Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17]2)=[N:14][CH:15]=1.C1COCC1.[OH-].[Na+]>CCO>[F:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:17][CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]2)=[N:14][CH:15]=1
Reactant: CCOC(=O)C1CCN(c2ncc(-c3cccc(CO)c3F)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(c2ncc(-c3cccc(CO)c3F)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
Ethyl 1-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylate (1.4 g) was mixed with THF (10 ml) and EtOH (15 ml), and a 1M aqueous NaOH solution (5.8 ml) was added thereto, followed by stirring at room temperature overnight. The insoluble matter was collected by filtration, and the filtrate was concentrated under reduced pressure. Water and 1M hydrochloric acid (5.8 ml) were added to the obtained residue at 0° C., followed by stirring at 0° C. for 30 minutes. The solid was collected by filtration, washed with water, and then dried at 50° C. under reduced pressure to obtain 1-{5-[2-fluoro-3-(hydroxymethyl)phenyl]pyrimidin-2-yl}piperidine-4-carboxylic acid (1.29 g).
Reaction SMILES: [OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5].ClC(Cl)(Cl)C(=N)O[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[CH2:23]([O:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][C:4]([O:6][CH3:7])=[O:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCC[C@@H](O)CC(=O)OC
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCC[C@H](CC(=O)OC)OCc1ccccc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 31.8 %

Procedure:
To a solution of compound 30 (2.8 g, 10.83 mmol) and benzyl trichloroacetimidate (3.4 g, 14 mmol) in DCM (100 mL) was added trifluoromethanesulfonic acid (0.24 mL, 2.7 mmol) dropwise at 0° C. The resulting mixture was stirred at 0° C. for 6 h and warmed to room temperature. The mixture was washed with a saturated solution of NaHCO3 (300 mL) and water (300 mL) and the organic layer dried over Na2SO4. The drying agent was removed by filtration, and the solvents removed using a rotary evaporator. The residue was purified by chromatography on silica gel (80 g RediSep column, eluting with a gradient of 0% through 30% ethyl acetate/hexanes over 60 min, 60 mL/min) to give the product 31 (1.2 g, 32%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.30-7.05 (m, 5H), 4.51 (s, 2H), 3.90-3.80 (m, 1H), 3.70 (s, 3H), 2.58-2.45 (m, 2H), 1.80-1.60 (m, 2H), 1.50-1.20 (m, 18H), 0.85 (t, J=5.8 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34](=[O:36])[CH3:35].[OH-].[Na+].O>C(O)C>[O:36]=[C:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[NH2:27])/[CH:35]=[CH:13]/[C:9]1[N:8]([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(=O)c1ccccc1N
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccccc1C(=O)/C=C/c1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.2 %

Procedure:
1-Triphenylmethyl-2-imidazole carbaldehyde (4) (25.0 g, 74 mmol) and 2'-aminoacetophenone (10.0 g, 74 mmol) were suspended in 700 ml of ethanol, and a 25% aqueous solution (120 ml) of sodium hydroxide was added to the suspension, The mixture was stirred at room temperature for 12 hours. Water (3,000 ml) was added to the resultant reaction mixture, and crystals deposited were collected by filtration, washed with water and dried. The thus-obtained crystals were recrystallized from ethanol to obtain 17.6 g (yield: 52%) of 2-[(E)-3-oxo-3-(2-aminophenyl)-1-propenyl]-1-triphenylmethylimidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-])=O.CCO.[H][H]>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][CH2:11][CH2:12][CH3:13])=[O:9])=[CH:14][CH:15]=1
Reactant: [H][H]
Reactant: CCCNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCNC(=O)c1ccc(N)cc1
Yield: 91 %

Procedure:
4-Nitro-N-propylbenzamide (3.31 g, 15.9 mmol) was dissolved in EtOAc (125 mL) and EtOH (125 mL) and passed through the H-Cube® at 1 mL/min equipped with a 10% Pd/C catcart (ThalesNano), at full hydrogen and temperature set to about 50° C. The solvent was stripped off and the solid was dried overnight in a vacuum oven set at about 50° C. to provide 4-amino-N-propylbenzamide (2.58 g, 91%): 1H NMR (DMSO-d6) δ 7.93 (t, J=5.48 Hz, 1H); 7.54 (d, J=8.57 Hz, 2H); 6.51 (d, J=8.67 Hz, 2H) 5.54 (br s, 2H) 3.13 (m, 2H) 1.47 (sextet, J=7.29 Hz, 2H) 0.85 (t, J=8.49 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[N:4]([CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][N:7]=1)#[N:2].[Na].[CH3:15][OH:16]>>[S:10]1[CH:11]=[CH:12][CH:13]=[C:9]1[CH2:8][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[C:1](=[NH:2])[O:16][CH3:15]
Reactant: N#Cc1nccn1Cc1cccs1
Reactant: CO
Agent: [Na]
Product: COC(=N)c1nccn1Cc1cccs1

Procedure:
A mixture was prepared from 7.6 g of 2-cyano-1-(2-thienylmethyl)-1H-imidazole, 300 ml of methanol and 100 mg of sodium. This gave a methanol solution of methyl 1-(2-thienylmethyl)-1H-imidazole-2-carboximidate which was mixed with 6.9 g of ammonium chloride. The resulting mixture was flash chromatographed (chloroform:methanol:ammonium hydroxide 56:7:1) to give a pale tan oil which crystallized on drying under vacuum. A portion of this solid was dissolved in hot ethanol and an ethanolic solution of hydrogen chloride was added. Crystals formed in the solution slowly. The solid which thus formed was separated by filtration to give 1-(2-thienylmethyl)-1H-imidazle-2-carboximidamide dihydrochloride melting at above 245°-248° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.Cl[C:26]1[N:35]=[C:34]2[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]2[CH:36]2[CH2:38][CH2:37]2)=[CH:28][C:27]=1[F:43].C(N(CC)CC)C.C[Si](C)(C)Cl>CS(C)=O>[C:21]([NH:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:24])[N:14]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][C@@H:9]3[CH2:13][CH2:12][N:11]([C:26]4[N:35]=[C:34]5[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]5[CH:36]5[CH2:38][CH2:37]5)=[CH:28][C:27]=4[F:43])[CH2:10]3)=[C:2]([F:1])[CH:3]=2)[CH2:18]1)(=[O:23])[CH3:22]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NC3CCNC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N[C@@H]3CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)C3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
A suspension of 119 mg N-{(5S)-3-[3-fluoro-4-(pyrrolidin-3-ylamino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.35 mmol), 100 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 148 μl triethylamine (, 1.05 mmol) and 89 μl trimethylchlorosilane (0.70 mmol) in 2 ml DMSO was stirred in a microwave oven at 150° C. for 10 min. The DMSO was evaporated, the residue digested in water and the solid filtrated. The solid was purified by chromatography using a 95/5 dichloromethane/methanol mixture.
Reaction SMILES: [C:1]([O:5][CH:6]1[O:9][CH:7]1[CH3:8])([CH3:4])([CH3:3])[CH3:2].[NH3:10]>>[NH2:10][CH2:8][CH:7]([OH:9])[CH2:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: CC1OC1OC(C)(C)C
Product: CC(C)(C)OCC(O)CN
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100 g of 1,2-epoxypropyl tert.-butyl ether are added dropwise to 500 ml of conc. aqueous ammonia under ice-cooling and tile mixture is stirred at room temperature for 20 hours. The reaction mixture is evaporated under reduced pressure to remove the aqueous ammonia. Chloroform is added to the residue. The mixture is dried with potassium carbonate. Insoluble materials are filtered off and the filtrate is evaporated to remove the solvent. The residue is distilled under reduced pressure. 49.3 g of 1-amino-3-tert.-butoxy-2-propanol are obtained.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)[C:3]([OH:5])=[O:4].[OH-].[Na+].[O:13]=[C:14]1[N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17][CH2:16][N:15]1[C:23](Cl)=[O:24]>O>[O:13]=[C:14]1[N:18]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:17][CH2:16][N:15]1[C:23]([NH:1][CH:2]([C:6]1[N:7]=[CH:8][S:9][CH:10]=1)[C:3]([OH:5])=[O:4])=[O:24]
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)C1=O
Reactant: NC(C(=O)O)c1cscn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)N1CCN(C(=O)NC(C(=O)O)c2cscn2)C1=O
Reaction time: 1 h
Yield: 53 %

Procedure:
DL-2-Amino-2-(thiazol-4-yl)acetic acid (214 mg) [prepared by the method described in J. Med. Chem. 16, 978 (1973)] was taken up in water (10 ml) and the pH was adjusted to 6.5 by the addition of 2N sodium hydroxide solution. 2-Oxo-3-methylsulphonylimidazolidin-1-ylcarbonyl chloride (310 mg) was added to the stirred solution at room temperature in portions; the pH being maintained between 6.0 and 7.0 by the addition of 2N sodium hydroxide solution. When the addition was complete, the mixture was stirred for one hour, filtered, and the filtrate was washed with ethyl acetate (2×20 ml), acidified to pH 1.0, and extracted with ethyl acetate (2×20 ml). The combined extracts were washed with saturated sodium chloride solution (20 ml), dried (MgSO4), filtered and evaporated to dryness in vacuo. The residue was triturated with methylene chloride and the solid product was separated by filtration to give the title compound as a white solid, (250 mg).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:14](=[O:15])[CH2:13][C:12]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:11][C:8]2=[CH:9][N:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[C:32]2[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=2)[N:26]=[C:25]([C:35](O)=[O:36])[CH:24]=1>>[C:1]([C:5]1[CH:6]=[C:7]2[C:14](=[O:15])[CH2:13][C:12]3([CH2:16][CH2:17][N:18]([C:35]([C:25]4[CH:24]=[C:23]([O:22][CH3:21])[C:32]5[C:27](=[C:28]([O:33][CH3:34])[CH:29]=[CH:30][CH:31]=5)[N:26]=4)=[O:36])[CH2:19][CH2:20]3)[O:11][C:8]2=[CH:9][N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)O)nc2c(OC)cccc12
Reactant: CC(C)(C)c1cc2c(cn1)OC1(CCNCC1)CC2=O
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(C(C)(C)C)ncc2O3)nc2c(OC)cccc12

Procedure:
The compound was prepared according to the procedure described in Example 1, using 6′-tert-butylspiro[piperidine-4,2′-pyrano[2,3-c]pyridin]-4′(3′H)-one instead of N-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)acetamide and using 4,8-dimethoxyquinoline-2-carboxylic acid in place of 4-methoxyquinoline-2-carboxylic acid. 1H-NMR (400 MHz, CDCl3) δ: 8.49 (1H, d, J=1.0 Hz), 7.77 (1H, dd, J=8.0, 1.1 Hz), 7.64 (1H, d, J=1.0 Hz), 7.47 (1H, t, J=8.0 Hz), 7.19 (1H, s), 7.08 (1H, dd, J=8.0, 1.1 Hz), 4.65-4.57 (1H, m), 4.23-4.15 (1H, m), 4.08 (3H, s), 4.03 (3H, s), 3.66-3.33 (2H, m), 2.90-2.76 (2H, m), 2.24-1.83 (4H, m), 1.36 (9H, s). MS (M+H)+=490.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(P(N(C)C)(N(C)C)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])=[CH:35][CH:34]=1>C1COCC1>[Si:41]([O:40][CH2:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]#[N:9])=[CH:38][CH:37]=1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:42])[CH3:43]
Reactant: N#CCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1ccc(CC(C#N)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 67.3 %

Procedure:
A solution of phenylacetonitrile (1.5 mL, 12.7 mmol) in THF (40 mL) containing HMPA (11 mL, 63.4 mmol) was cooled to -78° C. and treated with 16 mL (16 mmol) of a 1.0M THF solution of lithium bis(trimethylsilyl)amide dropwise while the temperature was maintained at -78° C. The reaction was stirred at -78° C. for 1.5 hours, and a solution of the product of Step B (2.00 g, 6.34 mmol) in THF (8 mL) was added dropwise with the temperature maintained below -70° C. The reaction temperature was maintained below -68° C. for 3 hours. The reaction was quenched at this temperature by addition of 1N NaHSO4. After warming to room temperature, the mixture was partitioned between EtOAc and water, and the combined organic layers were washed with water, saturated NaHCO3, brine, dried (MgSO4), filtered, then concentrated in vacuo. The residue was chromatographed on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 1.5 g (67%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[CH2:6]2.ClS([N:19]=[C:20]=[O:21])(=O)=O.C(#N)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([C:20]([NH2:19])=[O:21])[C:7](=[O:14])[CH2:6]2
Reactant: COc1cc2c(cc1OC)NC(=O)C2
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cc2c(cc1OC)N(C(N)=O)C(=O)C2

Procedure:
Following the procedure of Example 24, the title compound was prepared from 5,6-dimethoxy-2-oxindole (8.0 g, 0.042 mole), chlorosulfonyl isocyanate (7.08 g, 0.05 mole) and acetonitrile (75 ml). The crude product obtained upon evaporation of the ethyl acetate extract was recrystallized from acetonitrile/acetic acid (1:1). Yield=6.02 g (60%); m.p. 206.5°-209° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][N:13]=[C:14]([Cl:17])[CH:15]=2)[N:10]=[CH:9][CH:8]=1)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][N:13]=1)[N:10]=[CH:9][CH:8]=[C:7]2[N:20]1[CH2:25][CH2:24][CH2:23][C@H:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH2:21]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Reactant: O=S(=O)(Oc1ccnc2cnc(Cl)cc12)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccnc3cnc(Cl)cc23)C1
Yield: 61 %

Procedure:
A solution of 6-chloro-1,7-naphthyridin-4-yl trifluoromethanesulfonate (1.0 equiv.), (S)-tert-butyl piperidin-3-ylcarbamate (1.0 equiv.) and DIEA (1.5 equiv.) in CH2Cl2 (0.3 M) was stirred at rt for 120 hours. The solution was partitioned between EtOAc and Na2CO3(sat.). Upon separation, the organic layer was washed with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (EtOAc eluant) to yield (S)-tert-butyl 1-(6-chloro-1,7-naphthyridin-4-yl)piperidin-3-ylcarbamate (61%). LC/MS=363.2 (M+H), LC=2.47 min.
Reaction SMILES: C(O[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([CH2:26][O:27][CH:28]3[CH:33]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH2:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[O:52][CH3:53])=[CH:36][CH:35]=4)[CH2:32][CH2:31][N:30]([C:54]([O:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[O:55])[CH2:29]3)[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:64])=O)C1C=CC=CC=1.[H-].[Na+].CI.[C:69](=[O:72])([O-:71])O.[Na+]>CN(C)C=O>[CH2:26]([O:71][C:69]([CH2:9][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:21]2[CH:22]=[C:23]([CH2:26][O:27][CH:28]3[CH:33]([C:34]4[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][O:44][CH2:45][C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=5[O:52][CH3:53])=[CH:36][CH:35]=4)[CH2:32][CH2:31][N:30]([C:54]([O:56][CH2:57][C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)=[O:55])[CH2:29]3)[CH:24]=[CH:25][C:20]=2[O:19][CH2:18][C:17]1=[O:64])=[O:72])[C:23]1[CH:24]=[CH:25][CH:20]=[CH:21][CH:22]=1
Reactant: O=C([O-])O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCNC(=O)OCc2ccccc2)C(=O)CO3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(c2)N(CCCCNCC(=O)OCc2ccccc2)C(=O)CO3)cc1
Reaction time: 1 h

Procedure:
The stirred solution of 0.351 g of benzyl 3-[4-(4-benzyloxycarbonylaminobutyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 8 ml of N,N-dimethylformamide is admixed at 0° C. with 0.031 g of sodium hydride (60% dispersion). After 1 hour, 0.144 ml of methyl iodide is added and the mixture is kept at 75° C. over 18 hours. The mixture is cooled, poured onto aqueous 1M sodium hydrogencarbonate solution (40 ml) and extracted with ethyl acetate (2×40 ml). The organic phases are washed with brine (40 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.17 (1:1 EtOAc-heptane); Rt=6.18.
Reaction SMILES: [OH:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2([NH:13][C:14]([C:16]3[CH:17]=[N:18][CH:19]=[N:20][CH:21]=3)=[O:15])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.F[C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[C:33]([F:36])([F:35])[F:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CC(C)=O>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([O:1][C:2]2[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]3([NH:13][C:14]([C:16]4[CH:21]=[N:20][CH:19]=[N:18][CH:17]=4)=[O:15])[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)=[C:26]([C:33]([F:34])([F:35])[F:36])[CH:27]=1)#[N:30]
Reactant: O=C(NC1(C(=O)NCc2ccc(O)cc2)CC1)c1cncnc1
Reactant: N#Cc1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cncnc4)CC3)cc2)c(C(F)(F)F)c1
Yield: 82 %

Procedure:
A solution of 100 mg (0.32 mmol) of pyrimidin-5-carboxylic acid[1-(4-hydroxy-benzylcarbamoyl)-cyclopropyl]-amide, 60.5 mg (0.32 mmol) of 4-fluoro-3-trifluoromethyl-benzonitrile and 110 mg (0.8 mmol) of potassium carbonate in 5 mL DMF was stirred for two hours at 110° C. After cooling the mixture was diluted with approx. 3 mL acetone, filtered and evaporated down. The crude product thus obtained was purified by column chromatography (reversed phase).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH:32][C:33]([N:15]1[CH2:16][CH2:17][N:12]([C:10]2[S:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:11]=2)[CH2:13][CH2:14]1)=[O:34]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1Cl)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 2-chlorophenyl isocyanate (0.147 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 167 mg (51.5%) of the desired product as a solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9][CH2:8][C:7]=2[CH:23]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11](=[O:13])(=[O:12])[N:10]([CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:9][CH2:8][C:7]=2[CH:23]=1
Reactant: COc1ccc2c(c1)CCN(CCCc1ccccc1)S2(=O)=O
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S1(=O)c2ccc(O)cc2CCN1CCCc1ccccc1

Procedure:
6-Methoxy-2-(3-phenylpropyl)-3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide (1.2 g, 4 mmol) is dissolved in CH2Cl2 (200 mL) and the resulting solution is cooled to -78°. Boron tribromide (1.1 mL, 12 mmol) is then added and the reaction is allowed to come to ambient temperature. After 12 hours the mixture is cooled to 0° and subsequently neutralized with saturated NaHCO3 solution (100 mL). The aqueous phase is then extracted with CH2Cl2 (1×100 mL). The combined organics are washed with saturated NaCl solution (2×200 mL), dried over Na2SO4 and concentrated in vacuo to give 6-hydroxy-2-(3-phenylpropyl)-3,4-dihydro-2H-1,2-benzothiazine-1,1-dioxide.
Reaction SMILES: CS[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[CH:6]=[N:5][N:4]=1.[NH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[N:12]1([C:3]2[N:8]3[CH:9]=[N:10][CH:11]=[C:7]3[CH:6]=[N:5][N:4]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: C1CNCCN1
Reactant: CSc1nncc2cncn12
Solvent: Cc1ccccc1
Product: c1ncn2c(N3CCNCC3)nncc12

Procedure:
A mixture of 6.5 gm. of 4-(methylthio)-imidazo[1,5-d]-as-triazine, 17.2 gm. of anhydrous piperazine and 120 ml. of toluene is reacted as described in Example 40 giving the desired product, m.p. 160°-165° C.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]([F:36])([F:35])[C:21]([NH:23][C@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:27]([OH:34])[CH2:26][CH2:25]1)=[O:22].N1C=CN=C1>CN(C=O)C.CCOC(C)=O>[Si:5]([O:34][C@H:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:24]([NH:23][C:21](=[O:22])[C:20]([F:35])([F:36])[F:19])[CH2:25][CH2:26]1)([C:1]([CH3:4])([CH3:3])[CH3:2])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C(N[C@@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](NC(=O)C(F)(F)F)c2ccccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
tert-Butylchlorodiphenylsilane (4.4 mL) was added to a stirred solution of 2,2,2-trifluoro-N-((1R,4R)-4-hydroxy-1,2,3,4-tetrahydronaphthalen-1-yl)acetamide (2.2 g) and imidazole (1.7 g) in DMF (35 mL). The reaction mixture was stirred at room temp overnight. The reaction mixture was diluted with EtOAc (150 mL), and washed with distilled water (20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo and purified by column chromatography (eluting with 1:1 DCM/Hex), to give 4.0 g (95%) of the titled compound. 1H-NMR (300 MHz, CDCl3) □ 7.7 (d, 2H), 7.6 (d, 2H), 7.4 (m, 6H), 7.2 (m, 4H), 6.3 (broad s, 1H), 5.2 (q, 1H), 4.8 (t, 1H), 2.4 (m, 1H), 1.8 (m, 2H), 1.6 (m, 1H) ppm.
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH:18]1([NH2:21])[CH2:20][CH2:19]1>>[CH:18]1([NH:21][C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Product: N#Cc1c(NC2CC2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 100 mg (0.38 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 217 mg (3.80 mmol) of cyclopropylamine to give 44 mg (43% of theory) of the title compound.