Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[O:5][C:4](=O)[CH:3]=1.S([O-])([O-])(=O)=O.[OH:30][NH3+:31].O[NH3+].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[OH:30][N:31]1[C:6]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: [NH3+]O
Reactant: Cc1cc(COc2ccc(Oc3ccc(Cl)cc3)cc2)oc(=O)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(COc2ccc(Oc3ccc(Cl)cc3)cc2)n(O)c(=O)c1

Procedure:
171.4 g (0.5 mole) of 4-methyl-6-[4-(4-chlorophenoxy)phenoxymethyl]-2-pyrone in 50 ml of toluene were heated to 80° C. Then 59.9 g (0.36 mole) of hydroxylammonium sulfate and 38.3 g (0.36 mole) of sodium carbonate were added. 10 minutes later a further 59.9 g (0.36 mole) of hydroxylammonium sulfate and 38.3 g (0.36 mole) of sodium carbonate were added. After about 4 hours the heating was removed and, at about 40° C., 500 ml of methylene chloride were added. The dissolved reaction product was then filtered off from the insoluble salts. The filtrate was then dried over sodium sulfate, and the methylene chloride was evaporated off. When the residue was stirred with 500 ml of ethyl acetate, the reaction product crystallized out. For final purification, the 1-hydroxy-4-methyl-6-[4-(4-chlorophenoxy)phenoxymethyl]-2-pyridone was recrystallized from dimethylformamide. Yield 80.5 g (45%); melting point 168°-170° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([O:13][CH3:14])[CH:10]=[CH:11][CH:12]=1.[CH2:15]([N:17]([CH2:28][CH3:29])[C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=1)[CH3:16].CCN(CC)CC>CCCCCC.C1COCC1.C(Cl)Cl>[CH2:28]([N:17]([CH2:15][CH3:16])[C:18](=[O:27])[C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:26])[C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[CH:21][CH:20]=1)[CH3:29]
Reactant: COc1cccc(Br)c1
Reactant: CCN(CC)C(=O)c1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)c1ccc(C(=O)c2cccc(OC)c2)cc1
Temperature: 25 °C
Yield: 41.8 %

Procedure:
60 ml (96 mmol) of a 1.6 N solution of n-butyllithium in n-hexane were added slowly, under a nitrogen atmosphere and at −55° C., to a solution of 18 g (96 mmol) of 3-bromoanisole in 200 ml of dry THF. After 2 h the solution was added via cannula to a solution of 19.7 g (96 mmol) of N,N-diethyl-4-formylbenzamide in 200 ml of dry THF. The reaction mixture was allowed to warm up to room temperature overnight, then it was quenched with NH4Cl saturated solution. The aqueous phase was extracted with Et2O. The organic phase dried over Na2SO4 and the solvent removed in vacuo. The crude reaction mixture was employed in the next synthetic step without further purification. A solution of 15.3 ml of DMSO in 45 ml of CH2Cl2 was added slowly, under a nitrogen atmosphere and at −55 ° C., to a solution of 9 ml of oxalyl chloride in 200 ml of CH2Cl2. After 2 min. the crude reaction mixture obtained in the preceding step and dissolved in 90 ml of CH2Cl2 was added, followed, after 15 min. by 65 ml of Et3N. The reaction mixture was allowed to warm up to room temperature in 2 h, then it was quenched with 500 ml of H2O. The organic phase is separated and washed with 10% HCl solution, then dried over Na2SO4 and the solvent removed in vacuo. The crude reaction mixture was purified by flash chromatography, eluting with Et2O/hexane 9:1 respectively, yielding 12.5 g of the title compound.
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:12]1[CH:14]2[CH2:15][C:16]3[C:21]([CH:13]12)=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3>CN(C=O)C>[C:1]([NH:9][C@@H:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[CH2:15][C@H:14]1[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C1OC1C2
Reactant: NC(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1c2cc([N+](=O)[O-])ccc2C[C@H]1O)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of a benzamide (2 parts) in DMF is treated with NaH (2 parts) and the reaction is stirred until gas evolution ceases. To the reaction is added 1,2-epoxy-6-nitroindane (1 part) and the reaction is stirred over night at 60° C. The reaction is poured into ice-water and extracted with CH2Cl2. The organic extracts are washed with water, dried, and the solvent evaporated. The residue is chromatographed to obtain trans-1-benzamido-2-hydroxy-6-nitroindane. To a solution of the nitroindane (1 part) in a mixture of pyridine (16 parts), 4-dimethylaminopyridine (0.15 parts) and an inert organic solvent such as THF or CH2Cl2, acetyl chloride (1.2 parts) is added dropwise. After several hours, the reaction is treated with cold water and the organic layer separated. The organic solution is washed with cold 1 N HCL, the organic layer dried, and the solvent is evaporated to give trans-1-benzamidoamido-2-acetoxy-6-nitroindane. Processing of this protected indane as in Preparation 2 provides the trans-1-benzamido-2-hydroxy-6-carboxamido-indane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:18][CH3:19])([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1.[Br:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[Br:21][C:22]1[CH:27]=[CH:26][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[N:10]([CH3:11])[C:9](=[O:12])[O:8][C:7]([CH2:18][CH3:19])([C:13]4[S:14][CH:15]=[CH:16][CH:17]=4)[C:6]=3[CH:20]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CCC1(c2cccs2)OC(=O)N(C)c2ccc(N)cc21
Product: CCC1(c2cccs2)OC(=O)N(C)c2ccc(Nc3ccc(Br)cc3)cc21

Procedure:
Prepared 6-amino-4-ethyl-1-methyl-4-thien-2-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one and 4-bromophenyl boronic acid according to the coupling procedure described in Example 1. MS (ESI) m/z 443/445 ([M+H]+); MS (ESI) m/z 441/443 ([M−H]−); Anal. calcd for C21H19BrN2O2S: C, 56.89; H 4.32; N 6.32. Found: C, 56.65; H, 4.09; N, 6.18.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:17]=O.Cl>CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:17]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:19]=[CH:20][C:21]=1[O:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCOc1ccc(C=O)cc1OC
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Product: CCCCOc1ccc(C=C2Oc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Yield: 42.8 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-methoxy-4-butoxybenzaldehyde 1.66 g were dissolved in methanol 60 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for 2.5 hours. After the solution was cooled to room temperature, the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 0.97 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][OH:12].C(S)[CH2:14][S:15]([O-])(=O)=O.[Na+]>CS(C)=O.CO>[OH:12][CH2:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[S:15][CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)c(CO)c1
Reactant: O=S(=O)([O-])CCS
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CSc1ccc([N+](=O)[O-])cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.4 %

Procedure:
To a solution of 4-chloro-3-(hydroxymethyl)nitrobenzene (20 g, 0.10 mol) in DMSO (160 mL) and MeOH (80 mL), MeSNa (8.2 g, 0.12 mol) was added portionwise at 0° C. and the mixture was stirred for 2 h at room temperature. The mixture was poured into ice water (300 mL) and the yellow precipitate was collected by filtration and washed with ether (150 mL) gave the title compound (21 g, quantitative).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][CH2:25][O:26][CH3:27])[N:20]=2)[CH2:11][C:12]([O:14]C(C)(C)C)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][CH2:25][O:26][CH3:27])[N:20]=2)[CH2:11][C:12]([OH:14])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COCCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Product: COCCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
tert-Butyl (3R)-6-cyclohexyl-3-[3-(2-methoxyethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 50) (410 mg, 1.08 mmol) was treated with trifluoroacetic acid (3 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The solvent was removed under reduced pressure and the residue azeotroped from toluene then dichloromethane to afford the title compound (250 mg).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:19]3[NH:18][C:17]4[CH:22]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:23][CH2:24][C:16]=4[C:15]=3[CH:14]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2].[Li+].[OH-].O.Cl>O1CCOCC1>[CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:19]3[NH:18][C:17]4[CH:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:24][C:16]=4[C:15]=3[CH:14]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3cnc(OC(C)C)cn3)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)Oc1cnc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.035 g, 0.135 mmol) and cesium carbonate (0.048 g, 0.148 mmol) were dissolved in DMF (0.5 mL) and stirred at room temperature for 5 min. To this mixture at 0° C. was added a solution of 2-(bromomethyl)-5-isopropoxypyrazine (0.034 g, 0.148 mmol) in DMF (0.20 mL) and was stirred at room temperature for 60 h. The solids were removed by filtration. The filtrate was purified by HPLC to give ethyl 2-(7-((5-isopropoxypyrazin-2-yl)methoxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (11 mg). To the ester dissolved in dioxane (288 μL) was added aqueous LiOH (1 N, 72 μL). The mixture was stirred at room temperature for 16 h; before more aqueous LiOH (1 N, 200 μL) was added. Stirring was continued for 1 h. To the reaction mixture was added water (1.5 mL) and the reaction mixture was acidified to pH 3 with 1 N HCl. The mixture was purified by HPLC to give the title compound as a yellow solid (7 mg). LCMS m/z=382.4 [M+H]+; 1H NMR (500 MHz, CDCl3) δ ppm 1.32 (d, J=6.31 Hz, 6H), 1.95-2.18 (m, 1H), 2.28-2.41 (m, 1H), 2.56-2.79 (m, 4H), 3.36-3.56 (m, 1H), 5.09 (s, 2H), 5.15-5.33 (m, 1H), 6.71 (d, J=8.83 Hz, 1H), 6.94 (s, 1H), 7.20 (d, J=8.83 Hz, 1H), 8.20 (s, 1H), 8.30 (s, 1H), 10.37 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]3)=[CH:23][N:24]=2)[CH:3]=1.[CH3:34][O:35][C:36]1[C:41]([NH:42][S:43]([CH3:46])(=[O:45])=[O:44])=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F.[F-].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>CC(O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:32][C@H:30]1[CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:39]4[CH:40]=[C:41]([NH:42][S:43]([CH3:46])(=[O:44])=[O:45])[C:36]([O:35][CH3:34])=[N:37][CH:38]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][N:8]4[S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])=[N:24][CH:23]=2)[CH2:27][C@@H:28]([CH3:33])[O:29]1
Reactant: C[C@@H]1CN(Cc2cnc(-c3cc(Cl)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@H](C)O1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(C)(=O)=O
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Solvent: O
Product: COc1ncc(-c2cc(-c3ncc(CN4C[C@@H](C)O[C@@H](C)C4)o3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Temperature: 77.5 °C
Reaction time: 0.33 h

Procedure:
((2-(6-Chloro-1-(phenylsulfonyl)-1H-indazol-4-yl)oxazol-5-yl)methyl)-cis-2,6-dimethylmorpholine (1.00 wt, 460 g), N-(2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)methanesulfonamide (0.741 wt, 1.1 eq, 341 g) and potassium phosphate (0.523 wt, 1.2 eq, 241 g) are combined in IPA (5 vol, 2.3 L) and water (5 vol, 2.3 L) in a clean CLR under nitrogen. Potassium hydrogen difluoride (0.353 wt, 2.2 eq, 163 g) is added and the mixture is heated to 75-80° C. and degassed at this temperature for at least 1 hr. In a separate vessel IPA (5 vol, 2.3 L) is degassed by being heated to reflux, then stirred for a further 20 min at this temperature under a flow of N2 before being cooled to 20-25° C. under a nitrogen atmosphere. To the degassed IPA (5 vol, 2.3 L) is charged palladium (II) acetate (0.00922 wt, 0.02 eq, 4.25 g), followed by tricyclohexylphosphine (0.0230 wt, 0.04 eq, 10.6 g) and the mixture stirred at 20-25° C. for at least 0.5 hr. The resultant yellow solution is added to the reaction mixture and stirred at 75-80° C. for at least 2 hr, then monitored for completion by HPLC. The mixture is cooled to 30° C. over 1 hr and water (5 vol, 2.3 L) is added. The slurry is allowed to cool to 20° C., then aged at this temperature for at least 0.5 hr, filtered, washed with IPA:water (1:1 v/v, 2×2 vol, 2×920 ml) and sucked dry. The solid is dried in vacuo at 60° C. to constant probe temperature to afford N-(5-(4-(5-((cis-2,6-dimethylmorpholino)methyl)oxazol-2-yl)-1-(phenylsulfonyl)-1H-indazol-6-yl)-2-methoxypyridin-3-yl)methanesulfonamide as an off-white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]([CH3:29])([CH3:28])[CH:21]([NH2:27])[C:22]1[S:23][CH:24]=[CH:25][N:26]=1>>[CH3:19][C:20]([CH3:29])([CH3:28])[CH:21]([NH:27][C:10]([C:7]1[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])[C:22]1[S:23][CH:24]=[CH:25][N:26]=1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: CC(C)(C)C(N)c1nccs1
Product: CC(C)(C)C(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 24d, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2,2-Dimethyl-1-thiazol-2-yl-propylamine (CAN 1247122-26-4) as starting materials and isolated (15 mg, 32%) as a white solid; MS (ESI, m/z): 414.5 (M+H+).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22][CH2:23][CH:24]([NH2:27])[CH2:25][CH3:26]>>[CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13]([NH:27][CH:24]([CH2:23][OH:22])[CH2:25][CH3:26])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1n[nH]c2c(NCc3ccccc3)nc(Cl)nc12
Reactant: CCC(N)CO
Product: CCC(CO)Nc1nc(NCc2ccccc2)c2[nH]nc(C(C)C)c2n1
Temperature: 120 °C
Yield: 83.5 %

Procedure:
The mixture of 7-benzylamino-5-chloro-3-isopropylpyrazolo[4,3-d]pyrimidine XVI (100 mg, 0.331 mmol) and 2 mL of 1-(R,S)-(hydroxymethyl)propylamine was heated at 120° C. for 3 hours. The reaction mixture was evaporated to dryness in vacuo and then chromatographed on silica gel. The mixture of chloroform/methanol (97/3) was used as a mobile phase. Yield=83.5%; white syrupy; MS (ES+): 355.3 (100%, M+H+). 1H-NMR (400 MHz, CDCl3): 0.96 t (3H, J=7.2 Hz, CH3CH2), 1.299 d (3H, J=7.1 Hz), 1.307 d (3H, J=7.1 Hz), 1.6 m (2H), 3.20 sept (1H, J=7.1 Hz), 3.55-3.80 m (3H), 4.74 bs (2H), 7.22-7.35 m (5H).
Reaction SMILES: [C:1]([CH:4]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH:5]([CH3:9])[CH2:6][C:7]#[N:8])(=O)[CH3:2].C([OH:18])C>>[CH3:9][CH:5]1[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:1]([CH3:2])[NH:8][C:7](=[O:18])[CH2:6]1
Reactant: CC(=O)C(c1ccncc1)C(C)CC#N
Reactant: CCO
Product: CC1=C(c2ccncc2)C(C)CC(=O)N1
Reaction time: 1 h

Procedure:
The same compound was prepared by the following procedure: Into a solution containing 81 g of 4-acetyl-3-methyl-4-(4-pyridinyl)butanenitrile dissolved in 250 ml of absolute ethanol was bubbled hydrogen chloride gas at ambient temperature with no cooling. After about 1 hour, a white solid began to crystallize. The reaction vessel was then stoppered and allowed to stand overnight at room temperature. The reaction mixture was evaporated to dryness in vacuo and the residue was dissolved in a small amount of water. The aqueous solution was made alkaline with concentrated ammonia hydroxide and the mixture was extracted with ethyl acetate. The ethyl acetate solution was dried over anhydrous magnesium sulfate, the mixture filtered and the filtrate evaporated in vacuo. The residue was slurried with acetonitrile and the solid, 5.4 g, was collected. This solid was combined with the product obtained as described in the immediately preceding paragraph along with the product obtained hereinbelow in Example C-3 and the combined material was recrystallized from about 250 ml of acetonitrile to yield 9.9 g of 3,4-dihydro-4,6-dimethyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 186°-188° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH:11]=[C:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24].O>N1C=CC=CC=1>[C:1]([O:10][CH:11]=[C:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=2)[C:13]1=[O:24])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc2c(c1)CCC(=CO)C2=O
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2c(c1)CCC(=COC(=O)c1ccccc1)C2=O
Reaction time: 2 h
Yield: 80 %

Procedure:
Benzoyl chloride (11.4 ml, 0.1 mole) was added to a stirred solution of 2-hydroxymethylene-6-methoxy-1-tetralone 2 (10 g, 0.05 mole) in about 60 mL of pyridine at about 0°. After the addition was complete, the mixture was stirred at about 23° for about 2 hours then poured into water. The solid was filtered and washed with water. The pure product was obtained by recrystallization from methanol to yield 2-benzoyloxymethylene-6-methoxy-1-Tetralone (12.1 g, 0.04 mole, 80% yield), mp 128.5°-129.5°, [Lit. Kieboom et al., Synthesis, 476-478, (1970), mp 130°-130.5°].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[Br:15]Br.Br>C(OCC)(=O)C>[Br:15][CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11](=[O:13])(=[O:14])[NH2:12])[CH:4]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Agent: Br
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl

Procedure:
4.7 g of 4'-chloro-3'-sulfamoylacetophenone were suspended in 50 ml of ethyl acetate and to that suspension, some drops of a solution of 3.2 g of bromine were added until the mixture was distinctly brown. The suspension was heated to about 60°-70° C. until the color changed (addition of a drop of 48% hydrobromic acid possible), cooled and the residual amount of the bromine solution was added dropwise at room temperature, while stirring. After distilling off the solvent, 2-bromo-4'-chloro-3'-sulfamoylacetophenone was obtained which melted at 169° C. (from n-butanol).
Reaction SMILES: C([O:4][C@H:5]([CH3:30])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]([CH3:28])=[N:15][C:14]=2[N:13]([CH3:29])[C:11]1=[O:12])(=O)C.Cl>CO.CCOCC>[CH2:21]([N:17]1[C:18]2[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:30])[C:11](=[O:12])[N:13]([CH3:29])[C:14]=2[N:15]=[C:16]1[CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(nc(C)n2Cc2ccccc2)n(C)c1=O
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: Cc1nc2c(c(=O)n(CCCC[C@@H](C)O)c(=O)n2C)n1Cc1ccccc1
Reaction time: 12 h

Procedure:
A solution of (R)-1(5-Acetoxyhexyl)-7-benzyl-3,8-dimethylxanthine (500 mg) in methanol (20 ml) was treated with 1 M hydrochloric acid in ether (2.5 ml) and stirred for 12 hours. After evaporation of volatiles under reduced pressure, the residue was dissolved in ethyl acetate (100 ml), washed with saturated sodium bicarbonate solution (30 ml), dried over anhydrous magnesium sulfate and concentrated. Yield=420 mg.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:8]=O)[CH3:3].[S:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].NCCC(O)=O>C(O)(=O)C>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[C:22]2[S:16][C:17](=[S:18])[NH:19][C:20]2=[O:21])[CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH3:3]
Reactant: COc1cc(C=O)cc(CN(C)C)c1O
Reactant: O=C1CSC(=S)N1
Agent: NCCC(=O)O
Solvent: CC(=O)O
Product: COc1cc(C=C2SC(=S)NC2=O)cc(CN(C)C)c1O
Yield: 74.5 %

Procedure:
A mixture of 3-[(dimethylamino)methyl]-4-hydroxy-5-methoxybenzaldehyde (2.5 g, 12 mmoles), rhodanine (1.6 g, 12 mmoles), β-alanine (0.6 g, 7 mmoles), and acetic acid (35 ml) is stirred under an inert atmosphere and heated to reflux. After 4 hours the acetic acid is removed by rotary evaporator and the residue dissolved in water (250 ml). The solution is brought to approximate neutrality by addition of saturated aqueous sodium bicarbonate, and stirred for 3 hours. The precipitate is filtered off, rinsed three times with water and dried, then triturated in boiling methanol (100 ml), cooled, filtered off and dried to afford the pure product (2.9 g), mp 198° C. (dec).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[CH:10][CH:9]=1)=O)C.[BH4-].[Li+]>>[OH:3][CH2:4][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:16][CH:15]2[O:27][CH2:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)CCc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
Analogously to the procedure described in Example 22(e), by reducing tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-ethyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate using lithium borohydride there was obtained tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless solid; MS: 476 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[C:4]([CH3:11])[CH:3]=1.[N+:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])([O-:14])=[O:13].C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[CH:15]([N+:12]([O-:14])=[O:13])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:4]([CH3:11])[CH:3]=1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: Cc1cc(Br)ccc1N=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C(=O)Nc1ccc(Br)cc1C)[N+](=O)[O-]
Yield: 25 %

Procedure:
A mixture of 9.22 grams (0.04 mole) of 4-bromo-2-methylphenyl isocyanate, 5.78 grams (0.04 mole) of ethyl nitroacetate, 6.01 grams (0.04 mole) of anhydrous potassium carbonate and 90 milliliters of benzene was stirred and heated under reflux for 3 hours then cooled and stirred at room temperature for a period of about 16 hours. The precipitated material was filtered off and thoroughly triturated with 200 milliliters of ice water, filtering to remove a precipitate which was discarded. Chilling and acidification of the filtrate with concentrated HCl caused precipitation of a yellow-white solid which was collected, water-washed and air-dried. Recrystallization from benzene-cyclohexane (3:1) gave 3.38 grams (0.01 mole) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-2-nitro-3-oxopropanoate as white crystals having a melting point of 126° C.-129° C.