Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([F:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4]1.C(N(CC)CC)C.[CH3:32][O:33][CH2:34][C:35](Cl)=[O:36]>C1COCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C@@H:9]2[O:8][CH2:7][CH2:6][N:5]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:4][C@H:3]2[CH2:2][NH:1][C:35](=[O:36])[CH2:34][O:33][CH3:32])=[CH:11][C:12]=1[F:17]
Reactant: COCC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CN)C1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO[C@H]1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.1 %

Procedure:
To a solution of tert-butyl (6R,7R)-6-(aminomethyl)-7-(4-chloro-3-fluorophenyl)-1,4-oxazepane-4-carboxylate (1.30 g) in THF (18 mL) were added triethylamine (0.757 ml) and methoxyacetyl chloride (472 mg), and the mixture was stirred at room temperature for 4 hr. To the reaction mixture was added distilled water, and the mixture was extracted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (1.11 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH2:9]1[C@@H:13]([OH:14])[CH2:12][NH:11][CH2:10]1>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:10][CH2:9][C@@H:13]([OH:14])[CH2:12]2)=[N:3][CH:4]=1
Reactant: O[C@@H]1CCNC1
Reactant: Brc1ccc(Br)nc1
Solvent: Cc1ccccc1
Product: O[C@@H]1CCN(c2ccc(Br)cn2)C1
Temperature: 25 °C
Yield: 84.1 %

Procedure:
A mixture of 2,5-dibromopyridine (10.0 g, 42.2 mmol) and (R)-hydroxypyrrolidine (11.0 g, 126 mmol) in toluene (50 mL) was heated to reflux overnight. The mixture was allowed to cool to rt, and the solvents were removed under reduced pressure. The residue was dissolved with EtOAc (150 mL), and the mixture was washed with aq. 10% K2CO3. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (heptane→heptane/EtOAc 1:2) yielded the title compound (8.63 g, 84%). LC-MS: tR=0.48 min; ES+: 243.15.
Reaction SMILES: O.[OH-].[Li+].C1COCC1.[CH3:9][C:10]([NH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[N:25](S(C3C=CC(C)=CC=3)(=O)=O)[CH:24]=2)[N:18]=1)([CH2:14][CH3:15])[C:11]([O-:13])=[O:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O>[NH:25]1[C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:31]2[C:23]([C:19]2[N:18]=[C:17]([NH:16][C:10]([CH3:9])([CH2:14][CH3:15])[C:11]([OH:13])=[O:12])[CH:22]=[CH:21][N:20]=2)=[CH:24]1
Reactant: CCC(C)(Nc1ccnc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncccc23)n1)C(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)(Nc1ccnc(-c2c[nH]c3ncccc23)n1)C(=O)O
Temperature: 25 °C
Yield: 68 %

Procedure:
Lithium hydroxide hydrate (1.9 g, 45 mmol) was added to 50 mL THF and 15 mL water. Then 2-methyl-2-((2-(1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)butanoate was added and the mixture was heated to reflux for 18 hours. The reaction was cooled to rt and and 50 mL 1M citric acid solution was added. The mixture was extracted with 3×100 mL ethyl acetate where upon a white precipitate formed in the aqueous layer. The product was then filtered from the aqueous layer and dried under vacuum affording 1.6 g (68%) 2-((2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-2-methylbutanoic acid as white solid. 1H NMR (300 MHz, MeOD) 8.87 (dd, 1H), 8.32 (m, 2H), 7.94 (d, 1H), 3.31 (m, 3H), 2.80 (q, 1H), 2.29-1.95 (m, 2H), 1.68 (s, 3H), 0.96 (t, 3H). m/e m+1=312.22.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].CCN(C(C)C)C(C)C>C(O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[N:11][OH:12])[NH2:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: NC(=NO)c1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 5 h
Yield: 84.5 %

Procedure:
To a solution of 4-bromobenzonitrile (5.0 g, 27.5 mmol) in ethanol (42 ml) at room temperature, hydroxylamine hydrochloride (1.91 g, 27.5 mmol) and DIPEA (4.8 ml, 27.5 mmol) were added. The reaction mixture was stirred at 90° C. for 5 hours. After cooled to room temperature, the resulting mixture was concentrated to yield a colorless viscous liquid. The liquid was extracted with ethyl acetate and the organic layer was dried over magnesium sulfate, filtered and then concentrated to give a crude compound, which was washed with n-hexane to yield product 15 as a white solid (5.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7]1)=[O:5])[CH3:2].[C:16]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])[CH:17]=[CH2:18]>O.C1(C)C=CC=CC=1>[CH2:21]([O:20][C:16]([CH2:17][CH2:18][N:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[O:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CCOC(=O)C1CNc2ccccc2O1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1CN(CCC(=O)OCc2ccccc2)c2ccccc2O1

Procedure:
2.3 mmol (0.9 ml) of 40% Triton B in water are added at 0° C. to 22.6 mmol (5 g) of 2-ethoxycarbonyl-3,4-dihydro-2H-1,4-benzoxazine (described in J. Heterocyclic Chem., 1985, 22, 177) and 79 mmol (12.8 g) of benzyl acrylate in 17 ml of toluene. The reaction mixture is refluxed overnight, the solvent is evaporated off and the reaction mixture is heated again for 24 hours. After cooling, hydrolysis and extraction with ethyl acetate, the organic phase is concentrated and purified by chromatography on silica gel using an ethyl acetate/petroleum ether mixture (3/7) as eluant to yield the expected compound.
Reaction SMILES: C1(P(=[N:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37]([N:41]=[C:42]=O)[CH:38]=[CH:39][CH:40]=1>>[F:33][C:34]([F:44])([F:45])[C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[N:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][C:22]=2/[CH:27]=[CH:28]/[C:29]([O:31][CH3:32])=[O:30])[CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)/C=C/c1cnccc1N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: COC(=O)/C=C/c1cnccc1N=C=Nc1cccc(C(F)(F)F)c1

Procedure:
300 mg (0.34 mmol) of iminophosphorane from Example 12A are reacted by general procedure [B] with 70 mg (0.38 mmol) of 3-trifluoromethylphenyl isocyanate, and the crude product is reacted further without purification.
Reaction SMILES: [CH3:1][Li].[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]([OH:16])=O.[OH-].[Na+]>C1COCC1>[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14](=[O:16])[CH3:1]
Reactant: [Li]C
Reactant: O=C(O)c1cccc2c(F)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(=O)c1cccc2c(F)cccc12
Temperature: 25 °C

Procedure:
Methyl lithium (1.4M solution in ether; 6.6ml) was added dropwise to a stirred solution of 5-fluoro-1-naphthalene carboxylic acid (870mg) in dry THF (15 ml) at -78° under nitrogen. The reaction mixture was allowed to warm to room temperature over 2 h and was treated with 2N sodium hydroxide (60 ml). The mixture was extracted with ether (2×30 ml), and the combined, dried organic extracts were evaporated to give the title compound (865 mg) as an oil, t.l.c. (System B, 1:6) Rf 0.3
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1.C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Reactant: OC1CCOCC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)C1CCOCC1
Yield: 61.4 %

Procedure:
The 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (200 mg, 0.661 mmol) obtained in Example 5 and tetrahydro-4H-pyran-4-ol (0.13 ml, 1.36 mmol) were dissolved in toluene (10 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (330 mg, 1.37 mmol). Under an argon atmosphere, the resulting mixture was heated under reflux for 14 hours. After the reaction mixture was allowed to cool down, cyanomethylenetri-n-butylphosphorane (200 mg, 0.829 mmol) was added thereto. Under an argon atmosphere, the mixture was heated under reflux for 14 hours. The reaction mixture was then allowed to cool down. The residue obtained by concentrating the mixture under reduced pressure was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=4:1 eluate was concentrated under reduced pressure to give a white solid. The white solid was washed with hexane, whereby the title compound (157 mg, 0.406 mmol, 61%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].[C:31]([C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>N1C=CC=CC=1.C1(C)C=CC=CC=1>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([S:41]([NH:1][C:2]2[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][O:26]3)[C:11]=2[O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[C:5]([O:7][CH3:8])=[O:6])(=[O:43])=[O:42])=[CH:37][CH:36]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: COC(=O)c1cc(N)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.35 g of methyl 3-amino-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate was dissolved in pyridine (10 ml), treated dropwise while cooling with ice with a solution of 0.312 g of 4-tert.butyl-benzenesulphonyl chloride in toluene (3 ml) and subsequently stirred at RT for 24 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate, the organic phase was washed with 2M KHCO3 solution and dried over magnesium sulphate. After removing the solvent there was obtained the desired methyl 3-(4-tert-butyl-benzenesulphonylamino)-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[O:9][CH2:8][CH2:7][CH:6]2[N:3]1[C:4](=[O:13])[CH:5]2[N:10]=[N+]=[N-].[C:15]([O:18][CH2:19][CH3:20])(=[O:17])C>[Pd]>[CH3:1][C:2]1([CH3:14])[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:13])[C@@H:5]2[NH:10][C:15]([O:18][CH2:19][C:20]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)=[O:17]
Reactant: CC1(C)OCCC2C(N=[N+]=[N-])C(=O)N21
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CC1(C)OCC[C@@H]2[C@@H](NC(=O)OCc3ccccc3)C(=O)N21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
In 20 ml of ethyl acetate is dissolved 940 mg of 2,2-dimethyl-7-azido-1-aza-3-oxabicyclo[4,2,0]octan-8-one (1:4 cis-trans mixture) and catalytic reduction is carried out using 300 mg of 10% palladium-on-carbon (wet). The catalyst is then filtered off and washed with ethyl acetate. The filtrate and washings are combined and concentrated to about 20 ml. Then, 4 ml of propylene oxide and 0.9 ml of carbobenzoxy chloride are added and the mixture is stirred at room temperature for 1.5 hours and concentrated. The residue is subjected to column chromatography using silica gel (60 g), elution being carried out with chloroform-ethyl acetate (6:4) to give 388 mg of cis-(2,2-dimethyl-7-benzyloxyformamido-1-aza-3-oxabicyclo[4,2,0]octan-8-one) as the first product.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([C:14](=[O:19])C(F)(F)F)=[C:5]2[S:4][CH:3]=1.[OH-:20].[Na+]>C(O)C>[CH3:1][C:2]1[N:6]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]([C:14]([OH:19])=[O:20])=[C:5]2[S:4][CH:3]=1
Reactant: Cc1csc2c(C(=O)C(F)(F)F)c3ccccc3n12
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: Cc1csc2c(C(=O)O)c3ccccc3n12
Yield: 100 %

Procedure:
3-Methyl-9-trifluoroacetylthiazolo[3,2-a]indole (370 mg, 0.0013 mole) was treated with 20% NaOH solution (15 ml) and ethanol (15 ml) and heated under reflux for 6 h. The mixture was concentrated in vacuo to half its volume and the residue acidified with 2M HCl acid and then extracted with ethyl acetate (2×30 ml). The combined extracts were dried (Na2 SO4) and concentrated in vacuo to afford the title compound (D13) as a brown solid (300 mg, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:12]=2)=[C:4]([O:29][CH2:30][CH3:31])[CH:3]=1.[C:32](Cl)([Cl:34])=[O:33]>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:32]([Cl:34])=[O:33])[C:11]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[C:10]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)([CH3:21])[N:9]=2)=[C:4]([O:29][CH2:30][CH3:31])[CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: CCOc1cc(Br)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Product: CCOc1cc(Br)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(4-bromo-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole was reacted with phosgene in the presence of triethylamine to give the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([SH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].[OH-].[Na+].Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][Cl:23]>C(O)C>[ClH:23].[F:1][C:2]1[C:7]([S:8][CH2:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12]
Reactant: Fc1c(F)c(F)c(S)c(F)c1F
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Fc1c(F)c(F)c(SCc2ccccn2)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.1 %

Procedure:
Pentafluorothiophenol (5 g) was added to a solution of sodium hydroxide (2.0 g) in ethanol (50 ml) and the resulting solution was treated with a solution of 2-picolyl chloride, hydrochloride (4.1 g) in ethanol (25 ml). The mixture was stirred at ambient temperature for 4 hours, filtered through Kieselghur and the solvent removed by evaporation. The residue was converted into the hydrochloride with ethereal HCl solution and this was recrystallised from acetone-ether to give 2-(((pentafluorophenyl)thio)methyl)pyridine, hydrochloride (5.0 g) mp 157°-8° C. (Found: C,44.0; H,2.4; N,4.0; C12H6F5NS.HCl requires C,44.0; H,2.15; N,4.3%).
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>S1(CCCC1)(=O)=O>[CH2:19]([O:8][C:7]1[CH:9]=[C:2]([C:1]([O:11][CH3:12])=[O:10])[C:3]([OH:4])=[CH:5][CH:6]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1cc(O)ccc1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)ccc1O
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of methyl gentisate (16.8 g) and anhydrous potassium carbonate (7.0 g) in dry sulpholane (150 ml) was treated, with stirring, with benzyl chloride (12.7 g), and the mixture was stirred and heated at 100° C. for 4 hours. The mixture was then poured into water (800 ml) and the separated solid was filtered off and recrystallized from ethanol (with the aid of charcoal) to give methyl 5-benzyloxysalicylate (10.7 g), m.p. 108°-112° C. This ester (9.2 g) was heated at 150° C. for 3 hours with a mixture of anhydrous potassium carbonate (2.5 g) and benzyl chloride (4.52 g) in dry sulpholane (100 ml) and the mixture was then cooled and poured into a mixture of ice and water (700 ml), and the mixture was extracted with diethyl ether (2 × 300 ml). The ether extracts were combined and evaporated, the residual oil was triturated with water (100 ml), the oil was separated and the aqueous layer was extracted with diethyl ether (25 ml). The combined oil and extracts were washed with brine, dried over magnesium sulphate and evaporated to give crude methyl 2,5-dibenzyloxybenzoate (12.7 g). This ester (12.4 g) was heated at reflux with aqueous sodium hydroxide solution (2N; 400 ml) for 2 hours and allowed to cool. The separated sodium salt was filtered off and ground with hydrochloric acid (6N; 100 ml), the mixture was heated at reflux for 5 minutes and then cooled. The solid which separated was filtered off, washed with water and dried to give 2,5-dibenzyloxybenzoic acid (8.2 g), m.p. 107°-108.5° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]1[N:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[N:14]=1)[C:11]#[N:12].[OH-:27].[Na+]>S(=O)(=O)(O)O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:13]1[N:18]=[C:17]([C:19]([CH3:21])([CH3:22])[CH3:20])[CH:16]=[C:15]([C:23]([F:24])([F:25])[F:26])[N:14]=1)[C:11]([NH2:12])=[O:27]
Reactant: CC(C)(C)c1cc(C(F)(F)F)nc(C(C#N)=C2Nc3ccccc3S2)n1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)(C)c1cc(C(F)(F)F)nc(C(C(N)=O)=C2Nc3ccccc3S2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[Benzothiazol-2(3H)-ylidene]-2-[4-tert-butyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile (150 mg, 0.39 mmol) was dissolved in concentrated sulfuric acid (1.5 mL) and stirred at room temperature overnight. The mixture was cooled to 0° C., poured over ice, and neutralized with 50% aqueous sodium hydroxide. The product was partially extracted into chloroform, and dried to a brown solid (57 mg), which was purified by reverse phase preparative HPLC to give 2-[benzothiazol-2(3H)-ylidene]-2-[4-tert-butyl-6-(trifluoromethyl)pyrimidin-2-yl]acetamide (13 mg) as a yellow solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.CC(OC([N:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16]1[CH:24]=[O:25])=O)(C)C>ClCCl>[NH:15]1[C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16]1[CH:24]=[O:25]
Reactant: CC(C)(C)OC(=O)n1c(C=O)cc2cnccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1cc2cnccc2[nH]1
Yield: 75.5 %

Procedure:
Add to a solution of 2-(diethoxymethyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester (8b-1, 9.8 g, 30.6 mmol) in 100 ml THF, 6 ml of concentrated HCl. Stir the reaction mixture at room temperature for 20 h, basify with saturated sodium bicarbonate solution, pour into EtOAc, wash with saturated sodium bicarbonate and brine, dry the organic phase over MgSO4, filter, and concentrate to give a mixture of 2-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester and 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde 9b-1 as a solid. Separate the mixture by flash chromatography (silica, 1-3% MeOH/CH2Cl2) to give 2-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester (5.0 g) as an oil and 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde 9b-1 (1.0 g) as a tan solid. Add TFA (5.0 mL) dropwise to a solution of 2-formyl-1H-pyrrolo[3,2-c]pyridine-1-carboxylic acid 1,1-dimethylethyl ester (5.0 g, 20.3 mmol) in 250 ml dichloromethane. Heat the reaction mixture at reflux for 3 hours, concentrate, dilute the residue with 300 ml EtOAc, wash with saturated sodium bicarbonate solution (3×) and brine, dry the organic phase (MgSO4), filter and concentrate to yield 1H-pyrrolo[3,2-c]pyridine-2-carboxaldehyde 9b-1 (2.24 g) as a pure solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: C#CCCCCCCCCCC
Reactant: O=Cc1cccc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of 3-bromobenzaldehyde (26.5 g) and (25.0 g) 1-dodecyne in triethylamine (105 ml) was added bis(triphenylphosphine)palladium(II) chloride (1.73 g) followed by copper(I) iodide (0.24 g). The resultant mixture was stirred in the dark at 55° C. for 7 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 37.7 g 3-(1-dodecynyl)benzaldehyde. The filtrate was an oil.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[CH:9]=[N:8]1.[CH3:46][C@H:47]1[CH2:49][O:48]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:43]=[CH:44][CH:45]=1)[CH2:6][N:7]1[CH:11]=[C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([CH2:46][C@@H:47]([OH:48])[CH3:49])[CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:34])=[O:35])[CH:13]=2)[CH:9]=[N:8]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Yield: 48.8 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridinehydrochloride (step 1 example 103) (50 mg. 0.077 mmol) was alkylated using (S)-2-methyloxirane (9 mg, 0.155 mmol), DIPEA (29 mg, 0.231 mmol) and ethanol (2 mL) to get 25 mg (9.8% yield) of the titled compound. MS: m/z=664.8 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][C:6]([C@@H:10]([NH:12][S@@](C(C)(C)C)=O)[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[ClH:19]>CO.O1CCOCC1>[ClH:19].[NH:1]1[C:9]2[C:4](=[N:5][C:6]([C@@H:10]([NH2:12])[CH3:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C[C@H](N[S@](=O)C(C)(C)C)c1ccc2[nH]ccc2n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](N)c1ccc2[nH]ccc2n1
Temperature: 40 °C
Reaction time: 7 h
Yield: 99.5 %

Procedure:
To a solution of (R)—N—((S)-1-(1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (597.0 mg, 2.25 mmol) in anhydrous MeOH (9 mL) was added HCl (4.0 mol/L) in dioxane (11 mL). The reaction mixture was stirred at 40° C. under N2 for 7 h. Volatile solvent was removed under reduced pressure. The crude product was triturated with MeOH/ether until solid is seen. The light yellow solid was filtered and dried under high vacuum to afford 524.0 mg (99.5%) of the desired product as HCl salt: 1H NMR (400 MHz, DMSO-d6) δ 12.57 (s, 1H), 9.00 (s, 3H), 8.42 (d, J=6.8 Hz, 1H), 8.10 (s, 1H), 7.74 (d, J=7.4 Hz, 1H), 6.79 (s, 1H), 4.88 (s, 1H), 1.67 (d, J=6.8 Hz, 3H); MS (ESI) m/z: 162.1 [M+1]+.