Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)[N:3]=1.C(O[C:19](=[O:37])[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH:28]([SH:36])[CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH2:23][CH2:22]1)(C)(C)C.[O:38]=[C:39]1[NH:44][C:43]2[CH:45]=[C:46](C(O)=O)[CH:47]=[CH:48][C:42]=2[S:41][CH2:40]1>>[CH3:13][O:12][C:6]1[CH:5]=[C:4]2[C:9]([N:10]=[CH:11][C:2]([S:36][CH:28]([CH2:29][N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)[CH2:27][N:24]3[CH2:23][CH2:22][CH:21]([NH:20][C:19]([C:46]4[CH:47]=[CH:48][C:42]5[S:41][CH2:40][C:39](=[O:38])[NH:44][C:43]=5[CH:45]=4)=[O:37])[CH2:26][CH2:25]3)=[N:3]2)=[CH:8][CH:7]=1
Reactant: O=C1CSc2ccc(C(=O)O)cc2N1
Reactant: COc1ccc2ncc(Cl)nc2c1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC(S)CN2CCOCC2)CC1
Product: COc1ccc2ncc(SC(CN3CCOCC3)CN3CCC(NC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc2c1

Procedure:
The title compound is prepared as a light brown lyophilizated powder following Scheme 3 and in analogy to Example 1 using 2-chloro-7-methoxy-quinoxaline, [1-(2-mercapto-3-morpholin-4-yl-propyl)-piperidin-4-yl]-carbamic acid tert-butyl ester and 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid as starting materials.
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](OS(C1C(C)=CC=CC=1)(=O)=O)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].C(N(CC)CC)(C)C.[C:41]1([SH:47])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([S:47][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH3:3]
Reactant: Cc1ccccc1S(=O)(=O)OC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Reactant: Sc1ccccc1
Agent: CCN(CC)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(Sc3ccccc3)CC12
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cold, stirring solution of benzyl 6-(1-hydroxyethyl)-3-toluenesulfonyloxy-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (46 mg) in anhydrous DMF (1 ml) is added N-isopropyl-N,N-diethylamine (13 mg) and thiophenol (11 mg). The resulting solution is stirred in the cold for 15 mins. and at room temperature for 45 mins, then diluted with ethyl acetate (10 ml). The mixture is thoroughly washed with water (5×2 ml) and brine, dried with MgSO4, filtered, and evaporated to dryness. The residue is purified on a silica gel GF plate to yield benzyl 6-(1-hydroxyethyl)-3-phenylthio-1-azabicyclo[3.2.0]hept-b 2-en-7-one-2-carboxylate.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[C:13]([S:17](Cl)(=[O:19])=[O:18])[S:14][C:15]=2[Br:16])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(Cl)Cl>[Br:16][C:15]1[S:14][C:13]([S:17]([N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)(=[O:19])=[O:18])=[CH:12][C:11]=1[C:7]1[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)Cl)sc2Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCN(C)CC3)sc2Br)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
4-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]-5-bromothiophene-2-sulfonyl chloride, prepared as in Step III of Example 23 (4200 mg; 10.1 mmol; 1 eq), is dissolved in anhydrous DCM (200 ml). The reaction is put under nitrogen. Triethylamine (7.0 ml; 50.5 mmol; 5 eq) and 1-methylpiperazine (5.61 ml; 50.5 mmol; 5 eq) are added successively and the reaction mixture is stirred for 3 hours at room temperature. It is washed with water, NH4Cl sat, brine and dried over MgSO4, affording the title compound (4200 mg; 87%).
Reaction SMILES: C=O.[C:3]([BH3-])#N.[Na+].[NH2:7][CH:8]([CH:14]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:15]1[C:16]([Cl:21])=[N:17][CH:18]=[CH:19][CH:20]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])O.[Na+]>O.C(Cl)Cl.C(O)(=O)C>[Si:23]([O:22][CH:14]([C:15]1[C:16]([Cl:21])=[N:17][CH:18]=[CH:19][CH:20]=1)[CH:8]([NH:7][CH3:3])[C:9]([O:11][CH2:12][CH3:13])=[O:10])([C:26]([CH3:28])([CH3:27])[CH3:29])([CH3:25])[CH3:24]
Reactant: [BH3-]C#N
Reactant: CCOC(=O)C(N)C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(NC)C(O[Si](C)(C)C(C)(C)C)c1cccnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.9 %

Procedure:
182 mg of 35% formalin, 0.1 ml of acetic acid and 121 mg of sodium cyanoborohydride were added to a solution of 0.7 g of ethyl 2-amino-3-t-butyldimethylsilyloxy-3-(2-chloropyridin-3-yl)propionate (prepared as described in Preparation 78) in 4 ml of a 3:2 by volume mixture of methylene chloride and water at 0° C., and the resulting mixture was stirred at 0° C. for 15 minutes. At the end of this time, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, after Which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of hexane and ethyl acetate in ratios ranging from 8:1 to 1:1 by volume as the eluent, to give 200 mg of the title compound having Rf=0.38 (on silica gel thin layer chromatography using a 3:1 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]CC)=[O:15])[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c[nH]c2ccc(C(=O)OCC)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1c[nH]c2ccc(C(=O)O)cc12
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a mixture of Ethyl 3-butyl-1H-indole-5-carboxylate, EXAMPLE SP-225, step2, (0.4 g) in methanol (15 mL) was added 1N NaOH (5 mL). The mixture was stirred at 50° C. for 18 h, cooled to room temperature and poured into 1N HCl (50 mL). The mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure to give 0.145 g of the title compound: MS (ESI+) for C13H15N1O2 m/z 216.12 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][N:13]1[CH2:18][CH2:17][CH:16](O)[CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1.C(OCC)(=O)C.O>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][CH:16]1[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]1)[C:6]#[N:7]
Reactant: CN1CCC(O)CC1
Reactant: COc1cc(C#N)ccc1O
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C#N)ccc1OC1CCN(C)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
2.04 g 4-Hydroxy-3-methoxy-benzonitrile, 1.57 g 1-methyl-piperidine-4-ol and 7.17 g triphenylphosphine were placed in 125 mL tetrahydrofuran at 0° C. before 6.30 g di-tert-butylazodicarboxylate (DBAD) as a solution in 125 mL tetrahydrofuran was added over 15 min. The reaction was stirred for 5 min at 0° C. and then warmed to ambient temperature where it was maintained overnight. After this time additional 0.31 g 1-methyl-piperidine-4-ol, 1.79 g triphenylphosphine and 1.58 g di-tert-butylazodicarboxylate (DBAD) were added and the reaction was stirred for a further 3 h at ambient temperature. The mixture was then diluted with ethyl acetate and water and the organic phase was separated, washed with 1N sodium hydroxide (×2), water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The material that remained was dissolved in tert-butyl dimethyl ether and washed with 3N hydrochloric acid. The aqueous phase was then made basic with 5N sodium hydroxide and extracted with ethyl acetate (×3). The combined organic fractions were washed water, saturated sodium chloride solution, dried over sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. Purification on silica gel chromatography (SiO2: dichloromethane/methanol 5% then dichloromethane/7N ammonia in methanol 5%) provided the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH:5]1[C:13]2[C:8](=[C:9]([C:14]3[N:18]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([O:27]C(C)C)=[C:23]([CH:26]=4)[C:24]#[N:25])[O:16][N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:7][CH2:6]1.B(Cl)(Cl)Cl>ClCCCl>[OH:27][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[O:16][N:15]=[C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:8]=3[CH2:7][CH2:6][CH:5]4[NH:4][CH2:3][CH2:2][OH:1])[N:18]=2)=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC4NCCO)no2)cc1C#N
Agent: ClB(Cl)Cl
Solvent: ClCCCl
Product: N#Cc1cc(-c2nc(-c3cccc4c3CCC4NCCO)no2)ccc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 671.2 %

Procedure:
To 5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (15.0 mg, 0.37 mmol) in DCE (3 mL) was added BCl3 (1.85 mL of 1M DCM solution). The reaction mixture was stirred at room temperature for 18 hrs. The solvent was evaporated, and the residue purified by chromatography (DCM/MeOH) to give 900.0 mg (67%) of 2-hydroxy-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 102 as white solid. LCMS-ESI (m/z) calculated for C20H18N4O3: 362.4. found 363.1 [M+H]+, tR=2.13 min. Enantiomerically pure materials can be obtained in an analogous fashion from (R)- or (S)-5-(3-(1-(2-hydroxyethylamino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][SH:14].C1C[O:21][CH2:20][CH2:19]1>O>[C:20]([N:11]1[CH:12]([C:15]([OH:17])=[O:16])[CH2:13][S:14][CH:9]1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)(=[O:21])[CH3:19]
Reactant: C1CCOC1
Reactant: N[C@@H](CS)C(=O)O
Reactant: O=CCCc1ccccc1
Solvent: O
Product: CC(=O)N1C(CCc2ccccc2)SCC1C(=O)O
Reaction time: 1 h
Yield: 90 %

Procedure:
A solution of 10 g of 3-phenylpropionaldehyde in THF was added to a solution of 10 g of cysteine in water. The resulting solution was stirred for 1 hour and then concentrated in vacuo. The precipitate was filtered off and washed with water and diethyl ether. The solid substance was dissolved in water which contained 12.5 g of potassium carbonate. 7.8 g of acetic anhydride were added at 0° C. and the resulting was stirred for 1 hour, after which the mixture was acidified to pH=2 with dilute sulphuric acid. This mixture was stirred for 30 minutes. The precipitate was filtered off, washed with water and dried. Yield 90%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](/[C:14](/[CH3:18])=[CH:15]/[CH2:16][OH:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]>>[CH2:19]([O:21][C@@H:22]([CH2:28][C:29]1[CH:30]=[CH:31][C:32]([O:17][CH2:16]/[CH:15]=[C:14](/[C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][CH:10]=2)\[CH3:18])=[CH:33][CH:34]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH3:20]
Reactant: C/C(=C\CO)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(F)cc3)cc2)cc1)OCC
Yield: 89.1 %

Procedure:
The title compound (849 mg, 89%) was prepared as a colourless gum from (E)-3-(4′-fluorobiphenyl-4-yl)-but-2-en-1-ol (500 mg, 2.06 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (516 mg, 2.17 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)=[NH:4]>Cl>[OH:1][NH:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)=[NH:4]
Reactant: COC(=O)Cc1ccc(C(=N)NO)cc1
Agent: Cl
Product: N=C(NO)c1ccc(CC(=O)O)cc1

Procedure:
A solution of methyl [4-(N-hydroxycarbamimidoyl)-phenyl]-acetate (3.67 g, 17.6 mmol) in 25% aq. HCl (15 mL) is stirred at 65° C. for 4 h. The solvent is removed in vacuo and the residue is dried under high vacuum to give [4-(N-hydroxycarbamimidoyl)-phenyl]-acetic acid (3.80 g, presumably as hydrochloride) as a yellow solid; LC-MS: tR=0.34 min, [M+1]+=195.05.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[CH:5]=1)(=[O:3])[CH3:2].[Cl:14][C:15]1[CH:16]=[C:17]([C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[C:17]([C:22]([OH:27])([C:23]([F:24])([F:25])[F:26])[CH2:2][C:1]([C:4]2[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[CH:5]=2)=[O:3])[CH:18]=[C:19]([Cl:21])[CH:20]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CC(=O)c1ccc(C(=O)O)c(C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)O
Temperature: 60 °C
Reaction time: 13 h

Procedure:
4.46 g of 4-acetyl-2-methylbenzoic acid, 6.08 g of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 18.2 g of toluene and 3.79 g of triethylamine were fed and the mixture was stirred for 13 hours at 60° C. 12.2 g of toluene was added to the slurry-state reaction solution, and the mixture was cooled to room temperature. The reaction solution was filtered under reduced pressure, and the solid was washed with a small amount of toluene. 11.3 g of triethylamine salt of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutanoyl)-2-methylbenzoic acid as a white solid was obtained by drying under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.Cl.[NH2:17][C@@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20].CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:5]=[C:4]([NH:17][C@@H:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[N:3]=1
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)c1cc(Cl)nc(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)[C@H](C)Nc1cc(C(=O)OC(C)(C)C)nc(Cl)n1
Temperature: 50 °C
Yield: 88.7 %

Procedure:
To a mixture of tert-butyl 2,6-dichloropyrimidine-4-carboxylate (0.310 g, 1.24 mmol) in acetonitrile (5 mL) was added (S)-methyl 2-aminopropanoate hydrochloride (0.177 g, 1.27 mmol) and iPr2NEt (0.48 mL, 2.8 mmol). The mixture was heated at 50° C. overnight then concentrated in vacuo. The residue was chromatographed over silica gel with 10-50% EtOAc in hexanes. The product fractions were evaporated in vacuo to yield (S)-tert-butyl 2-chloro-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate as a colorless glass (0.347 g, 1.10 mmol, 89% yield). 1H NMR (400 MHz, DMSO-d6): 8.70 (1H, d, J=6.8 Hz), 7.12 (1H, s), 4.56-4.47 (1H, m), 3.65 (3H, s), 1.53 (9H, s), 1.39 (3H, d, J=7.2 Hz). LC/MS: m/z=316.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][CH2:20][C:21]1[O:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=1>>[CH:26]([OH:28])=[O:27].[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:24]3[N:25]=[C:21]([CH2:20][F:19])[O:22][CH:23]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1coc(CF)n1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3coc(CF)n3)ccc2F)N=C(N)OCC1(F)F
Product: O=CO

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 2-fluoromethyl-oxazole-4-carboxylic acid following procedure I yielded the title compound after purification by preparative HPLC as a white solid. MS (ISP): m/z=387.1 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>O>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[CH:11]3)=[CH:20][CH:19]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Clc1ccc(-c2ccc3[nH]ccc3c2)cc1
Yield: 40.7 %

Procedure:
A stirred slurry of 6.35 g (60 mmol) K2CO3, 2.94 g (15 mmol) 5-bromoindole, 2.50 g (16 mmol) 4-chlorophenylboronic acid, and 0.48 g (0.42 mmol) tetrakistriphenylphosphine palladium was heated to reflux for 2½ hours. The reaction mixture was allowed to cool and was then poured into 200 ml water and extracted with EtOAc. The organic layer was separated, dried over MgSO4, and concentrated. The residue was chromatographed on silica to afford 1.39 g 5-(4-chlorophenyl)indole as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])=[O:5].[CH:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:21]>[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.CN(C)C=O>[C:26]([C:25]1[CH:30]=[CH:31][C:22]([C:20](=[O:21])[CH2:2][CH2:3][C:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=3[CH:7]=2)=[O:5])=[CH:23][CH:24]=1)([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCCl)ccc21
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)CCC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 1 h
Yield: 45.5 %

Procedure:
5.6 g (0.02 mole) of 6-(3-chloropropionyl)-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnapthalene and 3.3 were stirred for 1 hour at room temperature. Thereafter, a solution of 3.6 g (0.025 mole) of methyl 4-formylbenzoate and 1 g of 3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride in 10 ml of dimethylformamide was added dropwise. Stirring was continued for 1 hour, after which the mixture was poured onto ice/water and extracted twice with ethyl acetate, and the combined organic extracts were washed several times with water, dried over magnesium sulfate and evaporated down. 3.7 g of 1-(4-carbomethoxyphenyl)-4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-butane-1,4-dione of melting point 139°-141° C. were obtained from the residue (6.4 g) after recrystallization from ethanol. 2-(4-Carbomethoxyphenyl)-5-(5,6,7,8-tetrahy-dro-5,5,8,8-tetramethyl-2-naphthalenyl)-thiophene:
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[C:3](=[O:21])[CH2:4][O:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:9]=[C:8]([C:18]([OH:20])=O)[CH:7]=1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[NH2:46][C@H:47]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[CH3:58])[CH2:48][C:49]([OH:51])=[O:50]>CN(C=O)C>[CH3:23][C:2]([CH3:22])([CH3:1])[C:3](=[O:21])[CH2:4][O:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[N:9]=[C:8]([C:18]([NH:46][C@H:47]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=2[CH3:58])[CH2:48][C:49]([OH:51])=[O:50])=[O:20])[CH:7]=1
Reactant: Cc1ccccc1[C@@H](N)CC(=O)O
Reactant: CC(C)(C)C(=O)COc1cc(C(=O)O)nn1-c1ccccc1F
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccccc1[C@H](CC(=O)O)NC(=O)c1cc(OCC(=O)C(C)(C)C)n(-c2ccccc2F)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 67 %

Procedure:
324 mg (0.675 mmol) of 5-(3,3-dimethyl-2-oxo-butoxy)-1-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid were dissolved in 5 ml of DMF and 0.675 mmol of TOTU and 1.35 mmol of EDIA were added. The mixture was stirred for 5 min at room temperature, then 0.675 mmol of (S)-3-amino-3-(2-methyl-phenyl)-propionic acid were added and the mixture was stirred overnight at room temperature. After evaporation of the solvent, the residue was subjected to preparative HPLC to give the title compound in a yield of 67%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:23])[C:13](=[CH:19]OCC)[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH3:10]>>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][CH:19]=[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:23])[C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)C(=CNc1cccc(Br)c1)C(=O)OCC
Temperature: 110 °C
Yield: 80.5 %

Procedure:
A mixture of 3-bromoaniline (10.0 g, 58.1 mmol) and diethyl(ethoxymethylidene)propanedioate (13.9 mL, 63.9 mmol) were heated to 110° C. for 1 h. After completion of the reaction, the reaction mixture was cooled to room temperature. The obtained solid was filtered and dried to afford 16.0 g 78% of diethyl {[(3-bromophenyl)amino]methylidene}propanedioate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]([CH2:14][CH2:15][NH:16][C:17](=O)[CH3:18])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].P(Cl)(Cl)(Cl)=O.[OH-].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>O.C(O)C>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]3[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:11]3=[CH:12][CH:13]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)NCCn1cccc1-c1ccc(Cl)c(Cl)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CC1=NCCn2c1ccc2-c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 65 %

Procedure:
N-[2-[2-(3,4-Dichlorophenyl)-pyrrol-1-yl]ethyl]-acetamide (4.6 g) was treated with 25 ml of phosphorus oxychloride under argon and boiled for 1 hour while stirring. The reaction mixture was hydrolyzed at 0° C. with 70 ml of 2N sodium hydroxide solution and 120 ml of 28% sodium hydroxide solution, diluted with 1400 ml of water and extracted with methylene chloride (1×500 ml, 2×250 ml). The organic extracts were combined, dried with MgSO4 and freed from solvent. 2.0 g of a total of 3.8 g of crude product were dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 2.1 g (65%) of 6-(3,4-dichlorophenyl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (1:1); m.pt.: 193°-195° C. (dec.).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([O:9][C:10]2[CH:11]=[C:12]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[N:22]([CH3:26])[C:21](=[O:27])[CH2:20][CH2:19]4)[CH:13]=[N:14][CH:15]=2)[CH2:5][CH2:4]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH3:26][N:22]1[C:23]2[C:18](=[CH:17][C:16]([C:12]3[CH:11]=[C:10]([O:9][C@H:6]4[CH2:5][CH2:4][C@H:3]([NH:2][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:8][CH2:7]4)[CH:15]=[N:14][CH:13]=3)=[CH:25][CH:24]=2)[CH2:19][CH2:20][C:21]1=[O:27]
Reactant: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CC[C@H](N)CC4)c3)ccc21
Reactant: CS(=O)(=O)Cl
Agent: Cl
Product: CN1C(=O)CCc2cc(-c3cncc(O[C@H]4CC[C@H](NS(C)(=O)=O)CC4)c3)ccc21

Procedure:
In analogy to the procedure described for the preparation of example 38, 6-[5-((trans)-4-amino-cyclohexyloxy)-pyridin-3-yl]-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 71) and methanesulfonyl chloride gave the title compound as a light yellow amorphous solid. MS: 430.4 (M+H+).