]#[N:16])=[N:11][CH:12]=[CH:13][CH:14]=1.C[Si](C#N)(C)C.[CH3:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>C(#N)C>[C:15]([C:10]1[C:9]([C:27]2[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=2)=[CH:14][CH:13]=[CH:12][N:11]=1)#[N:16]
Reactant: Cc1ccc(B(O)O)cc1
Reactant: N#Cc1ncccc1Br
Agent: C[Si](C)(C)C#N
Agent: [O-][n+]1ccccc1
Solvent: CC#N
Product: Cc1ccc(-c2cccnc2C#N)cc1

Procedure:
Synthetic Scheme XXVIII shows the 4-step preparation of the alkylating reagent 2-cyano-3-(4-bromomethylphenyl)pyridine (79) from 3-bromopyridine (80) (Aldrich). In step 1, the pyridine 80 was reacted with hydrogen peroxide in acetic acid at reflux to give the pyridine N-oxide 81. In step 2, the N-oxide 81 was converted to 3-bromo-2-cyanopyridine (82) by reaction with trimethysilylcyanide and triethyl anine in acetonitrile at reflux. In step 3, the nitrile 82 was coupled with 4-methylphenylboronic acid (56) (Scheme XXIV) using Snieckus conditions (Scheme XIII) to give 2-cyano-3-(4-methylphenyl) pyridine (83). In step 4, 83 was brominated with NBS/AIBN in carbon tetrachloride at reflux to give the desired alkylating reagent 79. ##STR86##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.[F:22][C:23]1[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=1[NH2:25].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:25][C:24]1[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=1[F:22]
Reactant: Nc1ccccc1F
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=c1c2cc(F)ccc2nc(CNc2ccccc2F)n1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.2 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.10 g, 0.33 mmol), 2-fluoroaniline (0.064 mL, 0.66 mmol) and acetic acid (0.038 mL, 0.66 mmol) in methanol (10 mL) was stirred 1.5 hours at ambient temperature. Sodium cyanoborohydride (0.083 g, 1.32 mmol) was added and the reaction was stirred overnight. The reaction was diluted with water and concentrated to remove most of the methanol. The milky white liquid residue was treated with saturated aqueous bicarbonate and extracted with ethyl acetate. The organic layer was washed with aqueous bicarbonate and brine, dried over magnesium sulfate and concentrated. The residue was flash chromatographed on silica gel (20 g) eluting the product with 5% and then 10% ethyl acetate/hexane. In this fashion 0.10 g (76%) of 3-(2-chloro-phenyl)-6-fluoro-2-[(2-fluoro-phenylamino)-methyl]-3H-quinazolin-4-one was isolated as a yellow foam which had: 1H NMR δ 7.95 (dd, J=3, 8.5 Hz, 1H), 7.85 (dd, J=5, 9 Hz, 1H), 7.69 (dd, J=2, 7.5 Hz, 1H), 7.63-7.46 (m, 3H), 7.43-7.37 (m, 1H), 7.05-6.90 (m, 2H), 6.70-6.62 (m, 1H), 6.43 (dt, J=1, 9 Hz, 1H), 5.30 (br s, 1H), 3.91 (ABq, Δv1-3=27.5 Hz, J=17 Hz, 2H). Analysis calculated for C21H14ClF2N3O•0.25 H2O: C, 62.70; H, 3.63; N, 10.44. Found: C, 62.78; H, 3.51; N, 10.29.
Reaction SMILES: [H-].[Na+].CO.[C:5]1([C:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([OH:22])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:29]OS(OC)(=O)=O>C1COCC1>[C:23]1([C:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)([O:22][CH3:29])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: C=CCCCCCCCCC(O)(c1ccccc1)c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCCCCCCCC(OC)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 1.2 g of sodium hydride and 0.1 mL of methanol in 50 mL of THF was added a solution of 10 g of 1,1-diphenyl-10-undecen-1-ol in 20 mL of THF over 2 hrs. The mixture was stirred at room temperature for 4 hrs, then 3.5 mL of dimethylsulfate was added. The mixture was stirred for an additional 75 hrs, then 2 mL of methanol was added to quench any excess sodium hydride. The solvent was distilled in vacuo, the residue taken up in ether, and the solution washed with 10% by wt of hydrochloric acid, water, and saturated sodium hydrogen carbonate. The solution was then dried with sodium sulfate and concentrated in vacuo to give 10.6 g of 11,11-diphenyl-11-methoxyundec-1-ene which is characterized by:
Reaction SMILES: [O:1]1CCN(C2CCCCC=2)CC1.[N+:13]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20])([O-:15])=[O:14].Cl.[C:25]1(C)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[OH:20][CH:19]([CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C:25]1=[O:1])[C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: Cc1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: O=C1CCCCC1C(O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1-Morpholino-1-cyclohexene (13.28 g) was added dropwise to a stirred solution of 3-nitrobenzaldehyde (10.0 g) and 65 mL of dry toluene, under nitrogen. After stirring at room temperature for 5 days the mixture was treated with 75 mL of 5N HCl, stirred an additional 15 minutes and the layers separated. The aqueous phase was extracted with three additional 75 mL portions of toluene, the toluene extracts were dried (MgSO4), filtered and the solvent evaporated. The resulting yellow oil which turned greenish on standing overnight was chromatographed, with methylene chloride as elutent, to yield 2-(α-hydroxy-3-nitrobenzyl)cyclohexanone (6.35 g) as a yellow oil; MS (CI, CH4): m/z=250(M+1). The yellow oil was dissolved in ethyl ether (50 mL) and treated with 50 mL of concentrated hydrochloric acid. After stirring overnight the layers were separated and the aqueous phase extracted with ethyl ether. The combined extracts were dried (MgSO4), filtered and evaporated to yield crude 2-(3-nitrophenyl)methylenecyclohexanone as low melting orange crystals (4.69 g), which were used without further purification. NMR CDCl3): 1.79-1.89 (m,2, CH2), 1.93-2.01 (m,2, CH2), 2.56-2.60 (m,2, CH2), 2.82-2.87 (m,2, CH2), 7.47 (s,1, olefinic), 7.58 (t,1, J= 7.9, Ar), 7.69 (d,1, J=7.7, Ar), 8.19 (d,1, J=8.9, Ar), 8.24 (s,1, Ar); MS (CI, CH4): m/z=232(M+1).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:23])=[C:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[C:12]#[N:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[S:31](Cl)([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>ClCCl>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([O:23][S:31]([C:34]2[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[C:11]([C:14]2[S:15][C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[C:12]#[N:13])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(=O)N1CCC(C(O)=C(C#N)c2nc3ccccc3s2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(C(OS(=O)(=O)c2ccc(C)cc2)=C(C#N)c2nc3ccccc3s2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 22.9 %

Procedure:
To a solution of the above prepared 3-(1-acetylpiperidin-4-yl)-2-benzothiazol-2-yl-3-hydroxyacrylonitrile (415 mg, 1.27 mmol) in anhydrous dichloromethane (20 mL) at room temperature under argon were added triethylamine (193 mg, 1.9 mmol) and tosyl chloride (303 mg, 1.59 mmol) in small portions. The resulting mixture was stirred at room temperature for 6 hrs. The reaction mixture was diluted with dichloromethane. The organic phase was washed with 1% HCl, 0.5% NaOH, water, brine, and dried over anhydrous sodium sulfate, filtered, and evaporated. The resulting crude product was purified by flash column chromatography eluting with CH2Cl2:MeOH=20:1 to yield 140 mg (23%) of toluene-4-sulfonic acid 1-(1-acetylpiperidin-4-yl)-2-benzothiazol-2-yl-2-cyanovinyl ester. MS (m/z, ES+): 482.1 (M+1, 100%).
Reaction SMILES: C(O)C.[CH2:4]([O:6][C:7]([CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)=[O:8])[CH3:5].[Br:16]Br.[NH2:18][C:19]([NH2:21])=[S:20]>CC(C)=O>[BrH:16].[CH2:4]([O:6][C:7]([CH:9]1[CH2:14][CH2:13][C:12]2[N:18]=[C:19]([NH2:21])[S:20][C:11]=2[CH2:10]1)=[O:8])[CH3:5]
Reactant: BrBr
Reactant: NC(N)=S
Reactant: CCOC(=O)C1CCC(=O)CC1
Solvent: CCO
Solvent: CC(C)=O
Product: Br
Product: CCOC(=O)C1CCc2nc(N)sc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
A 3 liter reactor equipped with mechanical stirrer, thermometer and condenser was loaded with 1500 ml of ethanol and 200 g of 4-oxo-cyclohexanecarboxylic acid ethyl ester. After cooling to 0° C., 188 g of bromine were dropped therein in about 1 hour. The temperature was raised to 10° C., then to the room one after discolouration. After 1 hour, 89.32 g of thiourea were added in portions to obtain a suspension, that was refluxed to obtain gradual dissolution of the solid. After 4 hours the solution was concentrated to small volume to obtain a solid mass, that was suspended in 800 ml of acetone and refluxed to obtain a solution. The solution was then cooled to room temperature to precipitate a solid, then to 0° C. and after 4 hours the solid was filtered, washed twice with 100 ml of cold acetone and dried to obtain 170 g of the title product.
Reaction SMILES: [C:1]([N:8]([CH3:40])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:41][C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][N:43]=1>>[NH2:41][C:42]1[N:43]=[CH:44][C:45]([C:31]2[CH:32]=[CH:33][C:34]([O:35][CH3:36])=[C:29]([CH:30]=2)[CH2:28][N:15]([C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH:12]2[CH2:13][CH2:14][CH:9]([N:8]([CH3:40])[C:1](=[O:2])[O:3][C:4]([CH3:6])([CH3:7])[CH3:5])[CH2:10][CH2:11]2)=[CH:46][CH:47]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(N)nc2)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 5 (175 mg, 0.29 mmol) is coupled to 2-amino-5-bromopyridine (62 mg, 0.36 mmol) using Method B to give the title compound.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Br-:1].[C:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][P+:19]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([OH:12])=[O:11]
Reactant: O=C(O)CCCCCCCCBr
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(O)CCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 110 °C
Yield: 101.1 %

Procedure:
To a solution of 9-bromo-nonanoic acid (7.00 g, 29.5 mmol) in toluene (10 mL) was added triphenylphosphine (7.74 g, 29.5 mmol). The solution was sealed under nitrogen in a pressure tube and heated at 110° C. for 18 hours. On reaction completion two phases were observed. The toluene top layer was decanted from the crude product which was washed with toluene. (8-Carboxy-octyl)-triphenyl-phosphonium bromide (14.9 g) was obtained, which was directly used in the next step. White semisolid, m/e=419.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-])=O)[NH:9][C:8](=[O:16])[CH2:7][CH2:6]2.CN(C)C=O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[NH2:13][C:12]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:16])[NH:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: [H][H]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NC(=O)CC2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1N)NC(=O)CC2
Yield: 92.7 %

Procedure:
6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-quinolinone (485 mg, 2.18 mmol) was taken in ethyl acetate (10 mL) and methanol (50 mL). Dimethylformamide (10 mL) was added and the mixture heated to ensure dissolution. 10% palladium on carbon (581 mg, Aldrich) was added and the reaction stirred under 60 psi hydrogen pressure for 16 h. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 7-amino-6-(methyloxy)-3,4-dihydro-2(1H)-quinolinone (387 mg, 2.02 mmol, 92%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32-2.37 (m, 2 H), 2.66-2.72 (m, 2 H), 3.69 (s, 3 H), 4.63 (s, 2 H), 6.20 (s, 1 H), 6.60 (s, 1 H), 9.70 (s, 1 H); ESIMS (M+H)+=193.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][C:29]=4[CH3:35])[CH2:24][CH2:23]3)[CH:17]=1)[C:10]([CH3:37])([CH3:36])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:35][C:29]1[CH:30]=[C:31]([CH3:34])[CH:32]=[CH:33][C:28]=1[N:25]1[CH2:26][CH2:27][N:22]([C:18]2[CH:17]=[C:16]([CH:11]3[C:10]([CH3:37])([CH3:36])[CH2:9][C:8]4[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=4)[NH:12]3)[CH:21]=[CH:20][CH:19]=2)[CH2:23][CH2:24]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N3CCN(c4ccc(C)cc4C)CC3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(N2CCN(c3cccc(C4Nc5ccc(C(=O)O)cc5CC4(C)C)c3)CC2)c(C)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
A mixture of 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.20 g, 0.40 mmol), lithium hydroxide hydrate (167 mg, 4.0 mmol), water (0.5 mL) in methanol (1 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (150 mg, 80%) as a white solid: LC/MS m/e calcd for C30H35N3O2 (M+H)+: 470.6, observed: 470.4.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33](O)=[O:34])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]=23)[CH2:3][CH2:2]1.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:39][CH2:38]1>>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:33]([NH:36][CH:37]4[CH2:38][CH2:39][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:41][CH2:42]4)=[O:34])=[C:22]([CH3:32])[N:23]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[C:16]=23)[CH2:3][CH2:2]1
Reactant: COc1cc(-c2ccnc3c(C(=O)O)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Product: COc1cc(-c2ccnc3c(C(=O)NC4CCN(C(=O)OC(C)(C)C)CC4)c(C)n(COCC[Si](C)(C)C)c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (example D.c7) and commercially available tert-butyl 4-amino-piperidine-1-carboxylate the title compound is obtained as pale yellow viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C>[C:8]([O:1][C:2]1[CH:6]=[C:5]([CH3:7])[O:4][N:3]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(O)no1
Solvent: CCN(CC)CC
Product: Cc1cc(OC(=O)c2ccccc2)no1

Procedure:
3-Hydroxy-5-methylisoxazole was reacted with benzoyl chloride in the presence of triethylamine to give 3-benzoyloxy-5-methylisoxazole, which was then reacted with N-bromosuccinimide, to give 3-benzoyloxy-5-bromomethylisoxazole. This was reacted with disodium thioglycolate to give 3-hydroxyisoxazol-5-ylmethylthioacetic acid, which was treated with diphenyldiazomethane to give the benzhydryl ester.
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]#[N:11].[N:12]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O)=[N+:13]=[N-:14].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C.O>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[N:13][N:12]2[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17](=[O:19])[NH:11][C:10]=12
Reactant: [N-]=[N+]=Nc1ccccc1C(=O)O
Reactant: N#CCc1ccccc1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: O=c1[nH]c2c(-c3ccccc3F)nnn2c2ccccc12
Yield: 108.4 %

Procedure:
Sodium metal (1.4 g, 60 mmol) was dissolved in ethanol (100 ml) at room temperature under nitrogen. 2-Fluorophenylacetonitrile (3.85 ml, 30 mmol) was added, followed by the dropwise addition of a solution of 2-azidobenzoic acid (4.71 g, 29 mmol) in ethanol (60 ml). The thick white suspension was refluxed for 18 h then cooled and poured into water (800 ml). The mixture was acidified to pH 3-4 with aqueous 1M citric acid and the precipitated solid was collected. The solid was washed with diethyl ether (20 ml) and dried in vacuo to give 3-(2-fluorophenyl)-[1,2,3]triazolo[1,5-α]quinazolin-5(4H)-one (8.81 g, 100%), m.p. 238-241° C. (DMF). Found: C, 64.33; H, 3.06; N, 20.29. C15H9FN4O requires C, 64.28; H, 3.24; N, 19.99%. δH (360 MHz; DMSO) 7.33-7.38 (2H, m), 7.46-7.55 (1H, m), 7.69-7.73 (2H, m), 8.02 (1H, ddd, J=9, 9 and 1), 8.24 (1H, dd, J=8 and 1), 8.38 (1H, d, J=8) and 12.40 (1H, br s); m/z (ES+) 821 (M+H+).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH2:13][NH:14][C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2].[Cl-].ClC=[N+](C)C.[C:24](=O)([O-])[O-:25].[K+].[K+]>ClCCCl>[C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([CH:24]=[O:25])[CH:9]=[C:8]1[CH2:13][NH:14][C:15](=[O:17])[CH3:16])(=[O:3])[CH3:2]
Reactant: CC(=O)NCCn1c(C)ccc1CNC(C)=O
Reactant: O=C([O-])[O-]
Agent: C[N+](C)=CCl
Agent: [Cl-]
Agent: [K+]
Solvent: ClCCCl
Product: CC(=O)NCCn1c(CNC(C)=O)cc(C=O)c1C
Reaction time: 1.5 h

Procedure:
4.9 g of N-((1-(2-acetylaminoethyl)-5-methyl-1H-pyrrol-2-yl)methyl)acetamide in 70 ml of 1,2-dichloroethane are added dropwise to 3.0 g (21 mmol) of chloromethylenedimethylammonium chloride in 30 ml of 1,2-dichloroethane at 10° C. The mixture is subsequently stirred for 90 min, hydrolysed using potassium carbonate solution and worked up as described in Example 1.
Reaction SMILES: Cl.N[CH2:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])[C:5]=1[OH:17].C1N2CN3CN(C2)CN1C3.FC(F)(F)C(O)=[O:31]>>[CH:3]([C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:6]([S:13]([CH3:16])(=[O:15])=[O:14])[C:5]=1[OH:17])=[O:31]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)c1cc(CN)c(O)c(S(C)(=O)=O)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: CC(C)c1cc(C=O)c(O)c(S(C)(=O)=O)c1

Procedure:
0.7 g (0.0025 mol) of 2-aminomethyl-4-isopropyl-6-methylsulfonylphenol hydrochloride are reacted with 0.45 g of urotropine in 8 ml of trifluoroacetic acid to give 2-formyl-4-isopropyl-6-methylsulfonylphenol in analogy to Example 1.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[CH2:9][NH:10][C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26]O)=[CH:22][CH:21]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:28]=[CH:29][CH:30]=1)[CH2:9][NH:10][C:11]1[C:12]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][Cl:3])=[CH:22][CH:21]=3)[NH:17][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(-c2cc3c(NCc4cccc(Cl)c4)ncnc3[nH]2)cc1
Solvent: Cc1ccccc1
Product: ClCc1ccc(-c2cc3c(NCc4cccc(Cl)c4)ncnc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 0.79 ml (10 mmol) thionylchloride in 5.5 ml of toluene is cooled to −10° C. Solid {4-[4-(3-chloro-benzylamino)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-phenyl}-methanol is added and the suspension stirred at 0° C. for 2 h and then at RT for 17 h. The solid is filtered off, washed with toluene and suspended in water (3 ml). The mixture is treated with saturated sodium bicarbonate solution (3 ml) and stirred for 10 min. The crystals are collected by filtration washed with water, a small amount of ethanol and ether and dried to give the title compound; m.p. decomposition ˜300° C.; Rf (dichloromethane/methanol/conc. ammonia 90:10:1)=0.61; MS-ES+: (M+H)+=383.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[C:24]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:23])[C@@H:5]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:24])=[CH:18][CH:17]=1)[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
N-Benzoyl-L-tyrosine ethyl ester (0.054 g, 0.17 mmol) was dissolved in DMF (1 mL). K2CO3 (1 eq, 0.17 mmol, 0.024g) was added, followed by methyl iodide (1 eq, 0.17 mmol, 0.011 mL). The slightly cloudy mixture was allowed to stir at room temperature under nitrogen for 3.5 hours. An additional 2 eq K2CO3 was added and the mixture was allowed to stir overnight. Water was poured into the flask, causing cloudiness. Precipitation was completed via refrigeration. The resulting white solid was filtered, washed well with water and dried in air (0.030 g, 54%).