Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=O)[CH2:3][C:4]([O:6]C)=[O:5].[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:19])(=[O:18])=[O:17].[OH-].[Na+].Cl>C(OCC)C.CN(C)C(=O)C>[O:17]=[S:16]1(=[O:18])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:2]([CH2:3][C:4]([OH:6])=[O:5])=[N:19]1
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Product: O=C(O)CC1=NS(=O)(=O)c2ccccc2N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
Methyl 3-chloro-3-oxopropionate (3.36 mL, 31.3 mmol) was added to a solution of 2-aminobenzenesulfonamide (4.91 g, 28.5 mmol) in a 1:1 mixture of N,N-dimethylacetamide and diethylether (100 mL) at 0° C. The cloudy reaction mixture was stirred at 0° C. for 3 h, and then was partitioned between half-saturated aqueous sodium bicarbonate (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and were concentrated in vacuo. The residue was then dissolved in water (75 mL) containing sodium hydroxide (3.42 g, 85.5 mmol) at 25° C. The mixture was heated at 100° C. for 1 h, and then was cooled to 0° C. Concentrated (12.0 M) aqueous hydrochloric acid solution (10.0 mL, 120 mmol) was added dropwise via addition funnel over 10 min, resulting in the formation of a white precipitate. The reaction mixture was stirred at 0° C. for an additional 15 min, and then was filtered through a medium frit. The collected material was washed with water (30 mL) and was air-dried overnight to afford the desired product, (1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (6.37 g, 26.6 mmol, 93%), as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 3.58 (2H, s), 7.30 (1H, d, J=7.4 Hz), 7.44 (1H, t, J=8.2 Hz), 7.64-7.68 (1H, m), 7.79 (1H, dd, J1=1.5 Hz, J2=7.8 Hz), 12.19 (1H, s).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C:3]([NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[NH:8][CH:9]=[N:10]2)=[O:4].[H-].[Na+].[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23]Cl>CN(C)C=O>[CH3:18][Si:19]([CH3:26])([CH3:25])[CH2:20][CH2:21][O:22][CH2:23][N:8]1[C:7]2[C:11](=[N:12][CH:13]=[N:14][C:6]=2[NH:5][C:3](=[O:4])[CH:2]([CH3:15])[CH3:1])[N:10]=[CH:9]1
Reactant: CC(C)C(=O)Nc1ncnc2nc[nH]c12
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1ncnc2ncn(COCC[Si](C)(C)C)c12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 2-methyl-N-(7H-purin-6-yl)propanamide (1.5 g, 24.36 mmol) in dimethylformamide (20 mL), sodium hydride (0.88 g, 36.55 mmol) was added portion wise in 10 minutes at 0° C. The above suspension was stirred for 10 minutes at 0° C. followed by addition of 2-(trimethylsilyl)ethoxymethyl chloride (4.87 g, 29.24 mmol) slowly at 0° C. under nitrogen atmosphere. The reaction was stirred at room temperature for 16 h. After completion of the reaction, the mixture was quenched with saturated aqueous solution of ammonium chloride and product was extracted with dichloromethane (2×50 mL). The organics were then separated, dried (magnesium sulfate) and concentrated to dryness under vacuum and the crude was purified by flash chromatography eluting with 2% methanol in dichloromethane. Concentration of the desired fractions afford 2-methyl-N-[7-(2-trimethylsilylethoxymethyl)purin-6-yl]propanamide (2) as white solid. Yield: 2 g, 24%.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH2:13])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.Cl.[CH3:28][O:29][C:30](=[O:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:35]([C:34]3[CH:38]=[CH:39][C:31]([C:30]([O:29][CH3:28])=[O:40])=[CH:32][CH:33]=3)=[O:36])=[CH:10][CH:11]=2)[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(-c2ccccc2)c2cc(N)ccc21
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)c(-c2ccccc2)nn3C(C)=O)cc1
Reaction time: 18 h
Yield: 74.2 %

Procedure:
To a flask containing 1-acetyl-5-amino-3-phenyl-1H-indazole (300 mg, 1.2 mmol) was added dichloromethane (10 mL), 4-(dimethylamino)pyridine (75 mg, 0.6 mmol) and triethylamine (180 mg, 1.8 mmol). The mixture was allowed to stir for ten minutes. Terephthalic acid monomethyl ester hydrochloride (285 mg, 1.44 mmol) was then added and stirring continued for 18 hours. The mixture was quenched with 5% sodium bicarbonate and extracted with dichloromethane. The extracts were dried using sodium sulfate, filtered and condensed to give a solid. The solid was recrystallized in ethanol to give the title compound (368 mg, 75%/; yield). ES-MS (m/z) 414 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@:10]([CH2:33][CH:34]=[O:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC(=CC)C.Cl([O-])=[O:42].[Na+].O.O.P([O-])(O)(O)=O.[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[N:12]([C@@H:21]([CH2:29][CH3:30])[CH2:22][N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:11](=[O:31])[C@:10]([CH2:33][C:34]([OH:42])=[O:35])([CH3:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 16 mg (0.03 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde (Example 121, Step O) and 1.0 mL (9.4 mmol) of 2-methyl-2-butene in t-BuOH (3 mL) was added a solution of 28 mg (0.31 mmol) of sodium chlorite and 4.6 mg (0.03 mmol) of sodium dihydrogenphosphate dihydrate in water (1.6 mL). The resulting mixture was stirred at room temperature for 2 h, and then was quenched with 1 M HCl and extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 35% MeCN in water to 60% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA provided the title compound as a white solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]1([S:18][N:19]([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=3)=[CH:30][CH:29]=2)[C:20](=[O:24])[O:21][CH2:22][CH3:23])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl>[C:12]1([S:18]([N:19]([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]3[CH:40]=[C:39]([F:41])[CH:38]=[C:37]([F:42])[CH:36]=3)=[CH:30][CH:29]=2)[C:20](=[O:24])[O:21][CH2:22][CH3:23])=[O:9])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)Sc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)N(CCOc1ccc(Oc2cc(F)cc(F)c2)cc1)S(=O)c1ccccc1

Procedure:
A solution of 8.1 g of 55% 3-chloroperbenzoic acid in 50 ml of dichloromethane is added dropwise at 0° to +5° C. in the course of 20 minutes to a solution of 11.5 g of ethyl N-phenylthio-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate in 80 ml of dichloromethane, with stirring. After the reaction mixture has been stirred for 2 hours at +20° to +22° C., it is extracted twice with a 10% sodium carbonate solution and washed to neutrality with water. The dichloromethane phase is dried over sodium sulfate, and the solvent is distilled off in vacuo. The residue is purified by chromatography on silica gel (eluent: n-hexane/diethyl ether, 3:1), which process gives ethyl N-phenylsulfinyl-2-[4-(3,5-difluorophenoxy)phenoxy]ethylcarbamate, colourless viscous oil nD20 :1.5645.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[C:25]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[C:9]2[NH:14][C:13](=[O:15])[C:12](=[CH:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:11][C:10]2=[O:24])=[N:6][CH:7]=1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=c1[nH]c(=Cc2ccc(O)cn2)c(=O)[nH]c1=CCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Oc1ccc(C=c2[nH]c(=O)c(=CCc3ccccc3)[nH]c2=O)nc1)c1ccccc1
Temperature: 150 °C
Yield: 10.3 %

Procedure:
A reaction mixture containing compound B (0.05 g, 0.16 mmole; obtained from Example 14), benzoyl chloride (15 ml, 0.16 mmole) and 50 mL of chloroform was heated to 150° C. for 2 hr. Chloroform was removed in vacuo to produce a residue. The residue was chromatographied using silica gel column with a developing solvent (CH2Cl2) to give 0.007 g (10%) of Compound 15.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].[CH:16]([CH2:27]S([O-])(=O)=O)=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]C.O>CS(C)=O>[CH2:25]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:27]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCCCCCCCCC=CCS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.33 h
Yield: 46.1 %

Procedure:
This example illustrates a synthesis for compound no. 1592. Sodium hydride(95%, 1.26 g, 50 mmol) was added to a solution of theobromine (7.2 g, 40 mmol) in dimethylsulfoxide (300 ml). After 20 minutes of stirring, undecenylmesylate (7.95 g, 30 mmol) was added and the resulting mixture stirred for 12 hours at room temperature. The reaction was warmed to 70°-80° C. and stirred for 4 hours. The reaction mixture was then poured into a separatory funnel containing 1 L of water and extracted with dichloromethane (5×200 ml). The organic extracts were combined, washed with water (100 ml) and brine (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 20% hexane and dichloromethane eluent, producing 4.6 g of 1-(10-undecenyl)-3,7-dimethylxanthine (46.3% yield).
Reaction SMILES: [Cl-].C(N(C(C)C)CC)(C)C.[OH:11][C@@H:12]([C@H:14]1[C:35](=[O:36])[N:16]2[CH:17]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=3)=[O:23])[C:18](=O)[C@H:19]([CH3:20])[C@H:15]12)[CH3:13].FC(F)(F)S(O)(=O)=O.FC(F)(F)S(O)(=O)=O.[SH:53][C@@H:54]1[CH2:58][N:57]([CH3:59])[C@H:56]([C:60]([N:62]2[CH2:67][CH2:66][N:65]([CH3:68])[CH2:64][CH2:63]2)=[O:61])[CH2:55]1>C(#N)C>[CH3:68][N:65]1[CH2:66][CH2:67][N:62]([C:60]([C@@H:56]2[CH2:55][C@H:54]([S:53][C:18]3[C@H:19]([CH3:20])[C@@H:15]4[C@@H:14]([C@H:12]([OH:11])[CH3:13])[C:35](=[O:36])[N:16]4[C:17]=3[C:22]([O:24][CH2:25][C:26]3[CH:27]=[CH:28][C:29]([N+:32]([O-:34])=[O:33])=[CH:30][CH:31]=3)=[O:23])[CH2:58][N:57]2[CH3:59])=[O:61])[CH2:63][CH2:64]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: CN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 50 %

Procedure:
540 μl of diphenylphosophoryl chloride and 470 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 920 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 10 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 1400 μl of diisopropylethylamine and a solution of 1350 mg of (2S,4S)-4-mercapto-2-(4-methyl-1-piperazinylcarbonyl)-1-methylpyrrolidine bis(trifluoromethanesulfonate) (prepared as described in Preparation 51) in 5 ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 2 hours, after which it was allowed to stand overnight in a refrigerator. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was purified by chromatography through a Lobar column (Merck, LiChroprep RP-8, size B). The column was successively eluted with 65% by volume aqueous methanol and with 70% by volume aqueous methanol. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 730 mg of the title compound, as a powder.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].CN(C)C=O.[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@:21]1([O:45][CH2:44]1)[C@H:22]([N:24]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])=[CH:31][CH:30]=2)[C:25]1=[O:43])[CH3:23]>O>[F:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[C@@:21]([OH:45])([CH2:44][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)[C@H:22]([N:24]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][C:37]([F:41])([F:42])[CH:38]([F:39])[F:40])=[CH:33][CH:34]=2)[C:25]1=[O:43])[CH3:23]
Reactant: C[C@@H](N1CCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: c1nc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](N1CCN(c2ccc(OCC(F)(F)C(F)F)cc2)C1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 0.41 g of 1H-1,2,4-triazole, 0.19 g of 60% sodium hydride in oil and 12 ml of dimethylformamide was stirred at room temperature for 20 minutes, and added with 0.85 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-imidazolidinone obtained in Step 3 and the resultant mixture was heated at 60° C. for 4 hours. After cooling, 20 ml of water was added to the reaction mixture and the mixture was extracted with 80 ml of ethyl acetate. The extract was washed with 20 ml of a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (gradient eluent: hexane:ethyl acetate=1:2→1:5) to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(2,2,3,3-tetrafluoropropoxy) phenyl]-2-imidazolidinone (Compound B) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH3:26][CH:27]([NH2:38])[C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:38][CH:27]([C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30][CH:29]=1)[CH3:26])=[O:20]
Reactant: CC(N)c1cccc2ccccc12
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(NC(=O)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), R-(+)-1-(1-naphthyl)ethylamine (0.570 g, 3.33 mmol), triethylamine (0.310 g, 3.06 mmol) and benzene (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclopentyloxyphenyl)-N'-{1-(1-naphthyl)ethyl)-3,4,5,6-tetrahydrophthalamide as white crystals (0.950 g, 64.7% yield).
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.[C:11](Cl)(=[O:13])[CH3:12].C(Cl)C>>[C:11]([P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10])(=[O:13])[CH3:12]
Reactant: CCOP(OCC)OCC
Reactant: CC(=O)Cl
Agent: CCCl
Product: CCOP(=O)(OCC)C(C)=O
Yield: 97.7 %

Procedure:
166.2 grams (1 mole) triethyl phosphite was added dropwise with stirring to 78.4 grams (1 mole) of acetyl chloride over a period of 30 minutes at a temperature of 30° to 35° C maintained by cooling. Ethyl chloride was evolved. The temperature was increased to 60° C over the next 1 hour and 15 minutes, at which time the evolution of ethyl chloride was complete. The product was distilled under vacuum yielding 176 grams of diethyl acetylphosphonate (DEAP) in 98% yield, B.P. about 80° C at 5 mm and having a refractive index of 1.4240 at 200° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH2:14]([CH:16]1[CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]([CH3:26])[NH:17]1)[CH3:15]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:17]3[CH:16]([CH2:14][CH3:15])[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:18]3[CH3:26])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CCC1Cc2ccccc2C(C)N1
Product: CCC1Cc2ccccc2C(C)N1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-Ethyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.1 %

Procedure:
4-Bromobenzene-1-sulfonyl chloride (2.56 g, 10 mmol) in anhydrous CH2Cl2 (10 mL) was added to a mixture of 1-methylpiperazine (2.0 g, 20 mmol), pyridine (2.37 g, 30 mmol) and anhydrous CH2Cl2 (10 mL) at 0° C. The mixture was stirred at room temperature for 16 h, concentrated, recrystallised, and dried over P2O5 to yield the sub-title compound (2.27 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=4[CH3:23])[CH2:14][C:13](=[O:24])[NH:12][CH:11]3[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=3)[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36].[H-].[Li+].[C:43]([O:47][C:48](=[O:53])[NH:49][CH2:50][CH2:51]Br)([CH3:46])([CH3:45])[CH3:44]>CN(C)C=O>[C:43]([O:47][C:48]([NH:49][CH2:50][CH2:51][N:12]1[C:13](=[O:24])[CH2:14][CH:15]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[CH3:23])[C:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[NH:8][C:9]2=[O:32])[CH:11]1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)=[O:53])([CH3:46])([CH3:45])[CH3:44].[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36]
Reactant: Cc1ccc(F)cc1C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: COC(C)[Si](C)(C)C
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1CC(=O)N(CCNC(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 14.3 %

Procedure:
In a manner similar to the method described in example 152a, racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (0.45 g, 0.75 mmol) was reacted with LiH (0.15 g, 18.8 mmol) and (2-bromo-ethyl)-carbamic acid tert-butyl ester (1.0 g, 4.52 mmol) in N,N-dimethyl-formamide (3 mL), a catalytic amount of KI to give racemic (2′S,3S,4′R)-1′-[(tert-butoxycarbonylamino)ethyl]-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a yellow solid (80 mg).
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: Cc1cc(-c2nc(CCl)c(C)o2)ccc1F
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccc(F)c(C)c3)oc2C)c1)C(=O)O
Yield: 48 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-2-(4-fluoro-3-methyl-phenyl)-5-methyl-oxazole, the title compound was obtained in 48% yield as a colourless solid. MS: (M+H)+ 437.3.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1([OH:19])[C:16]2[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])C>CCO.[Cl-].[Na+].O>[OH:19][C:8]1([C:6]([OH:7])=[O:5])[C:16]2[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1
Reactant: CCOC(=O)C1(O)CCc2c(OC)cccc21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cccc2c1CCC2(O)C(=O)O
Reaction time: 0.5 h

Procedure:
NaOH (19M; 1.0 mL) was added to a solution of 1-hydroxy-4-methoxyindan-1-yl-carboxylic acid ethyl ester (0.90 g; 3.8 mmol; from step (ii) above) in EtOH (20 mL) and the solution was stirred for 30 minutes. Brine (40 mL) was added and the mixture was washed with EtOAc, cautiously made acidic to pH 2 (HCl; 2M), and the aqueous solution was extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated, yielding 0.70 g (88%) of the sub-title substance.
Reaction SMILES: [CH-:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Na+].Br[CH2:8][Si:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:10]>O1CCCC1>[C:13]([NH:12][Si:9]([CH3:11])([CH3:10])[CH2:8][CH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)N[Si](C)(C)CBr
Reactant: c1cc[cH-]c1
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N[Si](C)(C)CC1C=CC=C1
Reaction time: 8 h
Yield: 80 %

Procedure:
32.7 ml of a 2.3 M solution (75 mmol) of sodium cyclopentadienide in tetrahydrofurane was added to a solution of 11.4 g (51 mmol) of 2-bromo-1-tertbutylamino-1,1-dimethylsilaethane. The immediate formation of a pinkish solid was observed, the reaction was continued for 8 hours, then it was concentrated to dryness and it was extracted with hexane, the resulting solution was evaporated in order to give a yellow oil, that corresponds to a mixture of isomers (12.5 g, 60 mmol, yield: 80%). 1H-NMR (CDCl3): 6.5-5.75(m,3H), 2.95(m,2H), 1.90(m,2H), 1.20(s,9H), 0.10(s,6H).