Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[N:20](CC1C=CC(OC)=CC=1)[CH2:19][CH2:18]2)([CH3:14])[CH2:3][O:4][CH2:5][CH2:6][O:7]C1CCCCO1>FC(F)(F)C(O)=O>[OH:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[C:21](=[O:25])[NH:20][CH2:19][CH2:18]2)([CH3:14])[CH3:1]
Reactant: COc1ccc(CN2CCc3cc(C(C)(C)COCCOC4CCCCO4)ccc3C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(COCCO)c1ccc2c(c1)CCNC2=O
Temperature: 80 °C
Yield: 94.9 %

Procedure:
140 mg 6-{1,1-Dimethyl-2-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-ethyl}-2-(4-methoxy-benzyl)-3,4-dihydro-2H-isoquinolin-1-one (0.3 mmol, 1 eq) was dissolved in 5 ml trifluoroacetic acid, and the mixture heated to 80° C. for 16 hours. The reaction was concentrated to dryness, partitioned between ethyl acetate and saturated sodium bicarbonate, separated layers and washed ethyl acetate with brine, dried Mg504 and concentrated to give 75 mg 6-[2-(2-Hydroxy-ethoxy)-1,1-dimethyl-ethyl]-3,4-dihydro-2H-isoquinolin-1-one, M+H =264 which was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]([NH2:12])=[S:11].[C:13]([C:19](OC)=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16]>CO>[CH3:18][O:17][C:15](=[O:16])[CH:14]=[C:13]1[S:11][C:10]([NH:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])=[N:12][C:19]1=[O:20]
Reactant: COC(=O)C#CC(=O)OC
Reactant: NC(=S)Nc1c(Cl)cccc1Cl
Solvent: CO
Product: COC(=O)C=C1SC(Nc2c(Cl)cccc2Cl)=NC1=O
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
2,6-Dichlorophenylthiourea (3.0 g, 13.6 mmol) was dissolved in 50 mL of dry methanol and dimethyl acetylenedicarboxylate (13.8 mmol, 1.7 mL) was added over a 10-minute period. The mixture was stirred at 25° C. for 40 minutes, then the mixture was heated at 55° C. for 3 hours. The solvent was removed by rotvap, and the crude product was recrystallized from methanol to yield the desired product.
Reaction SMILES: [CH:1]1[CH:5]=[C:4]([CH2:6][C:7]2[NH:11][CH:10]=[CH:9][CH:8]=2)[NH:3][CH:2]=1.C1([Mg]Br)C(C)=CC(C)=CC=1C.[CH:23](OC1C=CC=CC=1)=[O:24]>C1C2=CC3NC(C=C4N=C(C=C5NC(=CC(=N2)C1)C=C5)C=C4)=CC=3.C1COCC1>[CH:9]1[CH:8]=[C:7]([CH2:6][C:4]2[NH:3][C:2]([CH:23]=[O:24])=[CH:1][CH:5]=2)[NH:11][CH:10]=1
Reactant: O=COc1ccccc1
Reactant: c1c[nH]c(Cc2ccc[nH]2)c1
Agent: C1=Cc2cc3ccc(cc4nc(cc5ccc(cc1n2)[nH]5)CC4)[nH]3
Agent: Cc1cc(C)c([Mg]Br)c(C)c1
Solvent: C1CCOC1
Product: O=Cc1ccc(Cc2ccc[nH]2)[nH]1

Procedure:
As part of our work in chlorin chemistry, we recently developed an efficient route for the synthesis of 1-formyldipyrromethanes.21 The formylation method entailed traditional Vilsmeier formylation or treatment of a solution of dipyrromethane in THF at room temperature with 2 molar equiv of MesMgBr and then at −78° C. with 2 molar equiv of phenyl formate. The subsequent workup and column chromatography afforded the desired 1-formyldipyrromethane in good yields.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7](CC=C)[N:6]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:4].C[N+]1([O-])CC[O:28]CC1.S(OS([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[CH3:43][C:44]([CH3:46])=[O:45]>O.CC(O)(C)C.O=[Os](=O)(=O)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:43][CH:44]([OH:45])[CH2:46][OH:28])[N:6]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:4]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCC1CCCC(C(=O)OC)N1C(=O)OCc1ccccc1
Reactant: CC(C)=O
Agent: O=[Os](=O)(=O)=O
Agent: O=S(=O)([O-])OS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COC(=O)C1CCCC(CC(O)CO)N1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
6-Allyl-piperidine-1,2-dicarboxylic acid 1-benzyl ester 2-methyl ester (Compound 234, 0.087 g, 0.2 mmol) was dissolved in acetone (2 mL) and water (0.25 mL). N-Methylmorpholine oxide (0.068 g, 0.58 mmol) was added, followed by a 2.5% OsO4 solution in t-BuOH (0.14 mL). The mixture reaction was stirred at room temperature for 14 hours. Sodium pyrosulfate (0.3 g) in water (1 mL) was added with stirring, and the resultant solution was filtered through Celite and washed with ethanol (10 mL). The solvents were removed and the residue was purified by flash column chromatography (100% EtOAc) to afford Compound 235 (0.086 g, 89%, as a mixture of isomers). Rf=0.12 and 0.06 (2:1 EtOAc/hexanes).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[Cl:10][C:11]1[CH:12]=[C:13]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)[CH:14]=[N:15][CH:16]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: Cc1oc(Br)cc1C=O
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: COCCOC
Solvent: O
Product: Cc1oc(-c2cncc(Cl)c2)cc1C=O
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 5-chloropyridine-3-boronic acid (1.9 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.1 g, 49%) as a yellow solid.
Reaction SMILES: C(O[C:4](=[N:6][C:7](=O)[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)[CH3:5])C.[NH:16]([C:18]1[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1)[NH2:17].O>ClCCl.CO>[CH3:5][C:4]1[N:6]=[C:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[N:16]([C:18]2[N:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:20][CH:19]=2)[N:17]=1
Reactant: CCOC(C)=NC(=O)c1ccc(C)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cn1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Cc1ccc(-c2nc(C)nn2-c2ccc(S(N)(=O)=O)cn2)cc1
Reaction time: 8 h
Yield: 54 %

Procedure:
N-(1-ethoxy-ethylidene)-4-methyl-benzamide 429 mg (2.09 mmol) was dissolved in a mixed solvent of dichloromethane 20 ml and methanol 10 ml, and 6-hydrazinopyridine-3-sulfonic acid amide 433 mg (2.23 mmol) was added to the solution and stirred for 8 hours. After completing the reaction, water 20 ml was added to the reacting solution and extracted two times with dichloromethane, and then, the collected organic layer was washed with saturated brine. The organic layer was dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and the resulting product was re-crystallized in acetone and hexane phase. As a result, 6-(3-methyl-5-p-toly-[1,2,4]triazole-1-yl)-pyridine-3-sulfonic acid amide (372 mg, yield: 54%) was obtained as a solid phase.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O)(=O)C.[CH3:28][O:29][C:30](=[O:44])[C@H:31]([CH2:33][C:34]1[C:42]2[C:37](=[CH:38][C:39]([F:43])=[CH:40][CH:41]=2)[NH:36][CH:35]=1)[NH2:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:59]CCCl>>[ClH:59].[ClH:59].[CH3:28][O:29][C:30](=[O:44])[CH:31]([NH:32][CH:6]1[CH2:7][CH2:8][C:3]([N:2]([CH3:16])[CH3:1])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4][CH2:5]1)[CH2:33][C:34]1[C:42]2[C:37](=[CH:38][C:39]([F:43])=[CH:40][CH:41]=2)[NH:36][CH:35]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2cc(F)ccc12
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: ClCCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)C(Cc1c[nH]c2cc(F)ccc12)NC1CCC(c2ccccc2)(N(C)C)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Dimethylamino-4-phenylcyclohexanone (877 mg), sodium sulfate (2 g) and glacial acetic acid (230 μl, 4 mmol.) were added under argon to rac-6-fluorotryptophan methyl ester (952 mg) in 1,2-dichloroethane (approx. 30 ml). After one hour's stirring at RT, sodium triacetoxyborohydride (1.33 g, 6 mmol.) was added and the mixture was stirred for two days at RT. For working up, the mixture was concentrated, the residue was taken up in ethyl acetate (30 ml) and 1M NaOH (25 ml), the clear phases were separated in a separating funnel, the aqueous phase was extracted three times with ethyl acetate (10 ml each time) and the combined extracts were dried and concentrated by evaporation. The residue obtained (1.72 g) was purified by flash chromatography (eluant: MeOH/EtOAc 1:2, then MeOH/EtOAc 1:1 and MeOH/NH3 400:1). A portion (261 mg) of the nonpolar diastereomer (868 mg) was dissolved in 2-butanone (7 ml), and the corresponding dihydrochloride was precipitated with chlorotrimethylsilane (227 μl) (white solid; 224 mg; m.p. 164-169° C.).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([O:16][CH3:17])[CH:15]=2)[NH:12][C:11](=[O:18])[C:10]3=[O:19])=[C:5]([CH3:20])[O:4][N:3]=1.C1COCC1.[C:26]1([Mg]Br)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CC1CCCO1>CCOC(C)=O>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([O:16][CH3:17])[CH:15]=2)[NH:12][C:11](=[O:18])[C:10]3([OH:19])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: COc1cc(-c2c(C)noc2C)cc2c1NC(=O)C2=O
Solvent: CC1CCCO1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(-c2c(C)noc2C)cc2c1NC(=O)C2(O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 48 %

Procedure:
A suspension of 5-(3,5-dimethylisoxazol-4-yl)-7-methoxyindoline-2,3-dione (45 mg, 0.165 mmol) and anhydrous THF (1.5 mL) was added dropwise a solution of phenylmagnesium bromide in 2-methyltetrahydrofuran (2.9 M/L, 0.3 mL, 0.87 mmol). The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with EtOAc (30 mL), washed with saturated aqueous NH4Cl (10 mL), brine (3×10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo, purified by pre-TLC (CH2Cl2:EtOAc=3:2) to give the desired product as a light brown solid (28 mg, 48%). 1H NMR (400 MHz, DMSO-d6). δH 10.56 (s, 1H), 7.31-7.32 (m, 5H), 6.95-6.96 (m, 1H), 6.69-6.71 (m, 2H), 3.89 (s, 3H), 2.35 (s, 3H), 2.18 (s, 3H). MS (ESI) m/e [M+1]+ 351.
Reaction SMILES: [SiH:1]([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3].[CH2:8]([Cl:11])[CH:9]=[CH2:10].[SiH](Cl)(Cl)Cl>>[Si:1]([CH2:10][CH2:9][CH2:8][Cl:11])([CH2:6][CH3:7])([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: C=CCCl
Reactant: CC[SiH](CC)CC
Agent: Cl[SiH](Cl)Cl
Product: CC[Si](CC)(CC)CCCCl
Yield: 62.9 %

Procedure:
In a 25 ml apparatus, there were combined 11.6 g (0.1 mol) of Et3SiH and 0.05 ml of Pt catalyst solution. Heat was applied to 60° C. and addition of a mixture of 7.7 g (0.1 mol) of allyl chloride and 1.4 g (0.01 mol) of Cl3SiH begun. There was a smooth exothermic reaction up to 80° C. by the end of the addition (15 min) with temperature continuing to rise to 129° C. 5 min later. Vacuum distillation yielded 12.12 g (63.0%) of Et3SiCH2CH2CH2Cl, with a Et3SiCH2CH2CH2Cl/Et3SiCl molar ratio of 2.73. This example shows that low levels of Cl3SiH effectively promote both rate and yield of the reaction between Et3SiH and allyl chloride, particularly when the low levels are maintained throughout the reaction by replenishment.
Reaction SMILES: [CH2:1]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([C:24]([OH:26])=[O:25])=[CH:20][CH:21]=2)[NH:16]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH-].[Na+].[CH3:29]I>O.CO>[CH3:29][N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[C:19]([C:24]([OH:26])=[O:25])[CH:18]=2)[CH2:23][CH:15]1[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CI
Reactant: CCCCCCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCC1Cc2ccc(C(=O)O)cc2N1C

Procedure:
(RS)-2-(n-Tetradecyl)indoline-6-carboxylic acid (10.5 g) and sodium hydroxide (5.0 g) were refluxed together in a mixture of water (30 ml) and methanol (70 ml) for 1.5 hours, then methyl iodide (5 ml) was added. Water (30 ml) was added and the mixture was refluxed for 1 hour. The mixture was filtered, and the filtrate was diluted with water and acidified with acetic acid. The product was collected and recrystallised from a mixture of methanol and ethanol to give (RS)-1-methyl-2-(n-tetradecyl)indoline-6-carboxylic acid (7.0 g) in the form of off-white crystals, m.p. 115°-118° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C@@H:4]([C:5]#[C:6][C:7]([O:9][CH2:10][C:11](Cl)(Cl)Cl)=[O:8])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16].[C:35](O)(=[O:37])[CH3:36]>[Zn].O>[CH3:1][C:2]1([CH3:34])[C@@H:4](/[CH:5]=[CH:6]\[C:7](=[O:8])[O:9][CH2:10][CH2:11][O:37][CH2:35][CH3:36])[C@H:3]1[C:15]([O:17][C@H:18]([C:32]#[N:33])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:20]=1)=[O:16]
Reactant: CC(=O)O
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: O
Product: CCOCCOC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Reaction time: 1 h

Procedure:
5.9 g of zinc powder were introduced int a solution of 6.5 g of the product of Step D, 23.4 ml of acetic acid and 2.6 ml of water and the mixture was stirred for 1 hour and filtered. The filtrate was decanted and the organic phase was washed with water. The aqueous phase was extracted with methylene chloride and the combined organic phases were dried, filtered and evaporated to dryness to obtain 4.7 g of (S) α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3 (3-hydroxy-3-oxo-propynyl)-cyclopropane-carboxylate which was used as is for the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[CH:11][O:10][N:9]=2)=[N:6][CH:7]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:55][CH:56]1[CH2:61][CH2:60][O:59][CH2:58][CH2:57]1>CN(C=O)C>[O:59]1[CH2:60][CH2:61][CH:56]([NH:55][C:21]([C:17]2[S:16][C:15](/[CH:14]=[CH:13]/[C:12]3[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=4)=[N:9][O:10][CH:11]=3)=[N:19][C:18]=2[CH3:20])=[O:23])[CH2:57][CH2:58]1
Reactant: NC1CCOCC1
Reactant: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(/C=C/c2conc2-c2ccc(F)cn2)sc1C(=O)NC1CCOCC1
Reaction time: 1 h
Yield: 82.8 %

Procedure:
To a solution of 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (99 mg, 0.3 mmol) in DMF (1.5 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (106 mg, 0.33 mmol), N,N-diisopropyl ethyl amine (257 μL, 1.5 mmol) and 4-aminotetrahydropyran (33 mg, 0.33 mmol). The resulting reaction mixture was stirred for 1 h. The reaction mixture was then evaporated and purification by trituration from methanol/water afforded the title compound (103 mg, 83%) as an off white solid. MS: m/e=415.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][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=CC=1)CN1C=C(C2C3C(=NC=C(C4C=NC(N5CCN(C)CC5)=CC=4)C=3)NC=2)C=N1.Cl[CH2:81][C:82]([NH2:84])=[O:83].C(=O)(O)[O-].[Na+]>C(O)C.CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][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[CH2:31][CH2:30][N:29]([CH2:81][C:82]([NH2:84])=[O:83])[CH2:28][CH2:27]5)=[N:22][CH:21]=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
Reactant: NC(=O)CCl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)nc4)cnc32)cc1
Yield: 73.4 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (step 1 compound of example 137) (100 mg, 0.164 mmol) was alkylated using 2-chloroacetamide (23 mg, 0.247 mmol), sodium bicarbonate (42 mg, 0.494 mmol) and ethanol/acetone (3/3 mL) to get 80 mg (73.0%) of the titled compound after purification by column (Silica gel 60/120) chromatography using 5% methanol in dichloromethane as eluent. 1H NMR (CDCl3, 300 MHz): δ 8.60-8.06 (d, 1H), 8.40-8.39 (d, 1H), 8.11-8.08 (d, 2H), 8.00-7.99 (d, 2H), 7.85 (s, 1H), 7.80 (s, 1H), 7.71-7.67 (m, 2H), 7.37-7.33 (m, 2H), 7.06-6.90 (m, 3H), 7.76-7.73 (d, 1H), 5.45 (s, 1H), 5.37 (s, 2H), 3.65-3.62 (t, 4H), 3.09 (s, 1H), 2.71-2.68 (t, 4H), 2.37 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1)[NH2:5].[CH3:32][N:33]1[C:37]([CH3:38])=[CH:36][C:35]([C:39](Cl)=[O:40])=[N:34]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:39]([C:35]2[CH:36]=[C:37]([CH3:38])[N:33]([CH3:32])[N:34]=2)=[O:40])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:23][CH2:24][CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][CH:11]=1
Reactant: COc1cc2c(Oc3ccc(N)cc3F)ccnc2cc1OCCCN1CCOCC1
Reactant: Cc1cc(C(=O)Cl)nn1C
Product: COc1cc2c(Oc3ccc(NC(=O)c4cc(C)n(C)n4)cc3F)ccnc2cc1OCCCN1CCOCC1

Procedure:
Q5 was prepared from 3-fluoro-4-[[6-methoxy-7-(3-morpholinopropoxy)-4-quinolyl]oxy]aniline and 1,5-dimethyl-1H-pyrazole-3-carbonyl chloride following the general procedure reported in Preparative Example 1 Step 3. MS (ES) C29H32FN5O5 requires: 549. Found: 550 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1[CH:14]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH3:24])C=O.C1(P(=[CH:44][C:45]([O:47][CH3:48])=[O:46])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:49]1COCC1>>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:3]=1/[C:14](/[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[CH3:24])=[CH:49]\[CH2:44][C:45]([O:47][CH3:48])=[O:46]
Reactant: C1CCOC1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Cl)ccc1C(C=O)c1c(-c2ccccn2)nn(C)c1Cl
Product: COC(=O)C/C=C(/c1ccc(Cl)cc1C)c1c(-c2ccccn2)nn(C)c1Cl
Temperature: 60 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
To a solution of 2-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-2-(4-chloro-2-methylphenyl)acetaldehyde (13 g, 36.1 mmol) in THF (200 mL) was added methyl (triphenylphosphoranylidene)acetate (24.13 g, 72.2 mmol). The mixture was stirred at about 60° C. for about 16 h then cooled in an ice bath. The solids were removed by filtration then filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, 0-20% EtOAc/heptanes) to give (Z)-methyl 4-(5-chloro-1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-4-(4-chloro-2-methylphenyl)but-3-enoate (13.34 g, 89%): LC-MS (Table 1, Method g) Rt=2.62 min, m/z 416/418 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.41-8.38 (m, 1H), 7.81-7.70 (m, 2H), 7.27-7.20 (m, 1H), 7.19-7.17 (m, 1H), 7.09-7.05 (m, 1H), 7.02-6.99 (m, 1H), 5.91 (t, J=7.3 Hz, 1H), 3.91 (s, 3H), 3.52 (s, 3H), 3.11-2.96 (m, 2H), 2.34 (s, 3H).
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[C:12]2[O:13][CH2:14][O:15][C:11]=2[CH:10]=[CH:9][C:6]=1[CH:7]=O.[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][NH2:21])[CH3:17]>C(O)C.[Pt]=O>[CH2:16]([O:18][CH:19]([O:22][CH2:23][CH3:24])[CH2:20][NH:21][CH2:7][C:6]1[CH:9]=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[C:5]=1[O:4][CH3:3])[CH3:17]
Reactant: COc1c(C=O)ccc2c1OCO2
Reactant: CCOC(CN)OCC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: CCOC(CNCc1ccc2c(c1OC)OCO2)OCC
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
Platinum oxide was added in an amount of 1.0 g to 100 ml of ethanol, and hydrogen gas was passed through the mixture with stirring for 30 minutes. Then, 54.06 g (0.3 mol) of 2-methoxy-3,4-methylenedioxybenzaldehyde (1) and 40.78 g (0.3 mol) of aminoacetaldehyde diethylacetal (98% purity) in 100 ml of ethanol were added and hydrogenation was carried out while stirring the reaction mixture at room temperature for 8.5 hours. The catalyst was then removed by filtration and the solvent was distilled off at reduced pressure to obtain 89.43 g of N-(2-methoxy-3,4-methylenedioxybenzyl)aminoacetaldehyde diethylacetal (2) as an oil with 100% yield. IR and NMR of the resultant product are listed below.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[NH:10][C:5]2=[CH:4][CH:3]=1.[C:14]1([C:20]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:21]2[C:25]([C:26]3[C:31]([C:32]4[CH:37]=[CH:36][C:35]([CH2:38]Br)=[CH:34][CH:33]=4)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:24][N:23]=[N:22]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[H-].[Na+]>>[NH2:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:38][C:35]3[CH:34]=[CH:33][C:32]([C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:25]4[N:21]([C:20]([C:46]5[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=5)([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)[C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[N:22]=[N:23][N:24]=4)=[CH:37][CH:36]=3)[C:9]([CH2:11][CH2:12][CH3:13])=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCc1nc2nc(N)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCCc1nc2ccc(N)nc2n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
5-amino-2-propyl-3-(2'-(N-triphenylmethyltetrazol-5-yl)biphen-4-yl)methyl-3H-imidazo[4,5-b]pyridine was prepared according to the procedure described in Example 7, Part A from 5-amino-2-propylimidazo[4,5-b]pyridine (130 mg, 0.80 mmol), N-triphenylmethyl-5-(4'-bromomethylbiphen-2-yl)tetrazole (445 mg, 0.800 mmol), and NaH (2.4 mmol) Yield: 185 mg (as a glass like solid).
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].[CH:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29](Cl)=[O:30])=[CH:23][CH:22]=1.C(OCC)(=O)C>O1CCOCC1.O>[CH2:27]([O:28][C:29]([NH:1][C@H:2]1[C@H:6]([OH:7])[CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)=[O:30])[C:24]1[CH:25]=[CH:26][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](O)C1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.1 %

Procedure:
To a solution of (3R,4R)-tert-butyl 3-amino-4-hydroxypyrrolidine-1-carboxylate (4.40 g, 21.76 mmol) and Na2CO3 (2.77 g, 26.11 mmol) in dioxane (50 mL) and water (50 mL) was added Cbz-Cl (3.87 mL, 26.11 mmol) at 0° C. The reaction mixture was warmed to ambient temperature and stirred at ambient temperature for 3 hours. Ethyl acetate (50 mL) was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5:1 hexane/ethyl acetate) to give (3R,4R)-tert-butyl 3-(benzyloxycarbonylamino)-4-hydroxypyrrolidine-1-carboxylate (4.91 g, 67.1%) as an oil.