Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:22]([Cl:33])(=[O:32])[C:23]1[CH:31]=[CH:30][C:26]([C:27]([Cl:29])=[O:28])=[CH:25][CH:24]=1.ClCCl.CN(C1C=CC=CN=1)C>C(N(CC)CC)C>[CH2:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([C:31]3[C:23]([C:22]([Cl:33])=[O:32])=[CH:24][CH:25]=[C:26]([C:27]([Cl:29])=[O:28])[CH:30]=3)=[CH:7][CH:6]=2)=[CH:13][CH:12]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C(Cl)c1ccc(C(=O)Cl)cc1
Reactant: CCCCCCCCc1ccc(-c2ccc(O)cc2)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCc1ccc(-c2ccc(-c3cc(C(=O)Cl)ccc3C(=O)Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of 4-hydroxy-4'-octylbiphenyl (0.5 g) and terephthaloyl chloride (0.36 g) in about dichloromethane (30 ml) was added drop by drop triethylamine (0.2 g). To the solution was added dimethylaminopyridine (0.013 g) and the mixture was stirred at the room temperature for 10 hours to obtain the titled compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]=[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[CH:30]=[CH:29][NH:28][CH:27]=5)[CH:24]=4)[C:19](=[O:31])[NH:18][C:17]3=[O:32])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:42][C:43]([NH2:45])=[O:44]>CC(C)=O.CN(C)C=O>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][CH:15]=[C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]5[CH:30]=[CH:29][N:28]([CH2:42][C:43]([NH2:45])=[O:44])[CH:27]=5)[CH:24]=4)[C:19](=[O:31])[NH:18][C:17]3=[O:32])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: NC(=O)CBr
Reactant: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(-c5cc[nH]c5)cc43)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(-c5ccn(CC(N)=O)c5)cc43)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.3 %

Procedure:
To a solution of 4-{[4-(4-methyl-piperazin-1-yl)-phenylamino]-methylene}-6-(1H-pyrrol-3-yl)-4H-isoquinoline-1,3-dione (42 mg, 0.1 mmol) in acetone (3 mL) and N,N-dimethylformamide (1 mL) is added potassium carbonate (27 mg, 0.2 mmol) and shaken at room temperature for 2 hours. This is followed by addition of sodium iodide (30 mg, 0.2 mmol) and 2-bromoacetamide (17 mg, 0.12 mmol) and further shaking at room temperature overnight. The reaction mixture is then divided into 2 fractions and purified by C18 reverse phase HPLC. The pure fractions were combined and concentrated to yield the title compound (8.4 mg).
Reaction SMILES: C1C2C(=O)C3C(=CC=CC=3)C(=O)C=2C=CC=1.[CH3:17][C:18]1[CH:44]=[CH:43][C:21]([NH:22][C:23]2[CH:31]=[C:30]([C:32]([OH:34])=O)[C:29]([NH:35][C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)=[CH:28][C:24]=2[C:25](O)=[O:26])=[CH:20][CH:19]=1.CO>O>[CH3:17][C:18]1[CH:44]=[CH:43][C:21]2[NH:22][C:23]3[C:24]([C:25](=[O:26])[C:20]=2[CH:19]=1)=[CH:28][C:29]1[NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][C:37]=2[C:32](=[O:34])[C:30]=1[CH:31]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: O=C1c2ccccc2C(=O)c2ccccc21
Solvent: CO
Solvent: O
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 123 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To 300 g of polyphosphoric acid (112% phosphoric acid) heated at 88° C. was added 6.8 g of anthraquinone followed by 68.2 g of 2,5-di(4-methylanilino)terephthalic acid added over a period of 35 minutes, the temperature being maintained below 120° C. by adjustment of the addition rate. The mixture was heated at 123° C. for two hours. After the melt was cooled to 93° C., it was slowly poured into 494 g of methanol, the temperature being maintained below 64° C. by external cooling and adjustment of melt addition rate. The slurry was heated at reflux for one hour, cooled to below 60° C., diluted with water, filtered, and washed until acid free. The resultant presscake was reslurried in water. After adjustment of the pH to greater than 7, 5.5 g of 50% sodium hydroxide was added and the resultant slurry was heated at 90° C. for one hour. The slurry was cooled, filtered, and washed with water until alkali free, then reslurried in water. After adjustment of the pH to 9.5, the slurry was heated at 143° C. for two hours in a closed system (e.g., a pressure reactor), and cooled to 40° C. After the slurry was acidified to pH 3.3, an emulsion of 2.2 g of an anionic suffactant, 30 g of a petroleum distillate, and 80 g of water was added, and the slurry was stirred for three hours. The solid component was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 60 g of 2,9-dimethylquinacridone as a magenta pigment.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[OH:14].C([O-])([O-])=O.[Cs+].[Cs+].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26]Br.CCOCC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[CH:4][C:3]=1[O:14][CH2:26][C:22]1[O:21][CH:25]=[CH:24][CH:23]=1
Reactant: Oc1cc(Nc2nccs2)ccc1Cl
Reactant: BrCc1ccco1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: Clc1ccc(Nc2nccs2)cc1OCc1ccco1
Yield: 32 %

Procedure:
Following the general procedure for O-alkylation, Method B, a mixture of 2-chloro-5-(thiazol-2-ylamino)phenol (100 mg, 0.44 mmol) and Cs2CO3 (152, 0.44 mmol) in acetone (4.4 mL) was treated with a freshly prepeared solution of 2-furylbromomethane in ether (0.75 mL, 0.44 mmol) at room temperature. Reaction control by TLC showed full conversion after 2 hrs. The title compound was obtained after purification by flash chromatography on silica gel (hexane:EtOAc 3/1) in 32% yield (43 mg).
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH2:5][N:6]([CH3:11])[CH2:7][CH2:8][C:9]=2[N:10]=1.N([O-])=O.[Na+].[OH-].[K+]>S(=O)(=O)(O)O.[PH2](O)=O.O>[CH3:11][N:6]1[CH2:7][CH2:8][C:9]2[N:10]=[CH:2][S:3][C:4]=2[CH2:5]1
Reactant: CN1CCc2nc(N)sc2C1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=[PH2]O
Solvent: O
Product: CN1CCc2ncsc2C1
Yield: 67.5 %

Procedure:
2-Amino-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (10.00 g) was dissolved in a mixture of sulfuric acid (25 mL), hypophosphorous acid (50%,13 mL), and water (100 mL) at 15 to 18° C., to thereby give an orange solution. To the solution was added dropwise a solution of sodium nitrite (8.15 g) in water (30 mL) at −2 to 3° C. over 30 minutes. After the resultant mixture was stirred at 0 to 10° C. for 2.5 hours, 8N aqueous potassium hydroxide (130 mL) was added dropwise thereto, and the pH was found to be 12.6. The precipitated potassium sulfate was filtered off, and was washed with ethyl acetate (200 mL). The aqueous layer was separated from the filtrate, and was further extracted with ethyl acetate twice (200 mL×2). The organic layers were combined, and the combined organic layer was dried over sodium sulfate anhydrate (30.00 g). After any insoluble material was filtered off and washed with ethyl acetate (100 mL), the filtrate was concentrated under reduced pressure, to thereby give 6.15 g of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][O:17]C=C)=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28].Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]2[N:8]=[CH:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([NH:13][O:14][CH2:15][CH2:16][OH:17])=[O:12])[C:3]=1[NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][C:22]=1[F:28]
Reactant: C=COCCONC(=O)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NOCCO)c1cc2scnc2c(F)c1Nc1ccc(I)cc1F
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)-N-(2-(vinyloxy)ethoxy)benzo[d]thiazole-6-carboxamide (492 mg, 1.00 mmol) in CH2Cl2 (10 mL) was added 1.0 N HCl (aq., 5 mL, 5 mmol). After stirring for 1 h, the reaction mixture was neutralized with saturated NaHCO3 (aq.). The aqueous layer was washed with CH2Cl2 (30 mL). The combined organic layer was washed with water (30 mL×2) and brine (30 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (CH2Cl2/MeOH, 50:1, v/v) and gave the desired product as a white solid (446 mg, 75.9% yield for the two steps). 1H NMR (400 MHz, DMSO-d6): δ 11.80 (s, 1H), 9.55 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 7.55 (d, J=11.0 Hz, 1H), 7.31 (d, J=8.5 Hz, 1H), 6.48 (d, J=9.2 Hz, 1H), 4.72 (s, 1H), 3.84 (m, 2H), 3.57 (m, 2H). MS APCI (+) m/z: 491.8, [M+H].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=O.C(P(CCCC)(CCCC)[CH2:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1)CCC.CC([O-])(C)C.[K+].O>CS(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH:13]=[CH:20][CH:21]1[O:25][CH2:24][CH2:23][O:22]1
Reactant: CCCC[PH](CCCC)(CCCC)CC1OCCO1
Reactant: O=Cc1cccn1-c1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Brc1ccccc1-n1cccc1C=CC1OCCO1
Temperature: 47 °C

Procedure:
3.12 g (12.5 mmol) of 1-(2-Bromo-phenyl)-1H-pyrrole-2-carbaldehyde and 1.2 eqv. of tributyl-[1,3]dioxolan-2-ylmethyl-λ5-phosphane and 1.5 eqv. KOtBu in 20 ml DMSO was stirred for 2 hours. The reaction mixture was heated to 47° C. and stirred over night. The reaction mixture was cooled down to room temperature and poured into 200 ml of water and extracted with diethyl ether, dried over Na2SO4 and the solvent was evaporated. An oily residue was obtained which crystallised over night. The precipitate was washed with diethyl ether, filtered and dried. A mixture of E and Z isomers was obtained. Purification by column chromatography yielded 2 g (50%) of the E isomer 3b.
Reaction SMILES: CC1(NC2N=CC(C(F)(F)F)=CN=2)CCCC1NC(C1C(C2N=CC=CN=2)=CC=CN=1)=O.[CH3:33][C:34]1([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=2)[CH2:38][CH2:37][CH2:36][CH:35]1[NH2:39].[N:51]1[N:52]([C:56]2[C:57]([C:62](O)=[O:63])=[N:58][CH:59]=[CH:60][CH:61]=2)[N:53]=[CH:54][CH:55]=1.C(N(CC)CC)C>>[CH3:33][C:34]1([NH:40][C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:48])[F:49])=[CH:43][N:42]=2)[CH2:38][CH2:37][CH2:36][CH:35]1[NH:39][C:62]([C:57]1[C:56]([N:52]2[N:53]=[CH:54][CH:55]=[N:51]2)=[CH:61][CH:60]=[CH:59][N:58]=1)=[O:63]
Reactant: O=C(O)c1ncccc1-n1nccn1
Reactant: CC1(Nc2ccc(C(F)(F)F)cn2)CCCC1N
Agent: CC1(Nc2ncc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-c1ncccn1
Solvent: CCN(CC)CC
Product: CC1(Nc2ccc(C(F)(F)F)cn2)CCCC1NC(=O)c1ncccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-(2-methyl-2-{[5-(trifluoromethyl)pyrimidin-2-yl]amino}cyclopentyl)-3-(pyrimidin-2-yl)pyridine-2-carboxamide (Example 153) from 1-methyl-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine (Intermediate 51; 85 mg, 0.33 mmol), 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 75 mg, 0.33 mmol) and triethylamine (0.14 ml, 0.98 mmol) except this was then recrystallised from diisopropyl ether/pentane and then triturated with diethyl ether to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][CH3:10])[CH:5]=[C:4]([CH3:12])[C:3]=1[OH:13].Cl.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23]N)=[CH:19][CH:18]=1.O>C(O)(C)C>[OH:13][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]2[NH:23][C:20]3[C:21]([C:9]=2[CH3:10])=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)=[CH:5][C:4]=1[CH3:12]
Reactant: CCC(=O)c1cc(C)c(O)c(C)c1
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: COc1ccc2[nH]c(-c3cc(C)c(O)c(C)c3)c(C)c2c1
Yield: 72 %

Procedure:
5.1 g of 2,6-dimethyl-4-propionylphenol and 5.0 g of 4-methoxyphenylhydrazine hydrochloride were dispersed in 30 ml of isopropanol, and the dispersion was refluxed for 20 hours in a nitrogen stream. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, and washed with a 5% aqueous sodium hydroxide solution, water, 2N hydrochloric acid and water. The organic layer was dried, and the solvent was evaporated. Recrystallization of the resulting crude crystals from ethanol-hexane gave 5.8 g of 2-(4-hydroxy-3,5-dimethylphenyl)-5-methoxy-3-methylindole.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Na].CC(O)(C)C>C1(C)C=CC=CC=1.C(OCC)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)=[N:6][CH:5]=[CH:4][N:3]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1ccc(-c2nccnc2Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: [Na]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2-c2ccc(Cl)cc2)CC1
Yield: 53.7 %

Procedure:
Couple 2-chloro-3-(4-chlorophenyl)-pyrazine (0.148 g, 0.710 mmol) and piperazine-1-carboxylic acid t-butyl ester (0.216 g, 1.16 mmol), using 2-(dicyclohexylphosphino)biphenyl (0.0321 g, 0.0916 mmol), tris(dibenzylideneacetone) dipalladium (0.0328 g, 0.0388 mmol), and the sodium salt of 2-methylpropan-2-ol (0.104 g, 1.09 mmol) in toluene (9 mL) at 82° C. for 17 hr. Cool the reaction to room temperature, dilute with diethyl ether (50 mL), filter through a 1 cm pad of silica gel, rinse the pad with diethyl ether (2×25 mL), combine the organic solutions, concentrate and purify (silica gel chromatography, eluting with 0:100 to 1:1 ethyl acetate:hexanes) to give 3′-(4-chloro-phenyl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (0.143 g, 56%). MS (ES): m/z=303 [M+H-isobutylene]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2[CH3:12].[N+](C1C=C(B(O)O)C=CC=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[C:5]([CH3:12])[C:6](=[O:11])[N:7]=2)[CH:3]=1
Reactant: CC1C(=O)Nc2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1cccc(B(O)O)c1
Solvent: O
Solvent: COCCOC
Product: CC1=c2cc(Br)ccc2=NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 60.3 %

Procedure:
5-Bromo-3-methyl-1,3-dihydro-indol-2-one (0.50 g, 2.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.15 g) were stirred under an atmosphere of nitrogen in dimethoxyethane (18 cm3). After 15 min., 3-nitrophenyl boronic acid (0.74 g, 4.45 mmol) was added, followed by potassium carbonate (1.86 g, 13.5 mmol) in water (7 cm3). The reaction was heated to reflux for 8 h and then stirred at room temperature overnight. Saturated ammonium chloride was added; and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were dried (MgSO4), filtered, and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane 1:2); eluted: 2:1 hexane; ethyl acetate, to give the title compound (0.30 g, 47%), mp 200-203° C.; 1H NMR (DMSO-d6) δ 1.41 (d, 3H, J=7.61 Hz), 3.50 (q, 1H, J=7.60 Hz), 6.96 (d, 1H, J=8.08 Hz), 7.62 (d, 1H, J=8.06 Hz), 7.75-7.70 (m, 2H), 8.18-8.10 (m, 2H), 8.41-8.39 (m, 1H), 10.5 (s, 1H); IR (KBr) 3450, 1700 cm−1; MS (EI) m/z 267 (M−H); CHN calculated for C15H12N2O3+0.2C4H8O2: C, 66.61; H, 4.46; N, 9.83; Found: C, 66.26; H, 4.59; N, 10.06.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:17]>C(Cl)Cl>[CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N+:9]2[O-:17])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc2cccnc2c1
Solvent: ClCCl
Product: Cc1ccc2ccc[n+]([O-])c2c1
Reaction time: 1 h
Yield: 90.9 %

Procedure:
7-Methylquinoline (1-1, 240 g, 1.7 mol, 1.0 equiv) was dissolved in methylene chloride (5 L, 0.34 M). 3-Chloroperoxybenzoic acid (488 g, 2.2 mol, 1.3 equiv) was added portionwise with cooling so that the reaction temperature did not rise above 34° C. After stirring for 1 h, the reaction mixture was quenched with 2 L of 1N aqueous NaOH and the product was extracted with methylene chloride. The combined organic layers were washed with saturated aqueous sodium bicarbonate, dried over MgSO4 and filtered. Heptane was added and the organic layer was evaporated to dryness, giving 246 g of 7-methylquinoline N-oxide (1-2) as a pink solid that was carried on without further purification. LRMS m/z (M+H)+ 160.1 found, 160.2 required.
Reaction SMILES: [C@@H:1]1([NH:10][C:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([Cl:24])=[CH:18][C:19]=3[CH3:23])[NH:14]2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.IC.N1[CH2:28]CCN2CCCCCC=12>CN(C=O)C>[C@@H:1]1([NH:10][C:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([Cl:24])=[CH:18][C:19]=3[CH3:23])[N:14]2[CH3:28])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)N[C@H]3CCc4ccccc43)c(=O)c12
Reactant: C1CCC2=NCCCN2CC1
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc2c1c(=O)n(C(=O)N[C@H]1CCc3ccccc31)n2C

Procedure:
In analogy to example 2, 50 mg (0.146 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydropyrazolo[3,4-b]pyridine-2-carboxylic acid (S)-indan-1-ylamide were reacted with 31 mg (0.22 mmol) of iodomethane in DMF with 2,3,4,6,7,8,9,10-octahydro -pyrimido[1,2-a]azepin (DBU). Yield: 6 mg (12%), M+H+: 357.09.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([NH:22][C:23]2[CH:24]=[C:25]([CH:43]=[CH:44][CH:45]=2)[C:26]([C:28]2[CH:29]=[C:30]([CH2:37][CH2:38][CH2:39][C:40]([OH:42])=[O:41])[N:31]3[C:36]=2[CH:35]=[CH:34][CH:33]=[CH:32]3)=[O:27])[C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Na+:47]>C(O)C>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:11]([NH:22][C:23]2[CH:24]=[C:25]([CH:43]=[CH:44][CH:45]=2)[C:26]([C:28]2[CH:29]=[C:30]([CH2:37][CH2:38][CH2:39][C:40]([O-:42])=[O:41])[N:31]3[C:36]=2[CH:35]=[CH:34][CH:33]=[CH:32]3)=[O:27])[C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=2)=[CH:17][CH:16]=1)[CH:19]([CH3:20])[CH3:21].[Na+:47]
Reactant: CC(C)Cc1ccc(C(Nc2cccc(C(=O)c3cc(CCCC(=O)O)n4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Cc1ccc(C(Nc2cccc(C(=O)c3cc(CCCC(=O)[O-])n4ccccc34)c2)c2ccc(CC(C)C)cc2)cc1

Procedure:
To a solution of 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indolizin-3-yl]butyric acid (244 mg) in ethanol was added 1N sodium hydroxide. After removal of the solvent, the residue was dissolved in benzene, filtered through a cotton filter, and evaporated in vacuo to give sodium 4-[1-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]indolizin-3-yl]butyrate (240 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[N-:11]=[N+:12]=[N-:13].[Na+]>CC(C)=O>[N:11]([CH2:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1CBr
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1ccccc1CN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A mixture of 2-bromomethyl-benzonitrile (300 mg, 1.53 mmol) and sodium azide (129 mg, 1.99 mmol) in acetone was stirred overnight at rt. The solvent was removed, and the resulting residue was chromatographered using hexane/ethyl acetate (6:1) to give the title compound (212 mg, 88%). MS (DCI/NH3) m/z 176 (M+18)+. 1H NMR. (400 MHz, DMSO-d6) δ ppm 4.69 (s, 2 H) 7.58 (td, J=7.67, 1.23 Hz, 1 H) 7.66 (d, J=7.67 Hz, 1 H) 7.76 (td, J=7.67, 1.23 Hz, 1 H) 7.91 (dd, J=7.67, 1.53 Hz, 1 H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][N:67]=[CH:66][C:65]=1[O:70][CH3:71]>>[CH3:71][O:70][C:65]1[CH:66]=[N:67][CH:68]=[CH:69][C:64]=1[NH:63][C:30]([CH:20]1[NH:19][CH:18]([CH2:33][C:34]([CH3:35])([CH3:37])[CH3:36])[C:17]2([C:12]3[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)[NH:15][C:16]2=[O:38])[CH:21]1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[F:29])=[O:31]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cnccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COc1cnccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 42.8 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.26 g, 0.45 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.9 mmol), then reacted with 4-amino-3-methoxypyridine (Tyger) (0.08 g, 0.67 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (3-methoxy-pyridin-4-yl)-amide as a light yellow solid (Yield 0.11 g, 41%).
Reaction SMILES: CC1C=C(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:47]=[CH:48][CH:49]=[C:50]4[C:55]=3[N:54]=[CH:53][CH:52]=[CH:51]4)[C:41]2=[O:56])[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:47]=[CH:48][CH:49]=[C:50]4[C:55]=3[N:54]=[CH:53][CH:52]=[CH:51]4)[C:41]2=[O:56])[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3cccc4cccnc34)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3cccc4cccnc34)C2=O)sc1C(=O)O
Yield: 88 %

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(quinolin-8-ylmethyl) imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 88% yield: MS (ES+) m/z 369.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([S:10]([CH2:13][CH3:14])(=[O:12])=[O:11])[CH:3]=1.B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([S:10]([CH2:13][CH3:14])(=[O:11])=[O:12])[CH:3]=1
Reactant: CCS(=O)(=O)c1cc(Br)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCS(=O)(=O)c1cc(O)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
To a solution of 1-bromo-3-ethanesulfonyl-5-methoxy-benzene (670 mg, 2.4 mmol) in dichloromethane (25 mL) was added boron tribromide (4.8 mL, 4.8 mmol) in dichloromethane (1.0 M) at −70° C. Then, the resulting brown solution was stirred for 30 minutes at this temperature and then the cooling bath was removed to warm to room temperature and stirred for 15 h at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was quenched with water slowly (50 mL). The two layers were separated and the aqueous layer was extracted with dichloromethane (50 mL). The combined organic layer was washed with brine solution (100 mL) and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by using an ISCO 40 g column, eluting with 0-50% ethyl acetate in hexanes to obtain 3-bromo-5-ethanesulfonyl-phenol (576 mg, 90.5%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C8H9BrO3S (M+H)+ 264.9529, found 264.9528.