Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[C:3]([O:6][C:7](=O)[CH3:8])(=O)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:23])C(C)=C)=[CH:14][C:13]=1[C:24]([F:27])([F:26])[F:25])#[N:11]>O>[C:10]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:7]2([CH3:8])[CH2:3][O:6]2)=[O:23])=[CH:14][C:13]=1[C:24]([F:25])([F:26])[F:27])#[N:11]
Reactant: CC(=O)OC(C)=O
Reactant: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Agent: OO
Solvent: O
Product: CC1(C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)CO1
Temperature: 52.5 °C
Reaction time: 0.5 h

Procedure:
10 ml of 30% aqueous hydrogen peroxide is heated to 35-40° C. 20 ml of acetic anhydride is added dropwise under cooling, so that the temperature does not exceed 40-50° C. 0.02 g of wolframic acid is added and the reaction mixture is stirred for 0.5 hours at 50-55° C. 3 grams of the amide (7) is added to the mixture portionwise and the reaction mixture is stirred for 6 hours at 50-55° C. The suspension is then cooled to 20-25° C. and poured, under stirring, into 100 ml of cold (0-5° C.) water. The suspension is stirred for 30 minutes and the solid is filtered off, washed by water and dried at 40-50° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][N:12]([CH3:19])[CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][NH2:16].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:16][CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][N:12]([CH3:19])[CH3:11])=[O:8])=[CH:9][CH:10]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CN(C)CC(C)(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(C)(C)CNC(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-aminobenzoic acid (Aldrich; 4.0 g, 29.17 mmol) in DMF (100 mL) was added N,N,2,2-tetramethyl-1,3-diaminopropane (Aldrich; 5 mL, 31.38 mmol). An immediate solid precipitate formed. DIPEA (15 ml, 86.11 mmol) was added and the resultant suspension stirred HATU (13 g, 34.18 mmol) was added portionwise at such a rate and time interval as to maintain internal reaction temp <30° C.}. The resultant yellow solution was stirred at ambient temperature, overnight.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:17]([OH:31])([C:24]3[CH:29]=[CH:28][CH:27]=[C:26](C)[N:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)=[C:5]([CH3:32])[O:4][N:3]=1.[CH3:33][N:34](C1C=CC=C(Br)N=1)[CH3:35]>>[CH3:33][N:34]([CH3:35])[C:26]1[N:25]=[C:24]([C:17]([OH:31])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:9]2[C:10]3[NH:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:32])[CH:8]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)c1cccc(Br)n1
Reactant: Cc1cccc(C(O)(c2ccccn2)c2cc(-c3c(C)noc3C)cc3[nH]c(=O)[nH]c23)n1
Product: Cc1noc(C)c1-c1cc(C(O)(c2ccccn2)c2cccc(N(C)C)n2)c2[nH]c(=O)[nH]c2c1

Procedure:
A procedure similar to that used for 6-(3,5-dimethylisoxazol-4-yl)-4-(hydroxy(6-methylpyridin-2-yl)(pyridin-2-yl)methyl)-1H-benzo[d]imidazol-2(3H)-one, using 6-bromo-2-N,N-dimethylaminopyridine as the starting material was used to produce the intermediate (C32H36N6O5, 585.2 (M+1)), which was taken directly to the deprotection step to yield the title compound as a yellow oil.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[CH3:5][C:6]1[CH2:11][CH2:10][CH:9]([CH:12]=[O:13])[CH2:8][CH:7]=1.[Mg].O1CCCC1>C1(C)C=CC=CC=1>[CH2:3]([CH:12]([CH:9]1[CH2:10][CH2:11][C:6]([CH3:5])=[CH:7][CH2:8]1)[OH:13])[CH:2]=[CH2:1]
Reactant: C=CCCl
Reactant: CC1=CCC(C=O)CC1
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCC(O)C1CC=C(C)CC1
Temperature: 71 °C
Yield: 65.2 %

Procedure:
A solution of 251 grams (3.3 moles) of allyl chloride and 372 grams (3 moles) of 4-methyl-3-cyclohexenecarboxaldehyde is added dropwise to a stirred slurry of 77 grams of magnesium (3.2 moles) and 1500 ml of tetrahydrofuran at reflux under nitrogen over a three-hour period. The reaction mixture is heated at reflux (71° C.) for 30 minutes after the feed is complete, whereupon 500 ml of toluene is added. A distillation head is attached to the reaction flask and the tetrahydrofuran is distilled off at atmospheric pressure to a pot temperature of 100° C. The remaining organic solution is cooled to 0° C., whereupon 1000 ml of 18% hydrochloric acid solution is slowly added with external cooling. Two clear layers is formed. The aqueous layer is discarded and the organic layer is quickly distilled. The distillate is fractionally redistilled through a 1.5"×12" Goodloe packed column to afford 325 grams of alpha-allyl-4-methyl-3-cyclohexene methanol (b.p. 92° C., 3.0 mm Hg pressure).
Reaction SMILES: [OH-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([O:14]C)=[O:13]>CO.O>[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Add NaOH (82.0 mmol) to methyl indole-2-carboxylate 2 (27.0 mmol) as a suspension in MeOH/H2O (3:1, 160 mL). Stir at rt for 16 h, concentrate, and acidify with HCl. Collect the precipitate by filtration, wash with H2O and dry in vacuuo to afford indole-2-carboxylic acid 3.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([N:13]2[CH2:18][CH2:17][C:16]3([O:23][CH:22]([CH2:24][O:25][CH3:26])[CH2:21][NH:20][CH2:19]3)[CH2:15][CH2:14]2)=[O:12])=[CH:7][C:6]=1[CH3:27])([CH3:3])[CH3:2].[C:28]1(=O)[CH2:31][CH2:30][CH2:29]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.CC(OC)(C)C>[CH:28]1([N:20]2[CH2:19][C:16]3([CH2:15][CH2:14][N:13]([C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:27])[CH:7]=4)=[O:12])[CH2:18][CH2:17]3)[O:23][CH:22]([CH2:24][O:25][CH3:26])[CH2:21]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C1CCC1
Reactant: COCC1CNCC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Solvent: COC(C)(C)C
Product: COCC1CN(C2CCC2)CC2(CCN(C(=O)c3ccc(OC(C)C)c(C)c3)CC2)O1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of (4-isopropoxy-3-methyl-phenyl)-[10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl]methanone (343 mg, 0.912 mmol) and cyclobutanone (96.0 mg, 1.36 mmol) in dichloroethane (3 mL) was treated with acetic acid (78 μL, 1.4 mmol) and stirred for 30 min. NaBH(OAc)3 (387 mg, 1.82 mmol) was added and the reaction mixture stirred for 16 h. The reaction mixture was diluted with MTBE and washed with 1N NaOH (100 mL). The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography (5-80% ethyl acetate/hexane) provided (4-cyclobutyl-2-(methoxymethyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)(4-isopropoxy-3-methylphenyl)methanone (330 mg, 84%). ESI-MS m/z calc. 430.3. Found 431.3 (M+1)+; Retention time: 1.24 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.19 (d, J=8.4 Hz, 2H), 6.80 (d, J=8.1 Hz, 1H), 4.55 (hept, J=6.2 Hz, 1H), 4.30-4.10 (m, 1H), 3.94-3.75 (m, 1H), 3.62-3.46 (m, 1H), 3.48-3.33 (m, 6H), 3.30-3.16 (m, 1H), 2.75 (d, J=10.8 Hz, 1H), 2.67-2.57 (m, 1H), 2.55 (d, J=11.1 Hz, 1H), 2.47-2.27 (m, 1H), 2.20 (s, 3H), 1.98 (d, J=7.3 Hz, 2H), 1.91-1.76 (m, 1H), 1.76-1.61 (m, 4H), 1.57-1.39 (m, 3H), 1.34 (d, J=6.0 Hz, 6H).
Reaction SMILES: [CH:1]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([F:14])=[CH:11][C:12]=2[F:13])=[CH:5][C:4]([C:15]([OH:17])=[O:16])=[C:3]([OH:18])[CH:2]=1.Cl.CN(C)[CH2:22][CH2:23][CH2:24]N=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)CC>CN(C)C=O.O>[F:13][C:12]1[CH:11]=[C:10]([F:14])[CH:9]=[CH:8][C:7]=1[C:6]1[CH:5]=[C:4]([C:15]([O:17][CH2:22][CH2:23][CH3:24])=[O:16])[C:3]([OH:18])=[CH:2][CH:1]=1
Reactant: CN(C)CCCN=C=N
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCCO
Solvent: O
Solvent: CN(C)C=O
Product: CCCOC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
Diflunisal (500 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (458 mg), 1-hydroxybenzotriazole hydrate (36.7 mg), and propanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give propyl 5-(2,4-difluorophenyl)salicylate (179 mg, yield 30%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[C:12]([OH:20])=[N:13][CH:14]=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:43](N)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>CN(C)C=O.O>[CH2:1]([N:8]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:9]([C:11]1[C:12](=[O:20])[NH:13][CH:14]=[C:15]([C:16]([OH:18])=[O:17])[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnc(O)c(C(=O)NCc2ccccc2)c1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)c1c[nH]c(=O)c(C(=O)N(Cc2ccccc2)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a suspension of 5-benzylcarbamoyl-6-hydroxy-nicotinic acid 1.0 (3.67 mmol), EDAC.HCl 0.84 g (4.4 mmol), HOBT 0.59 g (4.4 mmol), in dimethylformamide (20 mL) was added benzylamine 0.47 g (4.4 mmol). The mixture was stirred overnight at room temperature. Water (20 mL) was added, and the reaction mixture was filtered. The solid product was then slurried in hot ethyl acetate. 1.1 g (81% yield). MS: m/z (APCI, AP+) 362.2 [M−]+. CHN Analysis: Calcd: C, 69.79; H, 5.30; N, 11.63. Found: C, 69.49; H, 5.38; N, 11.64.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH3:11])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH:12]12[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH2:17][CH2:18]1)[CH2:15][NH:14][CH2:13]2.C(N(CC)CC)C>C(O)(C)C>[CH3:11][C:10]1[C:3]2[C:2]([N:14]3[CH2:13][CH:12]4[N:19]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: Cc1c[nH]c2ncnc(N3CC4CCC(C3)N4C(=O)OC(C)(C)C)c12
Temperature: 180 °C
Yield: 71.4 %

Procedure:
To a solution of 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (25 mg, 0.15 mmol) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (30 mg, 0.14 mmol) in isopropanol (2 ml) was added triethylamine (36 μL, 0.26 mmol). The reaction was heated at 180° C. for 30 min in the microwave, then concentrated under vacuum. The residue was purified by prep HPLC (Sunfire C18 30×50 mm, 10-90% H2O/MeOH w/0.01% TFA, 15 min, 35 ml/min, 220 nm) to give tert-butyl 3-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (35 mg, 0.10 mmol, 66%).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[C:14]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[C:7]2[N:8]([CH3:14])[CH2:9][S:10](=[O:11])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=S1C=Nc2c(F)cccc21
Reactant: Cc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: COS(=O)(=O)OC
Product: CN1CS(=O)c2cccc(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
4-Fluorobenzothiazolone (4.23 g, 0.025 mole) was dissolved in a solution of sodium hydroxide (1.60 g, 0.0375 mole) in water (100 c.c.), and tetra-n-butylammonium bromide (0.24 g, 7.5×10-4 mole) and toluene (40 c.c.) were added thereto. Dimethyl sulfate (4.70 g, 0.0375 mole) was added dropwise thereto at room temperature, and the mixture was stirred at room temperature for 1 hour, followed by phase-separation. The toluene layer was washed once with water, and the solvent was removed under reduced pressure to obtain 4.47 g of 4-fluoro-N-methylbenzothiazolone as white crystals. Yield 97.6%, purity 98.7%, m.p. 121.5°-123.5° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:6](N)([NH2:9])(=[O:8])=[O:7]>O1CCOCC1>[N:1]1([S:6]([NH2:9])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCCC1

Procedure:
Pyrrolidine (3.37 g) and sulfamide (7.10 g) in 1,4-dioxane (110 ml) were heated at reflux for 24 h. The solvent was evaporated under reduced pressure and the resulting solid suspended in CHCl3. The suspension was filtered and the filtrate concentrated in vacuo to afford the subtitle compound as a white solid. Yield: 5.35 g.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([O:20]CC)=[O:19])=[C:6]([CH2:31][CH:32]=[CH2:33])[C:5]=1[O:34][CH3:35])=[O:3].[OH-].[Li+]>CO>[NH2:1][C:2]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[C:14]([CH2:26][CH2:27][CH3:28])=[C:15]([CH:23]=[CH:24][CH:25]=2)[O:16][CH2:17][C:18]([OH:20])=[O:19])=[C:6]([CH2:31][CH:32]=[CH2:33])[C:5]=1[O:34][CH3:35])=[O:3]
Reactant: C=CCc1c(OCCCOc2cccc(OCC(=O)OCC)c2CCC)ccc(C(N)=O)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: C=CCc1c(OCCCOc2cccc(OCC(=O)O)c2CCC)ccc(C(N)=O)c1OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound of Example 55 (100 mg, 0.195 mmol) and 390 μl of 1M lithium hydroxide (0.3896 mmol) were added to 2.0 ml of methanol, and the reaction mixture was stirred at room temperature for 4 hours. The solvent was removed under vacuum, 5.0 ml of water was added to the residue, and the mixture was acidified with 10% hydrochloric acid. The mixture was filtered, and the white solid which was recovered was dried in a 40° C. oven overnight to give the product.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH:12]1([OH:18])[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1>ClCCl.N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:17][CH:14]2[CH2:15][CH2:16][CH:12]([OH:18])[CH2:13]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: OC1CCC(O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC2CCC(O)C2)cc1
Temperature: 15 °C
Reaction time: 0.75 h

Procedure:
A solution of 9.00 g p-toluenesulphonic acid chloride in 30 ml dichloromethane is added dropwise to an ice-cooled solution of 4.97 g cyclopentan-1,3-diol (cis/trans mixture) in 15 ml of pyridine and 10 ml dichloromethane. The solution is stirred for 45 min at 15° C. The solution is diluted with 100 ml dichloromethane, washed twice with 2 N hydrochloric acid and once with water. After drying through sodium sulphate and elimination of the solvent the product is obtained as a brown oil.
Reaction SMILES: [Si:1]([O:5][Si](O)(O)O)([O-:4])([O-:3])[O-:2].[Na+:10].[Na+].[Na+].O.[Si](O[Si]([O-])([O-])[O-])([O-])([O-])[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+]>O>[Si:1]([O-:5])([O-:4])([O-:3])[O-:2].[Na+:10].[Na+:10].[Na+:10].[Na+:10]
Reactant: [O-][Si]([O-])([O-])O[Si](O)(O)O
Agent: [Na+]
Agent: [O-][Si]([O-])([O-])O[Si]([O-])([O-])[O-]
Solvent: O
Product: [O-][Si]([O-])([O-])[O-]

Procedure:
EP-A-0 444 415 proposes detergents containing 5 to 50% by weight of at least one surfactant, 0.5 to 60% by weight of a builder and typical detergent ingredients, characterized in that an amorphous low-water sodium disodium disilicate with a water content of 0.3 to 6% by weight is used as the builder. In a preferred embodiment, the amorphous sodium disilicate is said to contain 0.5 to 2% by weight of water. These substantially water-free amorphous disilicates are produced by a multistage process which initially comprises producing a powder-form amorphous sodium silicate with a water content of 15 to 23% by weight. This material is treated with waste gas in countercurrent in a rotary kiln at temperatures of 250° to 500° C. The amorphous sodium disilicate issuing from the rotary kiln is size-reduced by a mechanical crusher to particle sizes of 0.1 to 12 mm and subsequently ground in a mill to particle sizes of 2 to 400 μm.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:40]1[CH2:47][CH2:46][CH2:45][C@@H:41]1[C:42]([NH2:44])=[O:43].C([O-])(O)=O.[Na+]>CS(C)=O>[OH:32][C:29]([CH3:31])([CH3:30])[CH2:28][C@@:19]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[O:18][C:17](=[O:33])[N:16]([C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:40]4[CH2:47][CH2:46][CH2:45][C@@H:41]4[C:42]([NH2:44])=[O:43])=[N:7][CH:6]=3)=[CH:9][CH:10]=2)[CH3:15])[CH2:21][CH2:20]1
Reactant: NC(=O)[C@H]1CCCN1
Reactant: C[C@@H](c1ccc(-c2ccc(F)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H](c1ccc(-c2ccc(N3CCC[C@@H]3C(N)=O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-{(S)-1-[4-(6-fluoro-pyridin-3-yl)-phenyl]-ethyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (165 mg), potassium carbonate (76 mg), D-prolinamide (125 mg), and dimethyl sulfoxide (2 mL) was stirred at 100° (overnight. After cooling to room temperature, aqueous NaHCO3 solution was added and the resulting mixture was extracted with dichloromethane. The combined extracts were concentrated and the residue was purified by HPLC on reversed phase (water/methanol) to give the title compound. Yield: 85 mg (43% of theory); Mass spectrum (ESI+): m/z=543 [M+H]+.
Reaction SMILES: [C:1]([Si:5]([CH3:8])([CH3:7])Cl)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:17][CH:16]=1.O>CN(C)C=O>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:8])[CH3:7])=[CH:19][CH:20]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.3 %

Procedure:
tert-Butyldimethylchlorosilane (1.13 g) and imidazole (513 mg) were added to a solution of 4-(4-bromophenyl)butan-1-ol (1.15 g) in N,N-dimethylformamide (35 mL) under ice-cooling, and the mixture was stirred at room temperature for one hour. Water was added to the reaction solution, followed by extraction with a mixture of hexane-ethyl acetate (1:1). The organic layer was dried over sodium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:1→50:1→20:1) to give the title compound (1.78 g, quant.).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:26]([O:28][C:29](Cl)=[O:30])[CH3:27]>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[C:17]2=[O:25])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reactant: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)n1c(=O)n(C2CCN(C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
A suspension of 165 mg of sodium hydride in 10 ml of tetrahydrofuran is cooled at 0° C. To the suspension is added dropwise a solution of 2.2 g of 1-t-butyloxycarbonyl-4-(2-keto-1-benzimidazolinyl)-piperidine in 18 ml of tetrahydrofuran over 30 minutes in a stream of nitrogen. The mixture is stirred at room temperature for 2 hours and 760 mg of ethoxycarbonylchloride is added. The mixture is stirred at room temperature for one hour and 300 mg of ethoxycarbonylchloride is added. The mixture is stirred for 12 hours. The reaction solution is put into ice and the resulting oily product is extracted with ethyl acetate. The extract is washed and dried. Ethyl acetate is distilled away and the resulting residue is recrystallized from n-hexane to obtain 2.4 g of 1-t-butyloxycarbonyl-4-(2-keto-3-ethoxycarbonyl-1-benzimidazolinyl)-piperidine.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:36]([O:38]C)=[O:37])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([NH:23][CH2:24][C@@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)=[O:22])=[CH:18][C:17]4[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CI.[H-].[Na+].[CH3:44]NC(N)=O>CN(C=O)C.CO.CO.C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:36]([OH:38])=[O:37])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]([CH3:44])[CH2:24][C@@H:25]4[CH2:29][CH2:28][CH2:27][O:26]4)=[O:22])=[CH:18][C:17]4[CH:30]=[C:31]([O:34][CH3:35])[CH:32]=[CH:33][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)NC[C@@H]1CCCO1)=Cc1cc(OC)ccc1-3
Reactant: CNC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc2c(c1)C=C(C(=O)N(C)C[C@@H]1CCCO1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)O)cc21

Procedure:
Prepared from methyl 13-cyclohexyl-3-(methyloxy)-6-((((2S)-tetrahydro-2-furanylmethyl)amino)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxylate by methylation using MeI and NaH in DMF in a similar manner as described before; Analytical thin layer chromatography (5% MeOH/CH2Cl2) Rf=0.45; Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=529.21, HPLC Rt=2.035 min.