Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)/[C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:38][CH:39]1[C:65](=[O:66])[N:41]2[C:42]([C:53]([O:55][CH2:56][C:57]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][CH:58]=3)=[O:54])=[C:43](/[CH:46]=[CH:47]\[C:48]3[N:49]=[N:50][S:51][CH:52]=3)[CH2:44][S:45][C@H:40]12.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][O:33]2)/[C:27]([NH:38][CH:39]2[C:65](=[O:66])[N:41]3[C:42]([C:53]([O:55][CH2:56][C:57]4[CH:58]=[CH:59][C:60]([O:63][CH3:64])=[CH:61][CH:62]=4)=[O:54])=[C:43](/[CH:46]=[CH:47]\[C:48]4[N:49]=[N:50][S:51][CH:52]=4)[CH2:44][S:45][C@H:40]23)=[O:28])[N:25]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)/C(=N\OC1CCCCO1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: COc1ccc(COC(=O)C2=C(/C=C\c3csnn3)CS[C@@H]3C(N)C(=O)N23)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(COC(=O)C2=C(/C=C\c3csnn3)CS[C@@H]3C(NC(=O)/C(=N\OC4CCCCO4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 35.5 %

Procedure:
(Z)-2-(2-tritylaminothiazol-4-yl)-2-tetrahydropyranyloxyiminoacetic acid (0.39 g, 0.76 mmol) and p-methoxybenzyl 7-amino-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (1.33 g, 0.76 mmol) were dissolved in methylene chloride (10 ml) and stirred at room temperature for 12 hours by addition of DCC (0.18 g, 0.87 mmol). Insolubles were filtered and then the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography thereby p-methoxybenzyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-tetrahydropyranyloxyiminoacetamido]-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (0.25 g) was obtained as a light yellow powder compound.
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:41])([F:40])[F:39])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH2:46])[N:32]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:30][C:31]1[C:36]([C:37](=[O:42])[C:38]([F:39])([F:41])[F:40])=[CH:35][CH:34]=[C:33]([NH:43][CH2:44][CH2:45][NH:46][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:4]=2)[N:32]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Reactant: NCCNc1ccc(C(=O)C(F)(F)F)c(N)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C(=O)C(F)(F)F)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
250 mg (0.59 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]-triazolo[1,5-c]pyrimidine hydrochloride (Example 40A), 201 mg (0.71 mmol) of 1-{2-amino-6-[(2-aminoethyl)amino]pyridin-3-yl}-2,2,2-trifluoroethanone hydrochloride (Example 13A) and 0.615 ml (3.5 mmol) of N,N-diisopropylethylamine were initially charged in 4 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 210 mg (56% of theory) of the product as a solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][NH2:17].[BH4-].[Na+]>CO>[CH2:1]([O:3][CH:4]([O:13][CH2:14][CH3:15])[C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:17][CH3:16])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CN
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOC(OCC)c1ccc(CNC)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 98.5 %

Procedure:
A mixture of 4-(diethoxymethyl)benzaldehyde (1.04 g, 5 mmol) and methylamine (27-32% solution in methanol, 2.3 g, 20 mmol) in methanol (20 mL) was stirred at room temperature for 40 mins. The mixture was cooled to 0° C., sodium borohydride (0.284 g, 7.5 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature for 4 hr. Methanol was removed under reduced pressure. The residue was partitioned between water (50 mL) and ethyl acetate (50 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude 1-(4-(diethoxymethyl)phenyl)-N-methylmethanamine (1.1 g) as a light yellow oil which was used in the next step without further purification. LC-MS (ESI) m/z: 224(M+1)+.
Reaction SMILES: [F:1][C:2]1([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[N+:24]([O-])=O)[C:15]2=[O:27])[CH2:7][CH:6]([O:8][C:9](=[O:11])[CH3:10])[C:5](=[O:12])[NH:4][C:3]1=[O:13]>CO.[Pd]>[NH2:24][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:21]=1[C:22](=[O:23])[N:14]([C:2]1([F:1])[CH2:7][CH:6]([O:8][C:9](=[O:11])[CH3:10])[C:5](=[O:12])[NH:4][C:3]1=[O:13])[C:15]2=[O:27]
Reactant: CC(=O)OC1CC(F)(N2C(=O)c3cccc([N+](=O)[O-])c3C2=O)C(=O)NC1=O
Agent: [Pd]
Solvent: CO
Product: CC(=O)OC1CC(F)(N2C(=O)c3cccc(N)c3C2=O)C(=O)NC1=O

Procedure:
A solution of 3-fluoro-3-(4-nitro-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (1.0 g, 2.6 mmol) and Pd/C (10%, 0.19) in methanol (100 mL) is shaken under hydrogen (50-60 psi) for 3 hours. The suspension is filtered through a pad of Celite and washed with methanol to give 3-(4-amino-1,3-dioxoisoindolin-2-yl)-3-fluoro-2,6-dioxo-5-acetoxypiperidine which is further purified by column chromatography.
Reaction SMILES: Cl[CH:2]([CH:8]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[SH:10][C:11]1[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][N:12]=1.[OH-].[K+]>C(O)C>[CH2:6]([O:5][C:3]([C:2]1[S:10][C:11]2[N:12]=[CH:13][CH:14]=[CH:15][C:16]=2[NH:17][CH:8]=1)=[O:4])[CH3:7]
Reactant: Nc1cccnc1S
Reactant: CCOC(=O)C(Cl)C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=CNc2cccnc2S1
Temperature: 50 °C

Procedure:
4.8 g of ethyl α-chloro-formylacetate, dissolved in 70 ml of ethanol, are added to a solution of 4 g (0.0317 mole) of 2-mercapto-3-aminopyridine and 1.78 g (0.0317 mole) of potassium hydroxide in 200 ml of ethanol at 25° C. under nitrogen. The mixture is warmed at 50° C. for 1 hour, the ethanol is then stripped off in vacuo and the residue is chromatographed on silica gel with methylene chloride/methanol (95:5) as the mobile phase. Yield: 3.3 g (47% of theory) Melting point: 194°-195° C.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[CH:29]=[CH:28][S:27][CH:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1)=[O:5].[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[O:33]1[CH2:34][CH2:35][N:30]([C:36]([O:1][C:2]2[CH:24]=[CH:23][C:22]([C:25]3[CH:29]=[CH:28][S:27][CH:26]=3)=[CH:21][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[C:11]([C:13]([F:15])([F:14])[F:16])[CH:10]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:8]=2)=[O:5])=[O:37])[CH2:31][CH2:32]1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccsc2)ccc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccsc2)ccc1OC(=O)N1CCOCC1
Yield: 92.7 %

Procedure:
Using 2-hydroxy-5-(3-thienyl)-N-[3,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=2[O:17][CH3:18])[CH:5]=[CH:6][CH:7]=1.[CH2:20](C([Sn])=C(CCCC)CCCC)[CH2:21]CC>O1CCOCC1>[CH3:18][O:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:20]=[CH2:21])[C:3]1=[O:19]
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(Br)c1=O
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Solvent: C1COCCO1
Product: C=Cc1cccn(-c2ccc([N+](=O)[O-])cc2OC)c1=O

Procedure:
100 g (308 mmol) of the compound from Example 28A are dissolved in 1.4 l of anhydrous dioxane, and 8.9 g (7.7 mmol) of tetrakis(triphenylphospine)palladium and 117 g (370 mmol) of tributylvinyltin are added. The mixture is heated at reflux for 16 h. The reaction solution is then allowed to cool and filtered through kieselguhr. The filtrates are concentrated to dryness under reduced pressure. The residue is chromatographed on silica gel using a gradient of cyclohexane and ethyl acetate. The product-containing fractions are combined and concentrated to dryness under reduced pressure. Petroleum ether is added until crystallization sets in. The crystals are filtered off and dried under reduced pressure. This gives 37 g (41% of theory) of the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3]1.Br[CH2:36][C:37]1[CH:45]=[C:44]2[C:40]([C:41]([CH3:53])([CH3:52])[C:42](=[O:51])[N:43]2[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=1>>[CH3:27][O:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[CH2:19][O:18][CH2:17][CH2:16][CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:3][CH:2]2[O:1][CH2:36][C:37]2[CH:45]=[C:44]3[C:40]([C:41]([CH3:53])([CH3:52])[C:42](=[O:51])[N:43]3[CH2:46][CH2:47][CH2:48][O:49][CH3:50])=[CH:39][CH:38]=2)=[CH:9][CH:10]=1
Reactant: COCCCN1C(=O)C(C)(C)c2ccc(CBr)cc21
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN1C(=O)C(C)(C)c2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
Analogously to Method D, 0.853 g of tert-butyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)-propoxy]phenyl}piperidine-1-carboxylate and 0.504 g of 6-bromomethyl-1-(3-methoxypropyl)-3,3-dimethyl-1,3-dihydroindol-2-one are reacted. The title compound Is obtained as a slightly yellowish oil. Rf=0.14 (1:1 EtOAc-heptane); Rt=6.13.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:38])[CH2:7][CH2:8][N:9]([C:16]([C:18]1[CH:37]=[CH:36][C:21]2[N:22]([CH3:35])[C:23]([CH2:25][NH:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]#[N:34])=[CH:29][CH:28]=3)=[N:24][C:20]=2[CH:19]=1)=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)C>C(O)C.O>[C:33]([C:30]1[CH:31]=[CH:32][C:27]([NH:26][CH2:25][C:23]2[N:22]([CH3:35])[C:21]3[CH:36]=[CH:37][C:18]([C:16]([N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=4)[CH2:8][CH2:7][C:6]([OH:38])=[O:5])=[O:17])=[CH:19][C:20]=3[N:24]=2)=[CH:28][CH:29]=1)#[N:34]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCC(=O)O)c3ccccn3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of sodium hydroxide (50.0 mmol) in 500 mL ethanol and 50 mL water was added 3-({2-[(4-Cyano-phenylamino)-methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-propionic acid ethyl ester (41.4 mmol). The mixture was stirred at room temperature for three hours, then ca. 350 mL ethanol were distilled off, ca. 100 mL water was added and the pH was adjusted to 6. Then diethylether (50 mL) was added and the mixture stirred over night. The product was isolated by filtration and used without further purification.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][N:14]=1>C(#N)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: O=C(CBr)c1ccc(O)cc1
Reactant: Nc1ccc(Br)cn1
Solvent: CC#N
Product: Oc1ccc(-c2cn3cc(Br)ccc3n2)cc1
Temperature: 105 °C
Yield: 83.2 %

Procedure:
2.15 g (corresponding to 10.0 mmol) of 2-bromo-4′-hydroxyacetophenone and 1.74 g (corresponding to 10.0 mmol) of 2-amino-5-bromopyridine were dissolved in 50 mL of acetonitrile. The resulting solution was refluxed in an oil bath at 105° C. for 6 hours. After the completion of the reaction, the reaction solution was cooled down to room temperature, and precipitates were filtered and recovered. The precipitates were washed with acetonitrile, and dried under reduced pressure. The resulting crude crystals were suspended in a mixed solution of 20 mL of water and 20 mL of methanol, and then supplemented with about 25 mL of a saturated sodium hydrogencarbonate solution and sonicated for 5 minutes using an ultrasonic washing machine. Precipitates were filtered and recovered from the resulting mixture, sufficiently washed with water, and dried under reduced pressure, to obtain 2.41 g (corresponding to 8.32 mmol) of 6-bromo-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine (FIG. 8, Step 2).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH:18]=[CH:17][CH:16]=[C:14]([OH:15])[CH:13]=1)[OH:12].B(F)(F)F.CCOCC>CC([O-])=O.[Na+]>[OH:12][C:11]1[CH:13]=[C:14]([OH:15])[CH:16]=[CH:17][C:18]=1[C:8](=[O:10])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: Oc1cccc(O)c1
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: O=C(Cc1ccccc1)c1ccc(O)cc1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
Phenylacetic acid (0.82 g, 6 mmol), resorcinol (0.66 g, 6 mmol), and boron trifloride etherate (4 ml, 33 mmol) were mixed together and heated to 80° C. under argon. The mixture was then poured into 10% NaOAc (100 ml) and after standing for two hours a brown solid precipitate formed. This was purified by flash chromatography to give the required compound as a white solid (1.19 g, 87%); Rf 0.5 hexane/ethyl acetate (70/30).
Reaction SMILES: [Br:1]Br.[OH:3][C:4]1[CH:5]=[C:6]([C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[CH:10][C:11]=1[OH:12])[CH:7]=[O:8]>C(O)(=O)C.O>[Br:1][C:10]1[C:9]([CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:6]([CH:5]=[C:4]([OH:3])[C:11]=1[OH:12])[CH:7]=[O:8]
Reactant: COC(=O)Cc1cc(O)c(O)cc1C=O
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Cc1c(C=O)cc(O)c(O)c1Br
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Bromine (192 μl) was added to a suspension of 3,4-dihydroxy-6-(methoxycarbonylmethyl)benzaldehyde (0.79 g) in acetic acid (15 ml). The reaction mixture was stirred at ambient temperature for 5-6 hours, diluted with water (30 ml) and extracted into ethyl acetate (200 ml). The organic phase was washed with NaHCO3, water (100 ml) and brine, dried and evaporated under reduced pressure to give a brown solid. This was purified by chromatography using aqueous acetonitrile mixtures to give 3-bromo-4,5-dihydroxy-2-(methoxycarbonylmethyl)benzaldehyde (300 mg); NMR (DMSO-d6) 3.61(s,3H); 4.24(s,2H); 7.24(s,1H); 9.8(s,1H): CI M/S (M+H)+ 291.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24](O)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[O:27]=[C:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([N:32]3[CH2:31][CH2:30][NH:29][C:28](=[O:27])[CH2:33]3)=[O:25])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: O=C1CNCCN1
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: ClCCl
Product: O=C1CN(C(=O)Cn2nc(-c3ccccc3)c3c(Cl)c(-c4ccccc4)nnc32)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (111 mg, 0.3 mmol) in CH2Cl2 (2 mL) were added 2-oxopiperazine (33 mg, 0.33 mmol), diisopropylethylamine (DIPEA) (80 μL, 0.45 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (130 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 2 h then diluted with CH2Cl2. The organic phase was washed with aqueous water, dried over MgSO4, filtered and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 20 to 100% ethyl acetate/isohexane, then 0 to 100% ethyl acetate/acetone) followed by preparative HPLC yielding Compound 69 as a brown solid (69.7 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.P(=O)(O)(O)[OH:11].Cl[O-].[Ca+2].Cl[O-]>>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([OH:11])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: O=P(O)(O)O
Agent: [Ca+2]
Agent: [O-]Cl
Product: Cc1ccc(C(=O)O)cc1

Procedure:
In the like manner as Example 1, 23.6 g of p-methylbenzaldehyde as an aldehyde and 3 g of phosphoric acid were used. The oxidation was done by using 23 g of calcium hypochlorite at temperatures of -5° to -3° C., which was followed by refining to obtain p-methylbenzoic acid.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][C:22]#[CH:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([O:17][CH2:23][C:22]#[CH:21])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nn(-c2cc(O)c(Cl)cc2F)c(=O)o1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCOc1cc(-n2nc(C(C)(C)C)oc2=O)c(F)cc1Cl
Yield: 96.4 %

Procedure:
Reacted at 80° C. for 6 hours with stirring were 1.2 g of 5-t-butyl-3-(4-chloro-2-fluoro-5-hydroxyphenyl)-1,3,4-oxadiazol-2-one, 0.76 g of 3-bromopropyne, 40 ml of acetonitrile, and 0.3 g of potassium carbonate. After cooling, the reaction product was filtered and the filtrate was subjected to vacuum distillation to remove the solvent. To the residue was added 30 ml of methylene chloride, and the solution was washed with a 5% aqueous solution of sodium hydroxide and then with water. Upon removal of the solvent by distillation, 1.31 g of 5-t-butyl-3-(4-chloro-2-fluoro-5-propargyloxyphenyl)-1,3,4-oxadiazol-2-one was obtained. Upon recrystallization from n-hexane, a compound having a melting point of 72°-73° C. was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([OH:19])=O)[C:10](=[O:22])[CH:9]=2)[CH:7]=1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]2[N:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[NH:31][C:30]=2[CH:39]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:23]#[N:24])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH3:21])[C:17]([NH:25][C:26]3[CH:27]=[CH:28][C:29]4[N:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[NH:31][C:30]=4[CH:39]=3)=[O:19])[C:10](=[O:22])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Reactant: CCOC(=O)c1nc2ccc(N)cc2[nH]1
Product: CCOC(=O)c1nc2ccc(NC(=O)C(CC)n3cc(OC)c(-c4cc(Cl)ccc4C#N)cc3=O)cc2[nH]1

Procedure:
87 mg (0.25 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoic acid (racemate) and 56 mg (0.28 mmol, 1.1 eq.) of ethyl 6-amino-1H-benzimidazole-2-carboxylate were reacted according to General Method 5A. The crude product was purified by preparative HPLC (Reprosil C18, acetonitrile/water+0.1% formic acid gradient). Yield: 86 mg (64% of theory)
Reaction SMILES: [N:1](OCCCC)=O.[CH2:8]([CH:10]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[CH3:30])[C:15]=1[NH2:31])[CH2:11][CH3:12])[CH3:9].Cl.[OH-].[Na+]>C(#N)C>[CH2:8]([CH:10]([NH:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]2[N:21]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=3[CH3:30])[N:1]=[N:31][C:15]=12)[CH2:11][CH3:12])[CH3:9]
Reactant: CCC(CC)Nc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: CCCCON=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: CCC(CC)Nc1cc(C)nc2c1nnn2-c1c(C)cc(C)cc1C
Temperature: 65 °C
Yield: 77.8 %

Procedure:
A mixture of butyl nitrite (119 mg, 1.15 mmol) and N4-(1-ethyl-propyl)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3,4-triamine (250 mg, 0.766 mmol) in anhydrous acetonitrile (16 ml) was heated at 65° C. for 2 hours. The mixture was cooled to room temperature and 2N HCl (16 ml) was added. The mixture was neutralized with 2N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 250 mg of the crude product as a brown oil. The oil residue was purified through silica gel column using chloroform as eluent to give 201 mg of the title compound as golden yellow solid. Mp 131-133° C. 1H NMR (CDCl3) ä 7.022(s, 2H), 6.20(s, 1H), 5.44(d, 1H), 3.65(m, 1H), 2.50(s, 3H), 2.36(s, 3H), 1.96(s, 6H), 1.5-1.8(m, 4H), 1.03(t, 6H)ppm.
Reaction SMILES: COC(=O)C(C[C:10]1[C:11]([NH:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])=[N:12][C:13]([CH3:22])=[CH:14][C:15]=1[O:16][CH:17]([CH2:20][CH3:21])[CH2:18][CH3:19])C(OC)=O.[OH2:34]>>[CH2:18]([CH:17]([O:16][C:15]1[CH:14]=[C:13]([CH3:22])[N:12]=[C:11]([NH:23][C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[CH3:32])[C:10]=1[CH:10]([CH3:11])[C:15]([OH:16])=[O:34])[CH2:20][CH3:21])[CH3:19]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1CC(C(=O)OC)C(=O)OC
Reactant: O
Product: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1C(C)C(=O)O

Procedure:
Hydrolysis of 2-[4-(1-ethyl-propoxy)-6-methyl-2-(2,4,6-trimethyl-phenylamino)-pyridin-3-ylmethyl]-malonic acid dimethyl ester with phosphoic/water at reflux to give the title compound as a white foam. Anal. For C23H32N2O3. ¾H2O calc.: C, 69.40; H, 8.48; N, 7.04; found: C, 69.17; H, 8.62; N, 6.90.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([O-:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[Na+].Br[C:14]1[CH:22]=[CH:21][C:20]2[N:19]([CH3:23])[C:18]3[CH2:24][CH:25]4[NH:29][CH:28]([C:17]=3[C:16]=2[C:15]=1[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]4>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([C:14]2[CH:22]=[CH:21][C:20]3[N:19]([CH3:23])[C:18]4[CH2:24][CH:25]5[NH:29][CH:28]([C:17]=4[C:16]=3[C:15]=2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26]5)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(Br)ccc31)C1CCC(C2)N1
Reactant: COc1cccc(S(=O)[O-])c1
Agent: [Na+]
Product: COc1cccc(S(=O)(=O)c2ccc3c(c2C(=O)OC(C)(C)C)c2c(n3C)CC3CCC2N3)c1
Yield: 63 %

Procedure:
Intermediate 7 was coupled with the product of Example 27, step B following the procedure of Example 27, step C. The crude product was purified by flash column chromatography (SiO2, 7:3 hexanes/ethyl acetate) to give tert-butyl 2-(3-methoxyphenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (194 mg, 63%) as an off-white solid: 1H NMR (CDCl3, 300 MHz) δ 8.19 (s, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.47-7.52 (m, 2H), 7.26-7.37 (m, 2H), 6.98-7.08 (m, 1H), 5.25-5.29 (m, 1H), 4.70 (br s, 1H), 3.82 (s, 3H), 3.60 (s, 3H), 3.36-3.49 (m, 1H), 2.49 (d, J=16.0 Hz, 1H), 2.25-2.33 (m, 1H), 2.16-2.23 (m, 1H), 1.90-1.97 (m, 1H), 1.50-1.70 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]1=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18]Br>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C:10]2[CH:14]=[C:15]([Br:18])[CH:16]=[N:17][C:9]1=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCOc2cccnc21
Reactant: BrBr
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCOc2cc(Br)cnc21
Yield: 47.6 %

Procedure:
To a solution of 4-(tert-butoxycarbonyl)-3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazine (2.0 g, 8.46 mmole) in MeOH (40 mL) was added Br2 (0.53 mL, 10.2 mmole) dropwise at 0° C. After 1 hr the mixture was concentrated. The residue was taken up in 1:1 Et2O/hexanes and filtered. The filtrate was concentrated under reduced pressure to give the title compound (1.27 g, 48%) as an oil which solidified under vacuum: 1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.33 (s, 1H), 4.25 (m, 2H), 3.92 (m, 2H), 1.54 (s, 9H).