Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:9][C:7](=[O:8])[CH:6]([C:10]([CH3:12])=O)[C:4](=[O:5])[CH:3]=1.[NH2:13][CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1.C1(C)C=CC=CC=1>O>[CH3:12][C:10]1[N:13]([CH:14]2[CH2:15][C:16]([CH3:23])([CH3:22])[NH:17][C:18]([CH3:21])([CH3:20])[CH2:19]2)[C:2]([CH3:1])=[CH:3][C:4](=[O:5])[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Reactant: CC1(C)CC(N)CC(C)(C)N1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(=O)c(C(=O)O)c(C)n1C1CC(C)(C)NC(C)(C)C1
Temperature: 25 °C

Procedure:
A 1-liter, 3-neck, round-bottom flask was equipped with a mechanical stirrer, thermometer, and a Dean-Stark water trap topped with a water cooled condenser. The flask was charged with a mixture of 80.5 g (0.479 mol) dehydroacetic acid, 75.0 g (0.479 mol) 4-amino-2,2,6,6-tetramethylpiperidine, and 600 ml toluene. The stirred mixture in the flask was heated to the boiling point by means of an oil bath and the water formed during the reaction was collected in the trap. After 6 hours of reflux a total of 7.0 ml water had been collected and the flask and its contents cooled to room temperature. The mixture deposited crystals on standing which were collected by vacuum filtration. Reduction of volume of toluene in the filtrate caused a deposit of a second crop of crystals. The combined crystals were recrystallized from a 65/35 mixture of hexane/benzene to give 111 g (75.6%) of a white to colorless crystalline solid (M.P. 174° C.). The chemical structure and purity of these crystals were verified by mass spectroscopy, nuclear magnetic resonance spectroscopy; and by elemental analysis.
Reaction SMILES: [C:1](=[O:47])([O:35][CH2:36][CH2:37][CH2:38][O:39]CC1C=CC=CC=1)[O:2][CH2:3][O:4][C:5]1[C:6](=[O:34])[C:7]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])=[O:23])=[CH:8][N:9]2[CH2:14][C@H:13]3[N:15]4[CH2:20][CH2:19][CH2:18][C@@H:16]4[CH2:17][N:12]3[C:11](=[O:21])[C:10]=12>CO.CC(O)=O.[Pd]>[C:1](=[O:47])([O:35][CH2:36][CH2:37][CH2:38][OH:39])[O:2][CH2:3][O:4][C:5]1[C:6](=[O:34])[C:7]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])=[O:23])=[CH:8][N:9]2[CH2:14][C@H:13]3[N:15]4[CH2:20][CH2:19][CH2:18][C@@H:16]4[CH2:17][N:12]3[C:11](=[O:21])[C:10]=12
Reactant: O=C(OCCCOCc1ccccc1)OCOc1c2n(cc(C(=O)NCc3ccc(F)cc3F)c1=O)C[C@@H]1N(C[C@H]3CCCN31)C2=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(OCCCO)OCOc1c2n(cc(C(=O)NCc3ccc(F)cc3F)c1=O)C[C@@H]1N(C[C@H]3CCCN31)C2=O
Reaction time: 0.42 h
Yield: 99 %

Procedure:
A solution of {[(4aS,13aR)-8-({[(2,4-difluorophenyl)methyl]amino}carbonyl)-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazin-10-yl]oxy}methyl 3-[(phenylmethyl)oxy]propyl carbonate (2.30 g, 3.52 mmol) in 50 mL of 1:1 MeOH/AcOH was subjected to hydrogenation at 55 psi in the presence of 0.75 g of 10% palladium on charcoal. After 5 hours the reaction vessel was purged with nitrogen, catalyst removed by filtration through celite and the filtrate concentrated to dryness at reduced pressure. The residue was dissolved in dichloromethane and the solution mixed with saturated aqueous sodium bicarbonate. The mixture was stirred vigorously for 25 minutes and the phases separated. The aqueous phase was extracted with one additional portion of dichloromethane. The combined dichloromethane solutions were washed with saturated aqueous brine, dried over sodium sulfate and concentrated to dryness at reduced pressure to give the title compound (1.96 g, 99%) as a light tan foam. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.18 (t, J=5.8 Hz, 1 H), 8.39 (s, 1 H), 7.37-7.26 (m, 1 H), 6.84-6.72 (m, 2 H), 5.93 (d, J=6.6 Hz, 1 H), 5.85 (d, J=6.6 Hz, 1 H), 4.66-4.36 (m, 4 H), 4.34-4.10 (m, 3 H), 3.87 (t, J=11.3 Hz, 1 H), 3.79-3.64 (m, 3 H), 3.17-3.02 (m, 2 H), 2.90-2.74 (m, 2 H), 2.11-1.81 (m, 4 H), 1.71-1.57 (m, 2 H): ES+ MS: 563 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:4][CH:3]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[Br:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)=[O:18])=[CH:19][CH:20]=2)=[N:4][CH:3]=1
Reactant: NCc1ccc(O)cc1
Reactant: O=C(O)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
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: CN(C)C=O
Product: O=C(NCc1ccc(O)cc1)c1ccc(Nc2ncc(Br)n3ccnc23)cc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(5-bromoimidazo[1,2-a]pyrazin-8-ylamino)benzoic acid (116 mg, 0.35 mmol), 4-aminomethylphenol (43 mg, 0.35 mmol), and N,N-diisopropylethylamine (0.094 mL, 0.525 mmol) in DMF (1 mL) is cooled to 0° C., and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (160 mg, 0.42 mmol) is added. The cooling bath is removed, and the reaction mixture stirred at 25° C. for 18 hours. After this time the solvent is removed in vacuo, and the residue triturated with MeOH. The resultant solid is collected by filtration and identified as the desired phenol.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.O>CS(C)=O>[N:29]1([C:2]2[N:7]=[C:6]([C:8]3[C:16]4[C:11](=[CH:12][N:13]=[C:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=5)[CH:15]=4)[NH:10][N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1
Reactant: C1CNCCNC1
Reactant: Fc1cccc(-c2nn(C3CCCCO3)c3cnc(-c4cccnc4)cc23)n1
Solvent: O
Solvent: CS(C)=O
Product: c1cncc(-c2cc3c(-c4cccc(N5CCCNCC5)n4)n[nH]c3cn2)c1

Procedure:
Following the procedures of Example 143 and starting with 3-(6-fluoropyridin-2-yl)-5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine and homopiperazine, 187 was obtained and lyophilized from water to afford 42 mg (78%). ESI MS m/z 372.1 (M+1). 1H NMR (400 MHz, DMSO)•9.58 (s, 1H), 9.44 (s, 1H), 9.36 (s, 2H), 9.31 (s, 1H), 9.11 (d, J=8.3 Hz, 1H), 8.99 (s, 1H), 8.94 (d, J=5.4 Hz, 1H), 8.23-8.15 (m, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.52 (d, J=7.4 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 4.12 (s, 2H), 3.89 (t, J=6.0 Hz, 2H), 3.43 (d, J=21.5 Hz, 2H), 3.27-3.17 (m, 2H), 2.24 (s, 2H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([CH3:41])([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]([F:30])([F:29])[F:28])[O:23][CH2:22][C:21]2[N:16]3[CH:17]([CH3:40])[C:18](=[O:39])[N:19](COCC[Si](C)(C)C)[N:20]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:41][C:10]1([NH:12][C:13]2[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:24]3[O:23][CH2:22][C:21]4=[N:20][NH:19][C:18](=[O:39])[C@@H:17]([CH3:40])[N:16]4[C:15]=3[CH:14]=2)[CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:11]1
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@@H]1C(=O)NN=C2COc3cc(C(F)(F)F)c(NC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 80 °C
Yield: 19.2 %

Procedure:
To a solution of 3-methyl-3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino]-azetidine-1-carboxylic acid tert-butyl ester (4 g, 6.67 mmol) in THF (10 mL) was added a solution of TBAF (1M in THF, 80 mL, 80 mmol) The reaction mixture was heated at 80° C. for 15 h. The reaction mixture was cooled to ambient temperature and solvent was removed in vacuo. The residue was purified by preparative HPLC (Table 3, Method 17) and further separated by chiral SFC (Table 2, Method 10) to give (R)-tert-butyl 3-methyl-3-((1-methyl-2-oxo-8-(trifluoromethyl)-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)amino)azetidine-1-carboxylate (Enantiomer 1, SFC (Table 1, Method 16) Rt: 6.686 min, 0.600 g, 19%) as a white solid, LC/MS (Table 1, Method 2) Rt=1.192 min.; MS m/z: 492 [M+23]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:7][NH2:8])=[N:4][O:5][N:6]=1.C([N:17]=[C:18]=[S:19])(=O)C1C=CC=CC=1.N>CO>[CH3:1][C:2]1[C:3]([CH2:7][NH:8][C:18]([NH2:17])=[S:19])=[N:4][O:5][N:6]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Cc1nonc1CN
Agent: N
Solvent: CO
Product: Cc1nonc1CNC(N)=S
Yield: 78 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(a) by using 1-(4-methyl-1,2,5-oxadiazol-3-yl)methylamine (0.46 g, 4.1 mmol), benzoyl isothiocyanate (0.60 mL, 4.5 mmol) and ammonia in methanol (7 N, 25 mL) with the exception that the crude product isolated by filtration (0.55 g, 78% yield) was used in the next step without further purification.
Reaction SMILES: [CH3:1][NH:2][O:3][CH2:4][CH:5](O)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[Na+].[Na+].Cl.[CH3:21][N:22]([CH3:32])[C:23](Cl)=[N:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)(Cl)Cl>[CH3:21][N:22]([CH3:32])[C:23]([N:2]([CH3:1])[O:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[N:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)C(Cl)=Nc1ccccc1
Reactant: CNOCC(O)CN1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN(C)C(=Nc1ccccc1)N(C)OCCCN1CCCCC1
Yield: 10 %

Procedure:
344 mg (2.0 mmole) 1-methylaminooxy-2-hydroxy-3-(1-piperidinyl)-propane was dissolved in chloroform and 220 mg of Na2CO3 was added, then a solution of 438 mg (2.0 mmole) of N,N-dimethyl-N′-phenyl-chloroformamidine hydrochloride in 3 ml of chloroform was added dropwise. After 8 hours the solid state was filtered and the filtrate was evaporated. This residue was dissolved in ethyl acetate and the product was extracted by addition of HCl solution (pH=1) to water. The aqueous phase was made alkaline then by addition of 2N NaOH solution to pH=11, and extracted with ethyl acetate. The organic phase was evaporated, and the further purification was made by column chromatography to give the title compound as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>[OH-].[Na+]>[CH2:17]([O:16][C:14]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C@H:2]1[C:10]([OH:12])=[O:11])=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)[C@@H]1Cc2ccccc2N1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@@H]1Cc2ccccc2N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 20 g (122.56 mmol) of 2(S)-indolinecarboxylic acid in 2N NaOH (62 ml) is cooled in an ice/water bath and the solution is stirred using a powerful magnetic stirrer. 20.0 ml (140.09 mmol) of benzyl chloroformate and 68 ml of 2N NaOH are added thereto alternately in about 10 portions over 60 minutes. The temperature of the reaction mixture is maintained between 0° and 5° C. by controlling the rate of addition of the reactants. 50 ml of NaOH are then added and the mixture is maintained at room temperature for 30 minutes. The alkaline solution is washed with ether (4×150 ml) and is then acidified by addition of 5N HCl (80 ml, pH<2). A crystalline mass precipitates after leaving overnight at room temperature. It is filtered off and washed with distilled water (500 ml). After drying over P2O5, the desired product is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[CH:8]=[C:7]2[C:3]=1[C:4]([OH:34])([C:24]1[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=1)[C:5](=[O:23])[N:6]2[CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20]>CO.[Pd]>[Cl:1][C:2]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:8]=[C:7]2[C:3]=1[C:4]([OH:34])([C:24]1[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=1)[C:5](=[O:23])[N:6]2[CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20]
Reactant: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c(Cl)cc(C#CCCO)cc21
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c(Cl)cc(CCCCO)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.5 %

Procedure:
Under nitrogen stream, to a solution of 4-chloro-6-(4-hydroxy-1-butynyl)-1-(2-diethylaminoethyl)-3-hydroxy-3-(2-naphthyl)oxindole (8.6 mg, 0.0180 mmol) in methanol (1.5 mL) was added 10% palladium/carbon (4.0 mg). The mixture was stirred under hydrogen atmosphere at room temperature for one hour. After filtration with Celite, the solvent was removed to give the title compound (8.7 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.ClC1C=C(C=CC=1)C(OO)=[O:26]>C(Cl)Cl>[Cl:15][C:11]1[CH:10]=[C:9]2[C:14]([C:5]([O:4][C:3]3[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:2]=3[Cl:1])=[CH:6][CH:7]=[N+:8]2[O-:26])=[CH:13][CH:12]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1ccc(Oc2ccnc3cc(Cl)ccc23)c(Cl)c1
Solvent: ClCCl
Product: [O-][n+]1ccc(Oc2ccc(F)cc2Cl)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 6 h

Procedure:
A mixture of 5.0 g (16.22 mmol) of 4-(2-chloro-4-fluorophenoxy)-7-chloroquinoline, 4.20 g (19.47 mmol) of 80% 3-chloroperoxybenzoic acid, and 50 ml of CH2Cl2 was stirred at 0° C. for six hours. The CH2Cl2 was removed by reducing pressure, and the residue was dissolved in ethyl acetate and washed with base. After removing solvent from the organic layer by reducing pressure, a white solid formed. This was recrystallized in ethyl acetate. Yield 3.04 g (58%). M.P. 177°-178° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:19])[C:8]2[CH2:16][C:15](=[N:17][OH:18])[S:14][C:9]=2[N:10]([CH2:12][CH3:13])[CH:11]=1)=[O:5])C.Cl>O.[OH-].[Na+]>[CH2:12]([N:10]1[CH:11]=[C:6]([C:4]([OH:5])=[O:3])[C:7](=[O:19])[C:8]2[CH2:16][C:15](=[N:17][OH:18])[S:14][C:9]1=2)[CH3:13]
Reactant: CCOC(=O)c1cn(CC)c2c(c1=O)CC(=NO)S2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c1SC(=NO)C2
Reaction time: 1 h
Yield: 98 %

Procedure:
In 10 ml of water containing 0.4 g of sodium hydroxide was dissolved 0.125 g (0.42 mmol) of 4,7-dihydro-7-ethyl-2-hydroxyimino-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid ethyl ester, anti-isomer. The solution obtained was maintained under stirring at room-temperature for 1 hour and then acidified with concentrated hydrochloric acid. The precipitate obtained was filtered out, washed with water and then with alcohol. After drying, 4,7-dihydro-7-ethyl-2-hydroxyimino-4-oxo-thieno[2,3-b]pyridine-5-carboxylic acid, anti-isomer was obtained in a yield of 98%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:41]=[CH:40][C:38]([CH3:39])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[CH:12]=2)[CH:8]=[N:7]1.FC1C=C(C=C(F)C=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.[CH3:82][C@H:83]1[CH2:85][O:84]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[C:43]([F:45])[CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:27][CH2:28][N:29]([CH2:82][C@@H:83]([OH:84])[CH3:85])[CH2:30][CH2:31]5)=[N:22][CH:21]=4)[CH:18]=3)[N:13]([S:32]([C:35]3[CH:36]=[CH:37][C:38]([CH3:39])=[CH:40][CH:41]=3)(=[O:33])=[O:34])[CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Reactant: C[C@H]1CO1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cc(F)cc(F)c6)c5)c4c3)cn2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cc(F)cc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 82.3 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 2 compound of example 133) (100 mg, 0.16 mmol) was alkylated using (S)-2-methyloxirane (14 mg, 0.24 mmol), DIPEA (31 mg, 0.24 mmol) and ethanol (2 mL) to get 90 mg (82.5%) of the titled compound after purification by column (Silica gel 60/120) using 5% methanol in dichloromethane as eluent. MS: m/z=684.2 (M+1).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[NH2:7][C:8]1[N:9]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[C:10]([SH:13])=[N:11][N:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:7][C:8]1[N:9]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH:24]3[CH2:26][CH2:25]3)=[CH:16][CH:15]=2)[C:10]([S:13][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[N:11][N:12]=1
Reactant: COC(=O)CCl
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1nnc(N)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 80 %

Procedure:
Methyl 2-chloroacetate (0.73 mL, 8.3 mmol) was added dropwise over 5 mins to a suspension of 5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazole-3-thiol (2.24 g, 7.9 mmol) and potassium carbonate (1.21 g, 8.7 mmol) in DMF (40 mL) at room temperature. The reaction was stirred at room temperature for 24 h and slowly poured into a stirred ice-cold water solution. The tan precipitate was collected by vacuum filtration and dried under high vacuum at 50° C. for 16 h in the presence of P2O5 to yield methyl 2-(5-amino-4-(1-cyclopropylnaphthalen-4-yl)-4H-1,2,4-triazol-3-ylthio)acetate (2.24 g, 80%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[CH2:23]([N:25]1[CH2:32][C:31]2[CH2:30][NH:29][CH2:28][C:27]=2[CH2:26]1)[CH3:24].N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:29]4[CH2:30][C:31]5[CH2:32][N:25]([CH2:23][CH3:24])[CH2:26][C:27]=5[CH2:28]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCN1CC2=C(CNC2)C1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCN1CC2=C(C1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 73.5 %

Procedure:
1-Cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.48 g), N-ethyl-3,7-diazabicyclo [3.3.0] oct-1(5)-ene dihydrobromide (0.57 g) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU, 0.87 ml) were dissolved in acetonitrile (20 ml) and refluxed for 3 hours. After cooling the reaction mixture, the produced precipitate was collected by filteration and washed with acetonitrile (10 ml) and methanol (10 ml) to give the title compound (0.5 g, yield 73%)
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:25])[CH:6]([C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[CH2:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1.F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.O>CN(C=O)C>[CH3:3][O:4][C:5](=[O:25])[CH:6]([C:18]1[CH:19]=[CH:20][C:21]([O:24][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)=[CH:22][CH:23]=1)[CH2:7][C:8]1[CH:9]=[C:10]([O:16][CH3:17])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 80 °C
Yield: 69.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 0.25 g, 6.3 mmol) in DMF (2 mL) under argon, 15 (2.0 g, 6.3 mmol) in dry DMF (3 mL) was added. To the resulting yellow solution, 4-fluorobenzaldehyde (0.68 mL, 6.3 mmol) was added and heated at 80° C. for 18 h. The reaction mixture was cooled to room temperature, water (20 mL) was added and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and solvent was evaporated. An ethyl acetate solution of crude product was filtered through a small bed of silica gel to yield 16 (1.83 g, 69%) as oil: 1HNMR(400 MHz, DMSO-d6): δ 9.91 (s, 1H), 7.84 (d, J=8.7 Hz, 2H), 7.33 (d, J=8.7 Hz, 2H), 7.04 (d, J=5.4 Hz, 2H), 7.01 (d, J=5.4 Hz, 2H), 6.30 (t, J=2.1 Hz, 1H), 6.25 (d, J=2.1 Hz, 2H), 3.86 (t, J=7.8 Hz, 1 Hz), 3.76 (s, 6H), 3.66 (s, 3H), 3.36 (dd, J=12.6 and 8.1 Hz, 1H), 2.97 (dd, J=13.5 and 7.5 Hz, 1H); MS (EI) m/z 421 [M]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]#[N:13])=[CH:7][N:6]=1)=O.[NH3:14]>CO>[C:12]([C:8]1[CH:9]=[C:10]([CH3:11])[C:5]([C:3]([NH2:14])=[O:2])=[N:6][CH:7]=1)#[N:13]
Reactant: N
Reactant: COC(=O)c1ncc(C#N)cc1C
Solvent: CO
Product: Cc1cc(C#N)cnc1C(N)=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of 5-cyano-3-methylpyridine-2-carboxylic acid methyl ester (1 g, 5.6 mmol) in methanol (5 mL) was added ammonia (4 mL, 28 mmol, 7N solution in methanol). The mixture was then heated at 50° C. with stirring in a sealed tube. After 60 min, HPLC analysis revealed completion of reaction. The mixture was concentrated in vacuo to give the title compound as a pale yellow solid: ESIMS: 162; [(M+H)+]; 1H NMR (400 MHz, DMSO-d6): δ 8.87 (d, 1H), 8.30 (d, 1H), 8.09 (br s, 1H), 7.74 (br s, 1H), 2.50 (s, 3H)
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]([C:18]([OH:20])=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=2)=[C:5]([F:21])[CH:4]=1)#[CH:2].FC(F)(F)C(O[C:27]1[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=1[F:37])=O.N1C=CC=CC=1>CN(C=O)C>[F:33][C:32]1[C:27]([O:19][C:18]([C:11]2[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[CH:2])=[CH:4][C:5]=3[F:21])=[CH:15][C:14](=[O:16])[N:13]([CH3:17])[CH:12]=2)=[O:20])=[C:28]([F:37])[C:29]([F:36])=[C:30]([F:35])[C:31]=1[F:34]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (0.70 g, 2.44 mmol) was reacted with pentafluorophenyl trifluoroacetate (1.30 mL, 7.36 mmol) in the presence of pyridine (0.60 mL) in DMF. The solution was allowed to stir at room temperature for 15 hours, to afford the 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid pentafluorophenyl ester which was reacted directly with 2-aminoethanol (0.74 mL, 12.20 mmol) that is stirred at room temperature for 4 hours. The resulting precipitate was filtered and purified by column chromatography on silica gel (5% MeOH/CH2Cl2 as eluant) to give 4-(4-Ethynyl-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-hydroxy-ethyl)-amide as a yellow solid (0.24 g, 30%). 1H NMR [(CD3)2SO, 400 MHz] δ 10.27 (s, 1H), 8.41 (t, 1H), 8.13 (s, 1 H), 7.48 (dd, J=10.2, 1.8 Hz, 1H), 7.40 (dd, J=8.6 Hz, 1H), 7.31 (dd, J=8.5 Hz, 1H), 5.73 (s, 1H), 4.76 (t, 1 H, OH), 4.24 (s, 1H), 3.51 (t, J=4.9 Hz, 2H), 3.35 (s, 3H), 3.25 (t, J=8.3 Hz, 2H). (APCI+) calcd for C17H16FN3O3 329.33 (M+1), found 330.1.