Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH3:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][C:25]=1[C:26](O)=[O:27].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH:16][C:26]([C:25]3[CH:24]=[CH:23][N:22]=[CH:21][C:20]=3[CH3:19])=[O:27])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Reactant: Cc1cnccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)c2ccncc2C)CCN(C)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 4.7 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (0.1 g, 0.411 mmol), 3-methylpyridine-4-carboxylic acid (0.056 g, 0.411 mmol), N,N′-dicyclohexylcarbodiimide (0.093 g, 0.452 mmol) and 4-dimethylaminopyridine (0.055 g, 0.452 mmol) in dry dichloromethane (2.0 ml) were stirred at room temperature for 4 h. To the reaction mixture was added 10 ml of water and the product extracted with dichloromethane (10 ml×3). Combined dichloromethane layers were dried over sodium sulfate and concentrated under reduced pressure to obtain 7 mg of N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)-3-methylpyridine-4-carboxamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) 10.05 (bs, 1H), 8.7 (t, 1H), 8.45-8.55 (m, 2H), 7.4 (d, 1H), 7.22 (s, 1H), 7.15 (d, 1H), 7.0 (d, 1H), 4.6 (d, 1H), 3.72-3.85 (m, 3H), 3.4-3.6 (m, 3H), 3.1-3.2 (m, 3H), 3.0 (s, 3H), 2.4 (s, 3H), 2.2 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:11]([O:13][C:14](=[O:34])[CH:15]([NH:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:16][C:17]1[O:21][N:20]=[C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][NH:23]2)[CH:18]=1)[CH3:12].N1C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH2:11]([O:13][C:14](=[O:34])[CH:15]([NH:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[CH2:16][C:17]1[O:21][N:20]=[C:19]([CH:22]2[CH2:26][CH2:25][CH2:24][N:23]2[C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=1)[CH3:12]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)c2ccccc2)no1)C(=O)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.1 %

Procedure:
Benzoyl chloride (21 μl, 0.18 mmol, 1.0 equivalents) was added in one portion to a solution of 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride (1C) (74 mg, 0.20 mmol, 1.1 equivalents) in pyridine (29 μl, 0.36 mmol, 2.0 equivalents) and dichloromethane (2 mL) at 0° C. The reaction was stirred at room temperature for 4 hours then diluted with ethyl acetate (30 mL). The reaction was extracted with 1N hydrochloric acid (30 mL) and brine (30 mL). The organic portion was dried over sodium sulfate and concentrated in vacuo to give the title compound (66 mg, 84%). MS (CI) m/z 442.3 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:20])[C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:21].[Br:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27](Br)[CH:28]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.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:22][C:23]1[CH:28]=[C:27]([C:7]2[C:6]([CH3:20])=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[C:3](=[O:21])[CH2:4]3)[CH:26]=[N:25][CH:24]=1
Reactant: Brc1cncc(Br)c1
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2c1CC(=O)N2C
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: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: Cc1c(-c2cncc(Br)c2)ccc2c1CC(=O)N2C
Temperature: 120 °C

Procedure:
To 1,4-dimethyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-indol-2-one, prepared as described in Example 34a (90 mg, 0.31 mmol) was added 3,5-dibromopyridine (CAS#625-92-3, 223 mg, 0.940 mmol), 1,2-dimethoxyethane (3.0 mL), and 2 M aqueous sodium carbonate (0.376 mL, 0.75 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.11 mmol/g loading, (171 mg, 0.019 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 120° C. for 2 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0 to 65%) to furnish 5-(5-bromo-pyridin-3-yl)-1,4-dimethyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 317.0289 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 210 (s, 3H), 3.26 (s, 3H), 3.50 (s, 2H), 6.78 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.82 (t, J=2.0 Hz, 1H), 8.50 (d, J=1.8 Hz, 1H), 8.68 (d, J=2.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(N(CC)C(C)C)(C)C.[H][H]>[Pd].O1CCCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[CH:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=c1[nH]ncc2c1cc(Br)n2COCc1ccccc1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]ncc2c1ccn2COCc1ccccc1
Yield: 95.2 %

Procedure:
To 33.4 g (100 mmol) of 1-benzyloxymethyl-2-bromo-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 17-(d) were added 4.5 g of 5% palladium-active carbon, 330 ml of toluene, 330 ml of tetrahydrofuran and 21 ml (121 mmol) of N,N-diisopropylethylamine, and the mixture was stirred under 1 atm hydrogen atmosphere at 60° C. for 1 hour. After completion of the reaction, the insoluble material in the reaction suspension was removed by filtration, followed by washing with 300 ml of a mixed solution (chloroform/methanol=1/1 (V/V)), and the filtrate and the washing solution were combined, then concentrated under reduced pressure. To the obtained concentrate was added 400 ml of water, and the mixture was extracted with a mixed solvent comprising 500 ml of chloroform and 30 ml of ethanol. The organic layer after separation was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 24.3 g of the title compound as a yellowish brown solid. (Yield: 95%)
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:14][CH2:15][C:16](=[O:24])[NH:17][C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1)[C:10]([O:12]C)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O.CO.C1(C)C=CC=CC=1>ClCCl>[NH2:8][C@@H:9]([CH2:14][CH2:15][C:16](=[O:24])[NH:17][C:18]1[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=1)[C:10]([OH:12])=[O:11]
Reactant: COC(=O)[C@H](CCC(=O)Nc1nccn1C)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cn1ccnc1NC(=O)CC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.8 %

Procedure:
Methyl (2S)-2-t-butoxycarbonylamino-4-[(1-methylimidazol-2-yl)carbamoyl]butyrate (341 mg) was dissolved in dichloromethane (5 ml), and trifluoroacetic acid (1 ml) was added. The mixture was stirred at room temperature for 2 hours. Methanol and toluene were added, and then the solvents were evaporated under reduced pressure. The resulting residue was dissolved in water (4 ml), and 1N sodium hydroxide (4 ml) was added. The mixture was stirred at room temperature for 3 hours and neutralized by adding 1N hydrochloric acid. The solvent was evaporated under reduced pressure to precipitate colorless needles. The needles were separated by filtration, washed successively with water, methanol and ether, and dried to give the title compound (72 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19].[C:20]([OH:24])(=[O:23])[CH2:21][SH:22].C(=O)(O)[O-].[Na+]>C(O)C>[C:20]([CH2:21][S:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1[CH:18]=[O:19])([OH:24])=[O:23]
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: O=C(O)CS
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=CC1=C(SCC(=O)O)c2ccccc2OC1c1ccccc1

Procedure:
A solution containing 2.7 g 4-chloro-3-formyl-flav-3-ene, 0.85 ml thioglycolic acid and 2.5 g sodium bicarbonate in 30 ml absolute ethanol is refluxed for 15 hours. After evaporation, one adds water and extracts with methylene chloride. The aqueous phase is acidified to pH 1. Extraction with methylene chloride is followed by washing the organic solution with water, drying over magnesium sulfate and evaporation. The residue is purified by column chromatography on silicagel using a mixture of methylene chloride and ethanol as eluant. The best fractions are crystallized in a mixture of hexane and toluene. Pure 4-(S-carboxymethylthio)-3-formyl-flav-3-ene is obtained as yellow crystals; m.p. 127°-129° C.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1[N:19]=[N+]=[N-])(=[O:3])[CH3:2].[H][H]>CO.[C].[Pd]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][O:7][C@@H:6]1[NH2:19])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](N=[N+]=[N-])OC[C@@H]1OC(C)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(=O)O[C@H]1[C@H](OC(C)=O)[C@@H](N)OC[C@@H]1OC(C)=O
Yield: 29.6 %

Procedure:
997.2 mg (3.31 mmol) of 2,3,4-tri-O-acetyl-β-L-xylopyranosyl azide was dissolved in 30 ml of methanol, and the solution was allowed to react at 45° to 50° C. for 2 hours in a hydrogen gas stream in the presence of 300 mg of 5% palladium carbon catalyst. The reaction solution was then filtered and the filtrate concentrated under reduced pressure. The residue was dissolved in 60 ml of pyridine, and 10 ml of acetic anhydride was added. The mixture was allowed to react at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure and the residue extracted with chloroform (100 ml). The chloroform layer was washed with 2N aqueous hydrochloric acid solution (100 ml), 10% aqueous sodium carbonate solution (100 ml) and water in the stated order, dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (Waggle C-200, 30 g) and eluted with chloroform-methanol (300:1). The eluate was crystallized from ethyl acetate-hexane to obtain 309.9 mg (0.98 mmol, 30%) of 2,3,4-tri-O-acetyl-β-L-xylopyranosylamine as a colorless needle crystal. The physicochemical properties of this crystalline compound were as follows.
Reaction SMILES: [F:1][C:2]([F:16])=[CH:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](Cl)=[O:14].[CH2:17]([S:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:18][CH3:19].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[CH2:17]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([NH:27][C:13](=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[C:2]([F:16])[F:1])=[CH:28][CH:29]=1)(=[O:22])=[O:21])[CH2:18][CH3:19]
Reactant: CCCS(=O)(=O)c1ccc(N)cc1
Reactant: O=C(Cl)CCCCCCCCCC=C(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCS(=O)(=O)c1ccc(NC(=O)CCCCCCCCCC=C(F)F)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8.5 g of 12,12-difluorododec-11-enoic acid chloride are added at room temperature to 3.45 g of 4-propylsulfonylaniline, 2.5 g of triethylamine and 100 mg of 4-dimethylaminopyridine in 50 ml of toluene and the mixture is stirred for 2 days at room temperature. A further 50 ml of toluene is then added, the toluene phase is washed with water, dried over sodium sulfate and concentrated to dryness by evaporation in vacuo. The residue is chromatographed on silica gel with hexane:ethyl acetate (7:3), yielding the title compound having a melting point of 67°-70° C. (compound no. 3-4).
Reaction SMILES: CCN([C:6]1[CH:11]=[CH:10][C:9]2[C:12](C)=[CH:13][C:14]([O:16][C:8]=2[CH:7]=1)=[O:15])CC>C(OCC)(=O)C.[Pd]>[O:16]1[C:8]2[C:9](=[CH:10][CH:11]=[CH:6][CH:7]=2)[CH2:12][CH2:13][C:14]1=[O:15]
Reactant: CCN(CC)c1ccc2c(C)cc(=O)oc2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C1CCc2ccccc2O1
Reaction time: 6 h
Yield: 156.3 %

Procedure:
A solution of coumarin-1 (11.0 g, 47.5 mmol) in ethyl acetate (150 mL) was treated with 10% Pd/C (100 mg) in a parr bottle. The suspension was then hydrogenated at 80 psi and 80° C. for 6 hours. The suspension was filtered through a bed of celite to remove the Pd/C, and the celite bed washed with warm ethyl acetate (100 mL). The filtrate was concentrated and dried under vacuo to yield 11.0 g (100%) of the 3,4-dihydrocoumarin (2) as an oil;
Reaction SMILES: Cl[C:2]1[N:11]2[CH:12]=[N:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=2[N:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>C(O)C>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[N:11]3[CH:12]=[N:13][N:14]=[C:10]3[C:9]3[CH:8]=[C:7]([O:15][CH3:16])[C:6]([O:17][CH3:18])=[CH:5][C:4]=3[N:3]=2)[CH2:20][CH2:21]1
Reactant: COc1cc2nc(Cl)n3cnnc3c2cc1OC
Reactant: C1COCCN1
Solvent: CCO
Product: COc1cc2nc(N3CCOCC3)n3cnnc3c2cc1OC

Procedure:
A mixture of 10.0 g. of 5-chloro-8,9-dimethoxy-1,2,4-triazolo[4,3-c]quinazoline, 38.8 g. of morpholine and 100 ml. of ethanol is refluxed for 1.5 hours and the resulting mixture evaporated in vacuo to dryness. The residue is taken up with ethanol and diethyl ether and filtered. The resulting solid is then recrystallized from benzene, filtered, washed with diethyl ether, recrystallized from ethanol and dried in a high vacuum to obtain 5-morpholino-8,9-dimethoxy-1,2,4-triazolo[4,3-c]quinazoline, m.p. 216°-218° C.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([O:10][C:11]2[N:16]=[CH:15][C:14]([NH:17][C:18]([C@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].C(O)(C(F)(F)F)=O>ClCCl>[NH2:23][C@H:20]([CH2:21][CH3:22])[C:18]([NH:17][C:14]1[CH:15]=[N:16][C:11]([O:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:2]([CH3:1])[CH3:3])[CH:5]=2)=[CH:12][CH:13]=1)=[O:19]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Oc2cccc(C(C)C)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc(C(C)C)c2)nc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1,1-dimethylethyl ((1R)-1-{[(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)amino]carbonyl}propyl)carbamate (Intermediate 69, 1.28 g) was dissolved in 18 mL of dry dichloromethane. To this solution at 0° C. under argon was added dropwise 30 equivalents of TFA (7.15 mL, 93 mmol). The reaction was stirred during 3 hours at 0° C. The reaction mixture was evaporated. The residue obtained was purified by SCX on a 50 g cartridge. The cartridge was washed with 3 CV of methanol, then the compound was adsorbed on the cartridge, washed with 5 CV of methanol and desorbed with 2 CV of methanolic ammonia (1N). After evaporation of the volatiles, the title compound was obtained (932 mg).
Reaction SMILES: NC1N=C(N)C2C=C(C=C(C3C=CC(C(O)=O)=CC=3)C)C=NC=2N=1.[NH2:25][C:26]1[N:27]=[C:28]([OH:48])[C:29]2[CH:35]=[C:34]([CH:36]=[C:37]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[CH:41][CH:40]=3)C)[CH:33]=[N:32][C:30]=2[N:31]=1>>[NH2:25][C:26]1[N:27]=[C:28]([OH:48])[C:29]2[CH:35]=[C:34]([CH:36]=[CH:37][C:39]3[CH:44]=[CH:43][C:42]([C:45]([OH:47])=[O:46])=[CH:41][CH:40]=3)[CH:33]=[N:32][C:30]=2[N:31]=1
Reactant: CC(=Cc1cnc2nc(N)nc(O)c2c1)c1ccc(C(=O)O)cc1
Agent: CC(=Cc1cnc2nc(N)nc(N)c2c1)c1ccc(C(=O)O)cc1
Product: Nc1nc(O)c2cc(C=Cc3ccc(C(=O)O)cc3)cnc2n1

Procedure:
In a similar fashion, 2,4-diamino-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine is converted to 2-amino-4-hydroxy-6-[2-(4-carboxyphenyl)prop-1-enyl]pyrido[2,3-d]pyrimidine, mp >250° C.; NMR (DMSO-d6, 80 MHz) d 2.28 and 2.30 (brs, 3H), 6.77 and 7.06 (brs, 1H), 7.72 (d, 2H, J=8.5 Hz), 7.97 (d, 2H, J=8.5 Hz), 8.27 (d, 1H, J=2.0 Hz), 8.72 (d, 1H, J=2.0 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][NH:12][C:13](=O)[CH2:14][C@@H:15]2[CH2:19][CH2:18][N:17]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:16]2)=[O:10])=[C:4]([CH3:26])[CH:3]=1.C([O-])([O-])=O.[K+].[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:20]([CH:22]4[CH2:24][CH2:23]4)=[O:21])[CH2:16]3)=[N:12][NH:11][C:9]2=[O:10])=[C:4]([CH3:26])[CH:3]=1
Reactant: Cc1cc(Br)ccc1NC(=O)NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1cc(Br)ccc1-n1c(C[C@@H]2CCN(C(=O)C3CC3)C2)n[nH]c1=O
Temperature: 130 °C
Reaction time: 5 h
Yield: 54.8 %

Procedure:
To a suspension of N-(4-bromo-2-methylphenyl)-2-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetyl}hydrazinecarboxamide (925 mg, 2.185 mmol) in water (45 mL) was added K2CO3 (1510 mg, 10.93 mmol). The reaction flask was equipped with a reflux condenser and heated to reflux (bath=130° C.) with stirring. After 5 h (LCMS indicated no starting material remained), the reaction mixture was cooled to room temperature and filtered to collect a small amount of white precipitate (this was determined to contain very little product so it was discarded). The aqueous filtrate was adjusted to pH˜5.5 with 1N aq HCl and extracted with three 100 mL portions of ethyl acetate. The combined organics were dried over Na2SO4, filtered, concentrated under reduced pressure and dried to constant weight under high vacuum to provide 4-(4-bromo-2-methylphenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (485 mg, 1.197 mmol, 54.8% yield) as a white solid. MS(ES)+ m/e 405.2, 407.4 [M+H]+. The product was determined to be 90% pure by LCMS (UV214) and was carried on in the next step without further purification.
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[NH:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:23]1([CH2:28][CH2:29]O)[CH:27]=[CH:26][CH:25]=[N:24]1>>[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]([CH2:29][CH2:28][N:23]3[CH:27]=[CH:26][CH:25]=[N:24]3)[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: OCCn1cccn1
Reactant: Clc1c(-c2ccccc2)nnc2[nH]nc(-c3ccccc3)c12
Product: Clc1c(-c2ccccc2)nnc2c1c(-c1ccccc1)nn2CCn1cccn1

Procedure:
Compound XIVa was synthesized from 4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine and 2-(1H-pyrazol-1-yl)ethanol following the general procedure for the Mitsunobu reaction described in Example 20.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH2:13][C:14]2([N:18]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:17][O:16][CH2:15]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:33])[CH:8]=2)[N:3]=1.[F:34][C:35]1([F:46])[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[CH2:39][NH:38][CH2:37][CH2:36]1.C(N(CC)CC)C.O>CN(C)C=O>[CH2:19]([N:18]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1([CH2:13][NH:12][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([CH3:33])[CH:8]=3)[N:3]=[C:2]([N:38]3[CH2:37][CH2:36][C:35]([F:34])([F:46])[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[CH2:39]3)[N:11]=2)[CH2:17][O:16][CH2:15]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc2nc(Cl)nc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Reactant: FC1(F)CCNCc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(N3CCC(F)(F)c4ccccc4C3)nc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Temperature: 120 °C
Yield: 71.9 %

Procedure:
To a solution of 2-chloro-N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-6-methylquinazolin-4-amine (200 mg, 0.436 mmol) in N,N-dimethylformamide (3 mL) was added 5,5-difluoro-1,3,4,5-tetrahydro-2H-2-benzazepine (80 mg, 0.436 mmol) and triethylamine (89 mg, 0.872 mmol). The mixture was heated at 120° C. for 30 minutes under microwave irradiation. The reaction was poured into water (10 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (eluting with 20% ethyl acetate in petroleum ether) to afford 190 mg of the product as a brown solid (yield was 72%).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:36])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:22]1)=[O:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[NH2:8][C@@H:9]([CH3:36])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:22]1)=[O:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)Nc1ccc(F)cc1N[C@@H]1CCCN(CCOC(=O)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
To an ice-cooled solution of 2,2-dimethylpropionic acid 2-{(R)-3-[2-((S)-2-tert-butoxycarbonylaminopropionylamino)-5-fluorophenylamino]-piperidin-1-yl}ethyl ester (0.74 mmol) in DCM (20 mL) was added TFA (5 mL) and the mixture stirred at RT for 1.5 h. Toluene was added and volatiles were removed in vacuo. The resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a purple oil (0.255 g, 84% over 2 steps). LCMS (Method J): RT 1.65 min [M+H]+ 409.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].C([O:27][C:28](=O)[CH2:29][C:30](=[O:37])[CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)(C)(C)C>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:11])=[O:12])[CH2:7][N:6]1[C:28](=[O:27])[CH2:29][C:30](=[O:37])[CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1
Reactant: CC(C)(C)OC(=O)CC(=O)C1CCOCC1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1C(=O)CC(=O)C1CCOCC1

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 192e) was reacted with 3-oxo-3-(tetrahydro-pyran-4-yl)-propionic acid tert-butyl ester to give the title compound as yellow foam. MS (ESI): m/z=492.2 [M+H]+.