Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[C:9]([F:28])[CH:8]=1)C.[OH-].[Na+]>C1COCC1.C(O)C>[C:21]1(=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:10]2[CH:11]=[CH:12][C:7]([CH:6]=[CH:5][C:4]([OH:29])=[O:3])=[CH:8][C:9]=2[F:28])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)C=Cc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C=Cc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)c(F)c1
Temperature: 65 °C
Yield: 8.3 %

Procedure:
To a solution of 3-{4-[cycloheptylidene-(4-hydroxy-phenyl)-methyl]-3-fluoro-phenyl)-acrylic acid ethyl ester (176) (0.8 g, 2.15 mmol) in THF (10 mL) and ethanol (10 mL) was added 1 N sodium hydroxide (21 mL). The reaction mixture was heated at 65° C. for 2.5 h. The reaction mixture was partially concentrated to remove the EtOH and THF. To the basic aqueous mixture was added 1 N HCl to pH˜1 (according to litmus paper). The acidic aqueous solution was extracted with dichloromethane and the organic extract washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was triturated with dichloromethane, filtered and dried to give 0.065 g (10%) of compound 177 as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 1.51 (b, 8 H), 2.09 (m, 2 H), 2.25 (m, 2 H), 6.52 (d, J=16.1 Hz, 1 H), 6.65 (d, J=8.4 Hz, 2 H), 6.92 (d, J=8.4 Hz, 2 H), 7.19 (t, J=7.8 Hz, 1 H), 7.43-7.49 (m, 1 H), 7.51-7.53 (m, 2 H), 9.32 (s, 1 H), 12.43 (s, 1 H). HRMS (ESI) Calcd for C23H22FO3: 365.1553 (M−H)−. Found: 365.1543.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)N=[CH:3][CH:2]=1.[CH3:15]C1C=CC=CN=1.CC1C=NC=CC=1.CC1C=CN=CC=1>>[CH:9]1[C:8]2[C:7](=[N:6][C:5]3[C:14]([CH:13]=2)=[CH:1][CH:2]=[CH:3][CH:15]=3)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccccn1
Reactant: c1ccc2c(c1)cnc1ncccc12
Solvent: Cc1cccnc1
Solvent: Cc1ccncc1
Product: c1ccc2nc3ccccc3cc2c1

Procedure:
4,5-phenanthroline, 2-methylpyridine; 3-methylpyridine; 4-methylpyridine;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][NH:10][CH2:9]3)=[CH:4][CH:3]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[I:32][C:33]1[C:34](=[O:52])[N:35]([C:44]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:45])[C:36](=[O:43])[N:37]([CH2:39][CH2:40][CH:41]=O)[CH:38]=1>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]23[CH2:13][CH:12]2[CH2:11][N:10]([CH2:41][CH2:40][CH2:39][N:37]2[CH:38]=[C:33]([I:32])[C:34](=[O:52])[N:35]([C:44]([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:45])[C:36]2=[O:43])[CH2:9]3)=[CH:6][CH:7]=1
Reactant: Clc1ccc(C23CNCC2C3)cc1
Reactant: O=CCCn1cc(I)c(=O)n(C(=O)c2ccccc2)c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCN2CC3CC3(c3ccc(Cl)cc3)C2)c1=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
1-(4-chlorophenyl)-3-azabicyclo[3.1.0]hexane (racemate, reference procedure for preparation reported in WO2005/080382, 136 mg, 0.703 mmol), acetic acid (0.060 mL, 1.055 mmol), and sodium triacetoxyborohydride (164 mg, 0.774 mmol) were added at 0° C. to a solution of 3-[5-iodo-2,4-dioxo-3-(phenylcarbonyl)-3,4-dihydro-1(2H)-pyrimidinyl]propanal (P38, 280 mg, 0.703 mmol) in 1,2-Dichloroethane (DCE) (8.7 ml). The mixture was stirred at 0° C. for further 4 hours. Water was added and the reaction mixture was concentrated removing the solvent under vacuum. The residue was re-dissolved in ethyl acetate and the organic layer washed with aqueous saturated NaHCO3 solution. The aqueous solution was extracted with ethyl acetate (3×20 ml). The organic layers were collected, dried over Na2SO4, filtrated and evaporated. The crude was purified by chromatography (SPE Si 10 g) with toluene/acetone 8/2. The title compound was recovered as a light yellow oil (190 mg).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[C:11]1([C:17](=O)[CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C.ClCCl.CO.N>[Br:2][C:3]1[CH:8]=[C:7]2[C:6](=[CH:5][CH:4]=1)[NH:9][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[C:18]2[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(CCCN1CCCCC1)c1ccccc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: Brc1ccc2[nH]c(-c3ccccc3)c(CCN3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.5 %

Procedure:
4-Bromophenylhydrazine hydrochloride (1.45 g, 6.5 mmol) and 1-phenyl-4-(1-piperidinyl)butan-1-one (1.50 g, 6.5 mmol) were dissolved in ethanol (10 ml) and stirred at 25° C. for 4 hours. The solid was filtered and washed with ethanol and ether. The white product was dissolved in trifluoroacetic acid (10 ml) and heated at 70° C. for 2 hours. The reaction mixture was basified with saturated potassium carbonate solution and extracted into ethyl acetate. The organic phase was washed with brine, dried (sodium sulphate) and evaporated to give a yellow oil. Chromatography on silica gel with dichloromethane-methanol-ammonia (98:2:0.2) as eluent yielded the title compound (0.51 g, 20%) as a white solid. Oxalate salt, white crystals, mp 121-122° C. (from methanol/ether) (Found: C, 58.07; H, 5.23; N, 6.01. C21H23BrN2. C2H2O4. 0.1H2O requires C, 58.14; H, 5.35; N, 5.90%); δH (360 MHz, dG-DMSO) 1.5-1.6 (2H, m, piperidine H-4), 1.7-1.8 (4H, m, piperidine H-3), 3.1-3.3 (8H, m, CH2), 7.2 (1H, dd, J 2 and 8, indole H-6), 7.3 (1H, d, J 8, indole H-7), 7.4 (1H, t, J 7, Ar H-4), 7.5 (2H, t, J 7, Ar H-3), 7.6 (2H, d, J 7, Ar H-2), 7.8 (1H, ds, J 2, indole H-4), 11.6 (1H, br s, indole NH); m/z (ES+) 383 ( M++H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:27])[CH:5]([N:11]=[C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[OH:20])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([N:11]=[C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[O:20][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:27])[CH3:10]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1O)C(=O)OCC
Solvent: c1ccncc1
Product: CCOC(=O)C(N=C(c1ccccc1)c1cc(Cl)ccc1OC(=O)c1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 7.8 g. of [(5-chloro-2-hydroxy-α-phenylbenzyliden)amino] malonic acid diethyl ester in 15 ml. of pyridine is treated at 10°-15° C. with 3.5 ml. of benzoyl chloride. The mixture is stirred at room temperature for 1 hour and then poured on to 150 ml. of ice-water. The separated oil product is extracted with ehter and the organic phase washed with water, then with 2-N sodium carbonate solution and finally with water. After drying over sodium sulfate and evaporation of the solvent, the oily residue is triturated with hexane, crystallization setting in. There is obtained [(2-benzoyloxy-5-chloro-α-phenylbenzyliden)amino] malonic acid diethyl ester in the form of colorless crystals, having a melting point of 108°-110° C. Recrystallization from ethanol increases the melting point to 109°-111° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24](B3OC(C)(C)C(C)(C)O3)[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:44]1[CH:45]=[C:46]([Si:52]([CH3:55])([CH3:54])[CH3:53])[C:47](=[O:51])[N:48]([CH3:50])[N:49]=1.IC1C=C([Si](C)(C)C)C(=O)N(C)N=1>>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:27]=[CH:26][CH:25]=[C:24]([C:44]3[CH:45]=[C:46]([Si:52]([CH3:54])([CH3:53])[CH3:55])[C:47](=[O:51])[N:48]([CH3:50])[N:49]=3)[C:18]=1[CH2:19][O:20][C:21](=[O:23])[CH3:22])[N:9]=[CH:8]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1nc(Cl)cc([Si](C)(C)C)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: Cn1nc(I)cc([Si](C)(C)C)c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(=O)OCc1c(-c2cc([Si](C)(C)C)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reaction time: 5.5 h
Yield: 71 %

Procedure:
In round bottom flask was placed 3.21 g acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester, 2.06 g sodium carbonate, 0.68 g bistriphenylphosphine palladium dichloride, and 1.99 g a 6:4 mixture of 6-chloro-2-methyl-4-trimethylsilanyl-2H-pyridazin-3-one and 6-iodo-2-methyl-4-trimethylsilanyl-2H-pyridazin-3-one followed by 130 mL of dioxane (EM DriSolv)-water (10:1). The mixture was vacuum flushed 5× argon, then set in a bath at 95° C. and stirred (mechanical). After 5.5 hours, the mixture was cooled, taken up in 350 mL of ethyl acetate and washed 1×75 mL of brine. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (Silicycle 120 g, 3.5×21.5 cm, 207 vol), applied in dichloromethane eluting with CH2Cl2-ethyl acetate (80:20), followed by chromatography on silica gel (Silicycle 120 g, 3.5×21.5 cm, 207 vol), applied in dichloromethane, eluting with dichloromethane-ethyl acetate (80:20) afforded 2.5418 g (71%) of product as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][S:10][C:11]#[N:12])=[CH:4][C:3]=1[F:14].[BrH:15]>>[Br:15][C:11]1[S:10][CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([F:14])[CH:4]=2)[N:12]=1
Reactant: N#CSCC(=O)c1ccc(Cl)c(F)c1
Reactant: Br
Product: Fc1cc(-c2csc(Br)n2)ccc1Cl
Yield: 68 %

Procedure:
In the same manner as described in step 5 of Example 78, using 1-(4-chloro-3-fluoro-phenyl)-2-thiocyanato-ethanone (2.45 g, 10.7 mmol), prepared in the previous step, and hydrogen bromide (30% in acetic acid, 16 mL), the solid was collected by suction filtration to give 2-bromo-4-(4-chloro-3-fluorophenyl)-1,3-thiazole (2.1 g, 68%). The material was used without further purification, MS (ES) m/z 293[M+H+].
Reaction SMILES: O.[C:2]([OH:6])(=[O:5])[CH:3]=O.Cl.N1CCOCC1.O.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH:24]=[O:25])=[CH:19][CH:18]=1>O1CCOCC1>[OH:25][CH:24]1[O:6][C:2](=[O:5])[CH:3]=[C:23]1[C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1
Reactant: O=CC(=O)O
Reactant: COc1ccc(CC=O)cc1
Agent: Cl
Solvent: C1COCCN1
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C2=CC(=O)OC2O)cc1
Yield: 97.8 %

Procedure:
A suspension of glyoxalic acid hydrate (2.45 g, 26.6 mmol) and morpholine hydrochloride (3.28 g, 26.35 mmol) in dioxane (25 mL) was stirred as water (2 mL) was added. The homogeneous solution and 4-methoxyphenyl acetaldehyde (3.8 g, 25.3 mmol) was then added and the solution was stirred at reflux for 24 h. The solvent was evaporated and a solid was formed after addition of 20 mL of water. The solid was collected and washed with water to give 5.1 g (98%) of the product: MS m/z 189 (M−17+H).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:29]#[N:30])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH:14]=2)=[O:9])C.O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][C:15]2[CH:14]=[C:13]3[C:18]([C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:31])([CH3:32])[C:4]([OH:33])=[O:3])=[O:9])[N:11]=[C:12]3[C:29]#[N:30])=[CH:17][CH:16]=2)=[CH:27][CH:26]=1
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc(Cl)cc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccc(Cl)cc3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3-{[7-(4-Chloro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid ethyl ester (20 mg, 0.04 mmol) was dissolved in MeOH (4 mL) and 2 N NaOH (4 mL). After stirring for 5 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 11 mg. MS: (−) m/z 437.95 (M−1).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[O:23])[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4].[Cl-].[NH4+]>C1COCC1.CO>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][CH2:21][CH:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])[OH:23])[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4]
Reactant: CCOc1ccc(-c2nc(CCC(=O)c3ccccc3OC)cs2)cc1OCC
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1ccc(-c2nc(CCC(O)c3ccccc3OC)cs2)cc1OCC
Reaction time: 1 h
Yield: 73.2 %

Procedure:
Sodium borohydride (20 mg, 0.53 mmol) was added to a mixed solution of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)-1-propanone (458 mg, 1.11 mmol) in THF (10 ml) and methanol (10 ml) at room temperature, and the resulting mixture was stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1). The solvent was distilled off under reduced pressure, and the residue was recrystallized from a diethyl ether/n-hexane mixed solvent, to thereby obtain 336 mg (yield: 73%) of 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]-1-(2-methoxyphenyl)-1-propanol as a white powder.
Reaction SMILES: CC(O)C.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([C:21]2[N:22]=[C:23]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:24]3[CH:29]=[CH:28][N:27]=[C:26](Cl)[C:25]=23)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH3:35]>C(Cl)Cl>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([C:21]2[N:22]=[C:23]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[N:24]3[CH:29]=[CH:28][N:27]=[C:26]([NH2:35])[C:25]=23)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N
Reactant: COc1ccc(-c2nc(C3CCC3)n3ccnc(Cl)c23)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: CC(C)O
Product: COc1ccc(-c2nc(C3CCC3)n3ccnc(N)c23)cc1OCc1ccccc1
Temperature: 110 °C

Procedure:
An iPrOH (5 ml)/DCM (4 ml) solution of 1-(3-benzyloxy-4-methoxyphenyl)-8-chloro-3-cyclobutylimidazo[1,5-a]pyrazine (290 mg, 87%, 0.601 mmol), cooled to −78° C. in a dry ice/acetone bath, was charged with liquid NH3 for 15 min. The sealed tube was equipped with a Teflon washer, sealed and heated 110° C. for 14 h. After that time, the excess NH3 and the solvent were evaporated. The remaining material was purified by chromatography on silica gel to obtain the title compound as a brown oil. The impurities that could not be removed by conventional methods (eg. TLC, HPLC etc.), were removed by SCX column (washed with 7 ml of DCM, 7 ml of MeOH and 7 ml of 2 N NH3 in MeOH); 1H NMR (CDCl3, 400 MHz) δ 2.00-2.24 (m, 2H), 2.42-2.66 (m, 4H), 3.78 (quintet, 1H, J=8.4 Hz), 3.95 (s, 3H), 4.95 (brs, 2H), 5.23 (s, 2H), 6.98-7.02 (m, 2H), 7.07 (d, 1H, J=5.2 Hz), 7.17 (d, 1H, J=2.0 Hz), 7.23 (dd, 1H, J=2.0 and 8.0 Hz), 7.29-7.45 (m, 5H); MS (ES): 401.1 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:28][C:29]([O:31][CH3:32])=[O:30])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)COc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 100 °C
Yield: 27 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (30 mg, 0.11 mmol), potassium carbonate (31 mg, 0.23 mmol) and methyl bromoacetate (16 μL, 0.17 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 100° C. for 2 hours. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 3.5:0.5:4 followed by trituration with diethyl ether afforded 10 mg (26%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-methoxy-2-oxoethoxy) phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.87 (d, 1H), 8.23 (d, 1H), 8.22 (s, 1H), 8.01 (s, 1H), 7.92 (t, 1H), 7.50 (t, 1H), 7.42 (s, 1H), 4.81 (s, 2H), 3.86 (s, 3H).
Reaction SMILES: [CH3:1][O:2][NH2:3].C([O-])(=O)C.[Na+].S([O-])([O-])(=O)=O.[Mg+2].[CH3:15][O:16]/[N:17]=[C:18](/[C:22]1([CH3:28])[O:27][CH2:26][CH2:25][CH2:24][O:23]1)\[C:19](=O)[CH3:20].[OH-].[Na+]>CO.O>[CH3:15][O:16][N:17]=[C:18]([C:22]1([CH3:28])[O:27][CH2:26][CH2:25][CH2:24][O:23]1)[C:19](=[N:3][O:2][CH3:1])[CH3:20]
Reactant: CON
Reactant: CO/N=C(\C(C)=O)C1(C)OCCCO1
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CO
Product: CON=C(C)C(=NOC)C1(C)OCCCO1
Reaction time: 0.17 h
Yield: 89 %

Procedure:
239 g (0.4 mol) of 14% strength methanolic methoxyamine solution, 50 g (0.6 mol) of sodium acetate (anhydrous), dissolved in 250 ml of methanol, 75 g of magnesium sulfate and 92 g of the ketal (Example 3), dissolved in 100 ml of methanol, were initially charged at room temperature. The pH meter showed a value of 6. The mixture was stirred for 10 minutes, during which the pH decreased to 5.2, and a pH of 4.2 was set by dropwise addition of sodium acetate. The mixture was stirred at room temperature for another 20 hours and the conversion was monitored by HPLC. 7% of starting material was left. After a further 4 hours of stirring, the reaction mixture was neutralized using dilute aqueous sodium hydroxide solution and diluted with water. The mixture was extracted with methyl tert-butyl ether. The combined organic phases were washed with dilute ammonium chloride solution, dried over magnesium sulfate and concentrated. This gave 92 g (89% yield) of the title compound.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([CH:23]=O)=[C:16]3[N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2].[NH:25]1[CH2:31][C:29](=[O:30])[NH:28][C:26]1=[O:27].N1CCCCC1>CCO>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([CH:23]=[C:31]4[NH:25][C:26](=[O:27])[NH:28][C:29]4=[O:30])=[C:16]3[N:15]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)Cc1cccc(Nc2ccn3ncc(C=C4NC(=O)NC4=O)c3n2)c1
Temperature: 70 °C

Procedure:
To 5-(3-((diethylamino)methyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (10 mg, 0.031 mmol) in EtOH was added hydantoin (3 mg, 0.031 mmol) and piperidine (3 μL, 0.031 mmol). The mixture was heated at 70° C. overnight. The product was purified by HPLC to yield 5-((5-(3-((diethylamino)methyl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=406)
Reaction SMILES: [C:1]([CH:5]([CH3:21])[CH2:6][CH2:7][CH2:8][C:9]1([CH3:20])[CH:15]2[O:16][C:12]([CH2:17][CH2:18]O)([CH2:13][CH2:14]2)[CH2:11][O:10]1)([O:3][CH3:4])=[O:2].CS(OCCCC1(C)C2OC(CCO)(CC2)CO1)(=O)=O>>[C:1]([CH:5]([CH3:21])[CH2:6][CH2:7][CH2:8][C:9]1([CH3:20])[CH:15]2[O:16][C:12]([CH:17]=[CH2:18])([CH2:13][CH2:14]2)[CH2:11][O:10]1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C(C)CCCC1(C)OCC2(CCO)CCC1O2
Agent: CC1(CCCOS(C)(=O)=O)OCC2(CCO)CCC1O2
Product: C=CC12CCC(O1)C(C)(CCCC(C)C(=O)OC)OC2

Procedure:
Following the procedure for the preparation of (1RS,4SR,5RS)-4-(4-carbomethoxypentyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol, but substituting (1RS,4SR,5RS)-4-(3-methanesulfonyloxypropyl)-4-methyl-1-vinyl-3,8-dioxabicyclo[3.2.1]octane for (1RS,4SR,5RS)-4-(3-methanesulfonyloxypropyl)-4-methyl-3,8-dioxabicyclo[3.2.1]octane-1-ethanol, (1RS,4SR,5RS)-4-(4-carbomethoxypentyl)-4-methyl-1-vinyl-3,8-dioxabicyclo[3.2.1]octane is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[CH2:7][C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[Se](=O)=[O:37]>>[CH3:1][O:2][C:3]1[C:33]([O:34][CH3:35])=[CH:32][C:6]2[C:7](=[O:37])[C:8](=[O:31])[N:9]([CH2:12][CH2:13][CH2:14][N:15]([CH3:30])[CH2:16][CH2:17][CH2:18][S:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1ccc(SCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3CC2=O)cc1OC
Reactant: O=[Se]=O
Product: COc1ccc(SCCCN(C)CCCN2CCc3cc(OC)c(OC)cc3C(=O)C2=O)cc1OC

Procedure:
The title compound is prepared from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-N-[3-(3,4-dimethoxy-phenylthio)-propyl]-methylamine and selenium dioxide analogously to Example 55.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]3[C:15]([CH3:23])([C:20]([NH2:22])=[O:21])[CH2:16][C:17]([CH3:19])([CH3:18])[C:11]3=[C:10]2[CH3:24])[CH:6]=[CH:7][CH:8]=1.C(OO)=[O:26]>CC(C)=O>[CH3:1][S:2]([C:3]1[CH:4]=[C:5]([N:9]2[C:13]([CH3:14])=[C:12]3[C:15]([CH3:23])([C:20]([NH2:22])=[O:21])[CH2:16][C:17]([CH3:19])([CH3:18])[C:11]3=[C:10]2[CH3:24])[CH:6]=[CH:7][CH:8]=1)=[O:26]
Reactant: O=COO
Reactant: CSc1cccc(-n2c(C)c3c(c2C)C(C)(C(N)=O)CC3(C)C)c1
Solvent: CC(C)=O
Product: Cc1c2c(c(C)n1-c1cccc(S(C)=O)c1)C(C)(C(N)=O)CC2(C)C

Procedure:
Reaction of the 2-(3-methylmercaptophenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta[c]pyrrole-4-carboxamide described above in Example 1CK with one molar equivalent of performic acid in acetone at room temperature affords 2-(3-methylsulfinylphenyl)-2,4,5,6-tetrahydro-1,3,4,6,6-pentamethylcyclopenta [c]pyrrole-4-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[NH:14][N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[N:26]=[C:27]=[O:28]>CN(C=O)C>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:20]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=3[F:18])=[O:28])=[CH:7][CH:6]=2)[NH:14][N:15]=1
Reactant: Nc1ccc(-c2cncc3[nH]nc(N)c23)cc1
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3cncc4[nH]nc(N)c34)cc2)c1
Reaction time: 16 h

Procedure:
The product from Example 1D (50 mg, 0.22 mmol) in DMF (1 mL) was treated with 1-fluoro-2-isocyanato-4-methyl-benzene (0.03 mL, 0.22 mmol) and stirred for 16 hours. The crude product was directly purified via preparative HPLC on an Agilent Zorbax Stablebond C-18 (7 micron particle size) preparative column using a solvent gradient of 30% to 100% acetonitrile in 0.1% aqueous TFA at a flow rate of 15 mL/minute. The product was further purified via silica gel chromatography eluting with 5% methanol/CH2Cl2 to provide 4 mg ofthe title compound. MS (ESI(+)) m/e 377 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 4.61 (s, 2H) 6.77-6.85 (m, 1H) 7.12 (dd, J=11.53, 8.14 Hz, 1H) 7.49 (d, J=8.81 Hz, 2H) 7.63 (d, J=8.48 Hz 2 H) 7.94 (s, 1H) 8.01 (dd, J=8.31, 1.86 Hz, 1H) 8.55 (d, J=2.71 Hz, 1H) 8.73 (s, 1H) 9.24 (s, 1H) 12.26 (s, 1H).