Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][NH:26]1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[CH2:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][N:26]1[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5][N:4]2[CH:1]2[CH2:3][CH2:2]2)=[C:9]([NH:17][CH2:18][CH2:19][OH:20])[C:10]=1[F:16]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(NCCO)c2c1=O
Reactant: c1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4ccccc4C3)c(F)c(NCCO)c2c1=O
Yield: 42.7 %

Procedure:
205 mg of 1-cyclopropyl-5(2-hydroxyethylamino)-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 119 mg of isoindoline, 182 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 113 mg of the target compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5]/[CH:6]=[C:7](/[C:18]1[N:23]=[C:22]([O:24][CH3:25])[C:21]([Cl:26])=[CH:20][CH:19]=1)\[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:10][CH:9]=1.O>C(O)C>[C:14]([C:11]1[CH:12]=[CH:13][C:8](/[C:7](/[C:18]2[CH:19]=[CH:20][C:21]([Cl:26])=[C:22]([O:24][CH3:25])[N:23]=2)=[CH:6]\[CH2:5][C:1]#[N:2])=[CH:9][CH:10]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COc1nc(/C(=C/CBr)c2ccc(C(C)(C)C)cc2)ccc1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1nc(/C(=C/CC#N)c2ccc(C(C)(C)C)cc2)ccc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 53.3 %

Procedure:
Sodium cyanide (137 mg) was added to a solution of 6-[(1E)-3-bromo-1-(4-tert-butylphenyl)prop-1-en-1-yl]-3-chloro-2-methoxypyridine (500 mg) in ethanol (10 mL), and the mixture was stirred at room temperature for 22 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with a 2 M sodium hydroxide solution and brine, dried over sodium sulfate and filtered, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1→4:1) to give the title compound as a yellow oil (230 mg, 53%).
Reaction SMILES: [CH:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:5](=[O:10])[CH2:6][C:7](=O)[CH3:8])([CH3:3])[CH3:2].C(O)(=O)C.[NH3:28]>C(OCC)(=O)C>[CH:1]([N:4]([C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[C:5](=[O:10])/[CH:6]=[C:7](\[NH2:28])/[CH3:8])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC(=O)CC(=O)N(c1ccc(Nc2ccccc2)cc1)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C/C(N)=C/C(=O)N(c1ccc(Nc2ccccc2)cc1)C(C)C
Temperature: 35 °C
Reaction time: 2.5 h
Yield: 90.9 %

Procedure:
N-Isopropyl-3-oxo-N-[4-(phenylamino)phenyl]butyramide (30.0 g, 0.0967 mol) and conc. acetic acid (1.4 g, 0.0233 mol) in ethyl acetate (140 g) were introduced into an autoclave. Ammonia (16.0 g, 0.9395 mol) was introduced in the course of 10 minutes and the temp. of the reaction mixture was increased to 35° C. during this period. After the introduction a pressure of 14 bar is present. The temperature of the reaction mixture was heated to 70° C. in the course of 30 min. In the course of this, the pressure rose to 17 bar. After 2.5 h under these conditions, the reaction mixture was cooled to 25° C. and ammonia was released. The reaction mixture was further cooled to 5° C. in order to crystallize the product. The suspension was filtered. The pale grey solid was washed with cold (0° C.) ethyl acetate (20 ml) and dried in vacuo (50 mbar) at 35° C. for 2 days. (Z)-3-Aminobut-2-enoic acid N-isopropyl-N-[4-(phenylamino)phenyl]amide (27.2 g, 91.0%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[NH2:10].CC1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>O>[Cl:18][CH2:19][C:20]([NH:10][C:4]1[CH:5]=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C)cc1N
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C)cc1NC(=O)CCl
Reaction time: 1.5 h
Yield: 66 %

Procedure:
To a stirred solution of 49.2 parts of 2-methoxy-5-methylbenzenamine and 270 parts of methylbenzene were added dropwise 22.5 parts of 2-chloroacetyl chloride while cooling (ice-bath) at 10°-20° C. Upon completion, stirring was continued for 1.50 hours at room temperature. 200 Parts of water were added. The organic phase was separated, washed with water, dried, filtered and evaporated. The oily residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 28.2 parts (66%) of 2-chloro-N-(2-methoxy-5-methylphenyl)acetamide; mp. 83.9° C. (intermediate 66).
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:16]([NH:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=1)=[O:17]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)Nc1ccc(Cl)cc1
Reaction time: 0.21 h

Procedure:
After dissolving 14.2 g. (0.1445 mole) of 2-imino-1 -methylpyrrolidine in anhydrous benzene, 22.2 g. (0.1445 mole) of p-chlorophenylisocyanate dissolved in anhydrous benzene is added slowly with stirring and ice-bath cooling to the above solution. Solid material forms after 10 to 15 mins. The reaction mixture is stirred at room temperature overnight. The solid is collected (m.p. = 138°-141° C.) and titurated with hot CH2Cl2. The material which does not dissolve is filtered off. Removal of the methylene chloride and recrystallizations from methanol of the subsequent solid product, 1-(1-methyl-2-pyrrolidylidene)-3-p-chlorophenylurea, yields the pure material, m.p. - 142°-144° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:18]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:19]=2[S:20][CH:21]=1>>[Cl:26][C:25]1[C:18]2[C:17]([CH2:16][N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:14]=[C:6]3[C:4]([OH:3])=[O:5])=[CH:21][S:20][C:19]=2[CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Clc1cccc2scc(CBr)c12
Product: O=C(O)c1cc2ccccc2n1Cc1csc2cccc(Cl)c12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-4-chloro-benzo[b]thiophene (Li. 17) and the product obtained was hydrolyzed to give the title compound as a white solid. MS: 340.0 ([M−H]−).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]2[C:15]=1[C:16](=[O:25])[C:17](=[O:24])[NH:18]2.O>C(OCC)C.C1COCC1>[OH:25][C:16]1([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)[C:15]2[C:19](=[CH:20][C:21]([Cl:23])=[CH:22][C:14]=2[Cl:13])[NH:18][C:17]1=[O:24]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=C1Nc2cc(Cl)cc(Cl)c2C1=O
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C1Nc2cc(Cl)cc(Cl)c2C1(O)c1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
1.8 g of Grignard magnesium are placed in 19 ml of anhydrous ethyl ether in a round-bottomed flask equipped with a mechanical stirrer, and under a stream of nitrogen. A mixture of 8.9 ml of 4-bromotrifluoromethylbenzene in 46 ml of anhydrous ethyl ether is then added. The mixture is stirred for one hour, followed by addition of a solution of 5.7 g of 4,6-dichloro-1H-indole-2,3-dione in 100 ml of anhydrous THF. The mixture is stirred at room temperature for 4 hours 30 minutes. Water is added and the resulting mixture is extracted with ethyl acetate. The organic phase is separated out and dried over Na2SO4, filtered and evaporated under vacuum. The residue is taken up in ethyl acetate and washed with 1N sodium hydroxide solution. The organic phase is dried over Na2SO4, filtered and evaporated under vacuum. The solid is taken up in ethyl ether and filtered off. 4.7 g of expected product are obtained.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[CH2:3][CH2:4][Si:5]([CH3:11])([CH3:10])[O:6][SiH:7]([CH3:9])[CH3:8].[CH2:14]([O:17][CH2:18][CH:19]1[CH2:21][O:20]1)[CH:15]=[CH2:16]>>[CH3:11][Si:5]([CH3:10])([CH2:4][CH2:3][Si:2]([CH3:1])([CH3:13])[CH3:12])[O:6][Si:7]([CH3:9])([CH3:8])[CH2:16][CH2:15][CH2:14][O:17][CH2:18][CH:19]1[CH2:21][O:20]1
Reactant: C[SiH](C)O[Si](C)(C)CC[Si](C)(C)C
Reactant: C=CCOCC1CO1
Product: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC1CO1
Temperature: 90 °C

Procedure:
1-(2-trimethylsilylethyl)-1,1,3,3-tetramethyldisiloxane (18.8 g) and chloroplatininc acid catalyst (ethanolic solution, 30 ppm Pt) were charged to a 100 ml round-bottomed (RB) flask equipped with a magnetic stirrer, reflux condenser, and N2 inlet. The mixture was stirred and heated to 90° C. 2-Allyloxymethyl-oxirane (10 g) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 90° C. for an additional 4 hours. Reaction progress was followed by NMR spectroscopy. Upon reaction completion, excess 2-allyloxymethyl-oxirane was removed by vacuum distillation.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:15])=[C:4]([CH2:12][CH2:13][CH3:14])[C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH2:16]([O:18][C:19](=[O:41])[CH2:20][O:21][C:22]1[CH2:23][C:24]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)(CCC)[C:25]([C:28](=[O:30])[CH3:29])=[CH:26][CH:27]=1)[CH3:17].C(=O)([O-])[O-].[K+].[K+].[CH3:48][C:49]([CH3:51])=O>CN(C)C=O>[CH2:16]([O:18][C:19](=[O:41])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:15][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8](=[O:10])[CH3:9])=[C:5]([OH:11])[C:4]=2[CH2:12][CH2:13][CH3:14])[C:23]=1[CH2:48][CH2:49][CH3:51])[CH3:17]
Reactant: CC(C)=O
Reactant: CCCC1(OCCCCCBr)CC(OCC(=O)OCC)=CC=C1C(C)=O
Reactant: CCCc1c(O)c(Cl)cc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(O)c(C(C)=O)cc(Cl)c1OCCCCCOc1c(C(C)=O)ccc(OCC(=O)OCC)c1CCC
Yield: 34 %

Procedure:
A mixture of 1.10 g (0.0049 mole) of 1-(5-chloro-2,4-dihydroxy-3-propylphenyl)ethanone, 2.08 g (0.0049 mole) of [4-acetyl-3-[(5-bromopentyl)oxy]-3-propylphenoxy]acetic acid ethyl ester and 1.33 g (0.0097 mole) of potassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 22 hours. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC using 25% ethyl acetate-hexane to give 0.96 g (34% yield) of [4-acetyl-3-[5-(4-acetyl-6-chloro-3-hydroxy-2-propylphenoxy)pentyloxy]-2-propylphenoxy]acetic acid ethyl ester as an oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[N:10]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:11](=[O:30])[CH2:12][C:13]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:16]=2[S:15](=[O:29])(=[O:28])[N:14]=1)=O.[O-]CC.[Na+]>C(O)C>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][N:10]2[C@@H:6]3[C@@H:5]([CH2:9][CH2:8][CH2:7]3)[C:3]([OH:2])=[C:12]([C:13]3[NH:18][C:17]4[CH:19]=[CH:20][C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:22][C:16]=4[S:15](=[O:28])(=[O:29])[N:14]=3)[C:11]2=[O:30])=[CH:33][CH:34]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3CCC[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 60 °C
Reaction time: 4 h
Yield: 71.4 %

Procedure:
(1R,2S)-2-{(4-Fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid methyl ester (117 mg, 0.21 mmol) was dissolved in ethanol (10 mL). A 21% w/w solution of sodium ethoxide in ethanol (0.17 mL, 0.46 mmol) was added and the mixture was stirred at 60° C. for 4 h. The reaction was allowed to cool to 25° C. and quenched with 1.0 M aqueous hydrochloric acid solution (10 mL). The mixture was extracted with ethyl acetate (3×20 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 0-5% methanol in dichloromethane) to afford the desired product, (4aR,7aS)—N-{3-[1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-2,4a,5,6,7,7a-hexahydro-1H-[1]pyrindin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (80 mg, 0.15 mmol, 71%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.46-1.61 (4H, m), 1.95-2.12 (2H, m), 3.07 (3H, s), 3.85 (1H, bs), 4.48 (1H, bs), 4.91 (1H, d, J=14.8 Hz), 7.16 (2H, t, J=8.4 Hz), 7.40 (2H, bs), 7.50-7.61 (3H, m), 10.18 (1H, s). LC-MS (ESI) calcd for C23H23FN4O6S2 534.58. found 535.1 [M+H+]. e.e.=98% [HPLC-analysis: Chiralpak AS-RH 4.6×250 mm, 5 micron at 25° C., 0.7 mL/min, 310 nm, t1=14.89 min, t2=22.20 min (major)]. αD=−40.76 (c=0.92, dichloromethane/methanol 1:1). Anal. calcd for C23H23FN4O6S2.0.3 H2O.0.3 EtOAc.0.2 Et2O: C, 51.66; H, 4.86; N, 9.64. found C, 51.64; H, 4.90; N, 9.56.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=O)[CH2:12][C:11](=[O:16])[CH2:10]1.C([O-])(=O)C.[NH4+:21]>C(O)C>[NH2:21][C:13]1[CH2:14][CH:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:10][C:11](=[O:16])[CH:12]=1
Reactant: Cc1ccc(Cl)c(C2CC(=O)CC(=O)C2)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: Cc1ccc(Cl)c(C2CC(=O)C=C(N)C2)c1
Yield: 97.1 %

Procedure:
A solution of 5-(2-chloro-5-methylphenyl)cyclohexane-1,3-dione (3.0 g) and ammonium acetate (2.9 g) in ethanol (50 ml) was refluxed for 13 hours. Under reduced pressure, the solvent was evaporated, and precipitated crystals were washed with water and toluene, and dried to give 1-amino-5-(2-chloro-5-methylphenyl)cyclohexen-3-one (2.9 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:3]([NH:5][C@@H:6]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[O:17])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4].C(N(C(C)C)CC)(C)C.[Br:43][CH2:44][C:45](Br)=[O:46].CO>O1CCCC1>[C:30]([O:29][C:27]([CH2:26][CH2:25][C@H:2]([NH:1][C:45](=[O:46])[CH2:44][Br:43])[C:3]([NH:5][C@@H:6]([CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])=[O:17])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:4])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)N[C@@H](CCC(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(Br)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)CBr)C(=O)N[C@@H](CCC(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
The product of step 7H (397 mg, 0.813 mmol) was dissolved in dry tetrahydrofuran (5 mL) with diisopropylethylamine (180 μL, 1.05 mmol) and cooled to −10° C. under nitrogen. Bromoacetyl bromide (85 μL, 0.98 mmol), dissolved in 10 mL tetrahydrofuran, was added dropwise to the cold solution, keeping T.−5° C. The reaction was stirred in the cold for 1.5 hr, and 25 μL methanol added. The solids were filtered and rinsed and the combined filtrate concentrated to a brown oil, which was purified by flash chromatography (dichloromethane/ethyl acetate) to afford the product (388 mg, 78%) as a light tan oil. LRMS (ES): 609.3/611.3 [M+H]+, 631.3/633.3 [M+Na]+, 185.3, 144.2. 1HNMR (600.1343 MHz, CDCl3): 7.32 (m, 1H), 7.09 (m, 1H), 4.50 (m, 2H), 4.21 (m, 2H), 3.87 (m, 2H), 2.31 (m, 2H), 2.13 (m, 2H), 1.99 (m, 2H), 1.97 (m, 2H), 1.45 (s, 9H), 1.43 (s, 9H), 1.01 (m, 2H), 0.04 (s, 9H).
Reaction SMILES: [CH:1]1([C@H:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29][CH:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:31])=[O:27])=[CH:20][CH:19]=2)[C:8]([O:10]C2CCCC2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO>[CH:1]1([C@H:7]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21](/[CH:24]=[CH:25]/[C:26]([NH:28][O:29][CH:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH3:31])=[O:27])=[CH:20][CH:19]=2)[C:8]([OH:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)COC(C)ONC(=O)/C=C/c1ccc(CN[C@H](C(=O)OC2CCCC2)C2CCCCC2)cc1
Solvent: CO
Product: CC(C)COC(C)ONC(=O)/C=C/c1ccc(CN[C@H](C(=O)O)C2CCCCC2)cc1
Temperature: 45 °C
Reaction time: 96 h
Yield: 53.9 %

Procedure:
1N NaOHaq (3 mL) was charged to a solution of cyclopentyl (2S)-cyclohexyl[(4-{(1E)-3-[(1-isobutoxyethoxy)amino]-3-oxoprop-1-en-1-yl}benzyl)amino]acetate (prepared as described in Example 14-0.3 g, 0.6 mmol) in MeOH (5 mL) and stirred at 45° C. for 4 days. The MeOH was removed in vacuo and the residue washed with EtOAc (10 mL). The aqueous phase was acidified to pH˜2 with saturated citric acid solution, extracted with EtOAc (2×10 mL) and the organic phase dried (MgSO4) and concentrated in vacuo to afford the product as a yellow oil (0.14 g, 53%). m/z=433 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.Cl[CH2:13][C:14]1[S:18][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH3:29].C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:13][C:14]3[S:18][C:17]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=4)=[N:16][C:15]=3[CH3:29])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: Cc1c[nH]c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc2c(C)c[nH]c2c1

Procedure:
In analogy to the procedure described in example 27 e], 3-methyl-1H-indol-6-ol was reacted with 5-chloromethyl-4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole [PCT Int. Appl. (2002), WO 0292590 A1] in the presence of cesium carbonate to give 3-methyl-6-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-1H-indole as light brown crystals.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:10])([C:7](=[O:9])[CH3:8])[CH2:5][OH:6].S(OC)(O[CH3:15])(=O)=O>O>[CH3:3][C:4]([CH3:10])([C:7](=[O:9])[CH3:8])[CH2:5][O:6][CH3:15]
Reactant: COS(=O)(=O)OC
Reactant: CC(=O)C(C)(C)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCC(C)(C)C(C)=O
Temperature: 40 °C
Reaction time: 15 h

Procedure:
80 g (2 moles) of sodium hydroxide, dissolved in 100 ml of water, were added dropwise to 174 g (1.5 moles) of 2,2-dimethyl-1-hydroxy-butan-3-one (for the preparation, see Example 2a) and 150 ml (2 moles) of dimethyl sulphate at 40° C. (exothermic, slight cooling). After the addition, the mixture was subsequently stirred at 40° C. for 15 hours and the 2,2-dimethyl-1-methoxy-butan-3-one formed was distilled by means of steam. The aqueous phase was saturated with sodium chloride and the oily constituent was separated off and rectified under reduced pressure. 123.8 g (63% of theory) of 2,2-dimethyl-1-methoxy-butan-3-one of boiling point 48°-62° C./5-8 mm Hg were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:11](=[O:14])[CH:12]=[CH2:13])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[N:22]1[CH:27]=[CH:26][N:25]=[CH:24][C:23]=1[CH:28]=[O:29].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[C:11](=[O:14])[CH2:12][CH2:13][C:28]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][N:22]=2)=[O:29])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(SC)c(F)c1
Reactant: O=Cc1cnccn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2cnccn2)cc1F
Temperature: 25 °C
Yield: 74.9 %

Procedure:
To a solution of 4-[3-fluoro-4-(methylsulfanyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (433 mg) in ethanol (7 mL) were added pyrazine-2-carbaldehyde (182 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (41.5 mg) and triethylamine (84.1 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (438 mg, yield 75%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: [CH2:1]([CH2:8][CH:9]([C:15]([O:17]CC)=[O:16])[C:10]([O:12]CC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[OH-].[K+]>O>[CH2:1]([CH2:8][CH:9]([C:15]([OH:17])=[O:16])[C:10]([OH:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CCc1ccccc1)C(=O)O
Yield: 83.3 %

Procedure:
The diethyl benzylmethylmalonate (75 g) was combined with 300 ml of ethanol and a solution of 100 g potassium hydroxide in 300 ml of water and heated to a gentle reflux for 5 hours. After cooling, the mixture was extracted with diethyl ether (2×300 ml). The aqueous phase was then acidified with 120 ml concentrated hydrochloric acid, and extracted with diethyl ether (3×300 ml). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated to yield 49.2 g of benzylmethylmalonic acid as a yellow solid (83% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[Na+].Br[CH2:12][CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15]>COCCO>[CH2:14]([CH:13]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:15]
Reactant: CCCCC(CC)CBr
Reactant: Oc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Product: CCCCC(CC)COc1ccc(Br)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
A 1 1 sulfonating flask equipped with stirrer, condenser, dropping funnel and internal thermometer is charged with 86.5 g (0.5 mol) of 4-bromophenol in 500 ml of methylcellosolve. After the mixture is heated to 60° C., 70.0 g of 30% NaOH (0.53 mol) are slowly run in. Stirring is continued for 15 minutes before 116.8 g (0.575 mol) of 3-bromomethylheptane are added dropwise over a period of 45 minutes. The reaction is continued overnight at 100° C. The thin-layer chromatogram shows almost quantitative conversion. Solvent and excess bromide are removed in vacuo, and the residue (oil) is taken up in 600 ml of toluene. The resulting solution is extracted three times with water. The organic phase is dried over sodium sulfate and evaporated to dryness to give 119.3 g (84% of theory) of 4-(2-ethylhexyloxy)bromobenzene as a light yellow oil.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][C:17]=3[N:26]=[C:14]2[CH2:13][O:12][CH2:11]1)C1C=CC=CC=1.CO.C(Cl)(=O)C>[Pd].C(Cl)(Cl)Cl>[OH:8][CH2:9][C@@H:10]1[N:15]2[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=[CH:18][C:17]=3[N:26]=[C:14]2[CH2:13][O:12][CH2:11]1
Reactant: c1ccc(COC[C@H]2COCc3nc4cnc5ccccc5c4n32)cc1
Agent: [Pd]
Solvent: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OC[C@H]1COCc2nc3cnc4ccccc4c3n21
Reaction time: 264 h
Yield: 35.6 %

Procedure:
(11S)-11-[(benzyloxy)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline (7.5 g, 22 mmol) was added to a mixture of methanol (270 mL) and acetyl chloride (3.0 mL, 43 mmol) in a pressure bottle. Palladium on carbon (10%, 1.5 g) was then added and the reaction mixture was shaken under H2 at 48 PSI (3.3×105 Pa). After 11 days, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol. The combined filtrates were treated with 2 mL of 50% aqueous NaOH solution and the mixture was concentrated under reduced pressure to afford an orange oil. Chromatography (SiO2, 0-30% CMA/CHCl3) gave an oil that was concentrated from acetonitrile under reduced pressure to give 2.0 g of (11S)-11-hydroxymethyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline as a tan solid.