Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[CH2:9][NH:8][S:7]1(=[O:13])=[O:12].[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34]O)=[CH:30][CH:29]=1)([CH3:23])([CH3:22])[CH3:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:20]([O:24][C:25](=[O:36])[NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][N:8]2[CH2:9][C:10](=[O:11])[N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:3]=3[O:2][CH3:1])[S:7]2(=[O:13])=[O:12])=[CH:32][CH:33]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Reactant: COc1ccc(CN2C(=O)CNS2(=O)=O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)CN(Cc3ccc(CNC(=O)OC(C)(C)C)cc3)S2(=O)=O)c(OC)c1
Reaction time: 0.17 h

Procedure:
A solution of the title B compound in Example 9, 2-(2,4-dimethoxybenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (742 mg, 2.59 mmol) and (4-hydroxymethyl-benzyl)-carbamic acid t-butyl ester (738 mg, 3.11 mmol) in THF (15 mL) is treated with triphenylphosphine (1.36 g, 5.18 mmol). The mixture is stirred for 10 min and diethyl azodicarboxylate (902 mg, 5.18 mmol) is added dropwise over 1 min. The mixture is stirred for 72 h. The solvent is evaporated and the residue is chromatographed on silica gel using 1% MeOH/CH2Cl2 as the eluent to afford {4-[5-(2,4-dimethoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl]-benzyl}-carbamic acid t-butyl ester as a white solid: [M+NH4]+=523.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH:32]([CH2:36][OH:37])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:20]([O:27][C:28]([N:30]1[CH2:35][CH2:34][N:33]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH:32]([CH2:36][OH:37])[CH2:31]1)=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: O=C(OCc1ccccc1)N1CCNC(CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)OCc4ccccc4)CC3CO)nc(-c3ccccc3O)nc2c1
Temperature: 40 °C
Yield: 49 %

Procedure:
To 2-(4-chloro-7-methyl-quinazolin-2-yl)-phenol (245 mg, 0.91 mmol) in 3.0 mL of CH2Cl2 was added sequentially 3-hydroxymethyl-piperazine-1-carboxylic acid benzyl ester (336.3 mg, 1.34 mmol) and triethylamine (190 mL, 1.37 mmol), and the reaction mixture was heated at 40° C. for 6 h. The reaction mixture was cooled and extracted with water (2×10 mL) and the organic layer was separated and dried over Na2SO4. The solvent was removed under reduced pressure to give an oil. The residue was purified by normal phase LC (20-85% EtOAc-hexanes) to give 3-hydroxymethyl-4-[2-(2-hydroxy-phenyl)-7-methyl-quinazolin-4-yl]-piperazine-1-carboxylic acid benzyl ester (216 mg, 64% yield). LC/MS: m/z 485.4 (M+H)+ at 3.02 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:20]2[CH:24]=[CH:23][NH:22][N:21]=2)=[C:6]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[C:8](=[O:19])[C:7]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][S:2][C:3]1[S:4][C:5]([C:20]2[CH:24]=[CH:23][NH:22][N:21]=2)=[C:6]2[CH2:11][CH2:10][NH:9][C:8](=[O:19])[C:7]=12
Reactant: CSc1sc(-c2cc[nH]n2)c2c1C(=O)N(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(-c2cc[nH]n2)c2c1C(=O)NCC2
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of tert-butyl 3-(methylsulfanyl)-4-oxo-1-(1H-pyrazol-3-yl)-6,7-dihydrothieno[3,4-c]pyridine-5(4H)-carboxylate (20 mg, 0.055 mmol) in CH2Cl2 (274 μL) at 0° C. was added TFA (274 μL). The solution was stirred at 0° C. for 15 min. The resulting mixture was quenched with saturated aq. NaHCO3 and extracted with CH2Cl2. The combined extracts were dried (Na2SO4) and concentrated. Purification by silica gel chromatography (gradient elution, 0-10% MeOH/dichloromethane) afforded the title compound. 1H NMR (400 MHz, ppm, CDCl3) δ 11.66 (s, 1 H); 8.05 (s, 1 H); 7.77 (d, J=2.6 Hz, 1 H); 6.53 (d, J=2.6 Hz, 1 H); 3.58 (t, J=6.5 Hz, 2 H); 3.07 (t, J=6.5 Hz, 2 H); 2.64 (s, 3 H). HRMS (ES+) m/z 266.0414 [(M+H)+; calcd for C11H11N3OS2: 266.0416].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:23])[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]2[CH:30](O)[CH2:31][CH2:32][C:25]=12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([O:23][CH:30]2[C:26]3[C:25](=[N:24][CH:29]=[CH:28][CH:27]=3)[CH2:32][CH2:31]2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([C:20](=[O:22])[CH3:21])[CH2:16][CH2:15]3)[N:10]=2)=[N:6][CH:7]=1
Reactant: CC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3O)n2)CC1
Reactant: OC1CCc2ncccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)N1CCC(c2nsc(Nc3ncc(Br)cc3OC3CCc4ncccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.3 %

Procedure:
1-(4-(5-(5-Bromo-3-hydroxypyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (0.083 g, 0.21 mmol), 6,7-dihydro-5H-cyclopenta[b]pyridin-5-ol (0.028 g, 0.21 mmol) and triphenylphosphine (0.057 g, 0.22 mmol) were combined in THF (1 mL) under nitrogen. Diisopropyl azodicarboxylate (0.043 ml, 0.22 mmol) was added in one portion. The reaction stirred at ambient temperature overnight. The solution was diluted with water, extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated. Flash chromatography gave 1-(4-(5-(5-bromo-3-(6,7-dihydro-5H-cyclopenta[b]pyridin-5-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)piperidin-1-yl)ethanone (0.022 g, 21%); Mass spectrum (apci) m/z=515.0, 517.0 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH:8]1[NH:17][C:18]([C:20]1[C:21](Cl)=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19])[CH2:14]2.[CH:28]1([SH:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[CH:9]12[CH2:15][CH:13]3[CH2:12][CH:11]([CH2:16][CH:7]([CH2:14]3)[CH:8]1[NH:17][C:18]([C:20]1[C:21]([S:33][CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[N:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[O:19])[CH2:10]2
Reactant: SC1CCCC1
Reactant: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NC1C2CC3CC(C2)CC1C3)c1ccc(Cl)nc1SC1CCCC1
Temperature: 60 °C
Reaction time: 6 h

Procedure:
Anhydrous Sodium carbonate (2.201 mL, 52.58 mmol) was added in one portion to N-(2-adamantyl)-2,6-dichloro-pyridine-3-carboxamide (5.7 g, 17.53 mmol) and cyclopentyl mercaptan (1.885 mL, 17.53 mmol) in DMF (50 mL) under nitrogen. The resulting suspension was stirred at 60° C. for 6 hours.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]2[CH:13]=[CH:14][C:15]([N+:23]([O-:25])=[O:24])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[C:17]=2[CH:18]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][CH2:9][C:10]1[NH:11][C:12]2[CH:13]=[CH:14][C:15]([N+:23]([O-:25])=[O:24])=[C:16]([C:19]([O:21][CH3:22])=[O:20])[C:17]=2[CH:18]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc2[nH]c(CCCO)cc12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c([N+](=O)[O-])ccc2[nH]c(CCCOS(C)(=O)=O)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.8 %

Procedure:
Methanesulfonyl chloride (0.176 g) was added to a solution of methyl 2-(3-hydroxypropyl)-5-nitro-1H-indole-4-carboxylate (Intermediate 21, 0.360 g) in pyridine (1 mL) and DCM (10 mL) and the reaction mixture was stirred at room temperature for 4 hours. The mixture was diluted with DCM, washed with aqueous citric acid (5%), aqueous sodium bicarbonate and brine, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was dissolved in toluene and evaporated to dryness, four times to give methyl 2-(3-methanesulfonyloxypropyl)-5-nitro-1H-indole-4-carboxylate (0.460 g) as an orange gum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[N:5]2[C:10]=1[C:9]([NH2:11])=[N:8][CH:7]=[N:6]2.[CH2:19]([N:26]1[CH:34]=[C:33]2[C:28]([CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32]2)=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([N:26]1[CH:34]=[C:33]2[C:28]([CH:29]=[C:30]([C:2]3[CH:3]=[C:4]([C:12]4[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=4)[N:5]4[C:10]=3[C:9]([NH2:11])=[N:8][CH:7]=[N:6]4)[CH:31]=[CH:32]2)=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ncnn2c(-c3ccnc(Cl)c3)cc(Br)c12
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Product: Nc1ncnn2c(-c3ccnc(Cl)c3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Yield: 28 %

Procedure:
Using a procedure similar to that of Example 4 with 5-bromo-7-(2-chloro-pyridin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine and 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-2H-indazole as starting materials, 60 mg (28%) of the desired product was isolated. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.5 (d, 2 H), 8.0 (m, 2 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 3 H), 7.25-7.15 (m, 4 H), 7.20 (s, 1 H), 5.70 (s, 2 H); ES-MS m/z 45224 [M+H]+, HPLC RT (min) 3.33.
Reaction SMILES: [CH:1]1([O:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C:9]([NH:11]C2SC=CN=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)N[Si](C)(C)C>ClCCl.CN(C)C=O>[CH:1]1([O:7][CH:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[C:9]([NH2:11])=[O:10])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1
Reactant: O=C(Nc1nccs1)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C(OC1C=CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of rac-(cyclohex-2-enyloxy)-(3,4-dichloro-phenyl)-acetic acid (Example 3; 409 mg, 1.36 mmol) in dichloromethane (10 mL) and N,N- dimethylformamide (one drop) cooled to 0° C. was treated with oxalyl chloride (2.0 M solution in dichloromethane, 0.95 mL, 1.90 mmol). The reaction was stirred at 0° C. for 1 h, then 1,1,1,3,3,3-hexamethyldisilazane (1.0 mL, 4.75 mmol) was added and the resulting cloudy mixture was stirred at 25° C. for 16 h. The reaction was quenched with methanol (10 mL), washed with an aqueous solution of 5% sulfuric acid (2×15 mL) and extracted with dichloromethane (3×10 mL). The combined organic extracts were washed with brine (1×10 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. The reaction product was purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 hexanes/ethyl acetate) to give rac-2-(cyclohex-2-enyloxy)-2-(3,4-dichloro-phenyl)-acetamide (311 mg, 76% yield) as a white solid: 103.6-108.9° C.; EI-HRMS m/e calcd for C14H15NCl2O2 (M+) 299.0479, found 299.0492.
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH2:22])[NH:20][N:21]=2)[CH:10]=[C:11]([O:13][CH3:14])[CH:12]=1.[CH3:23][CH:24]1[N:29]([CH3:30])[CH2:28][CH2:27][N:26]([C:31]2[N:36]=[CH:35][C:34]([C:37](OC)=[O:38])=[CH:33][N:32]=2)[CH2:25]1.Cl>C1(C)C=CC=CC=1.CO>[CH3:14][O:13][C:11]1[CH:10]=[C:9]([CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([NH:22][C:37]([C:34]3[CH:33]=[N:32][C:31]([N:26]4[CH2:27][CH2:28][N:29]([CH3:30])[CH:24]([CH3:23])[CH2:25]4)=[N:36][CH:35]=3)=[O:38])[NH:20][N:21]=2)[CH:8]=[C:7]([O:6][CH3:5])[CH:12]=1
Reactant: COC(=O)c1cnc(N2CCN(C)C(C)C2)nc1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3cnc(N4CCN(C)C(C)C4)nc3)[nH]n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 35.8 %

Procedure:
Trimethylaluminium (2M in toluene, 1.31 ml, 2.62 mmol) was added dropwise to a suspension of 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (260 mg, 1.05 mmol) and methyl 2-(3,4-dimethylpiperazin-1-yl)pyrimidine-5-carboxylate (263 mg, 1.05 mmol) in toluene (5.26 ml) at 25° C. The resulting solution was stirred at 60° C. for 18 h. The reaction mixture was poured into methanol (50 mL) and acidified with HCl (2M aqueous solution, to obtain a clear freely stirring solution). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford impure product. The impure material was purified by silica column chromatography, eluting with a gradient of 0 to 5% 7M NH3/MeOH in dichloromethane. Fractions containing product were evaporated to dryness to give material that was still impure. The residue was repurified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (175 mg, 36%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([N+:13]([O-])=O)[CH:7]=2)[CH2:5][CH2:4][CH2:3]1>[Pd].C(O)C>[CH3:1][C:2]1([C:6]2[CH:7]=[C:8]([NH2:13])[C:9]([NH2:10])=[CH:11][CH:12]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: CC1(c2ccc(N)c([N+](=O)[O-])c2)CCC1
Agent: [Pd]
Solvent: CCO
Product: CC1(c2ccc(N)c(N)c2)CCC1
Reaction time: 4 h
Yield: 101.1 %

Procedure:
A solution of 4-(1-methylcyclobutyl)-2-nitroaniline (138 mg. 0.668 mmol) in ethanol (8.5 mL, 140 mmol) was carefully treated with 10% Palladium on Carbon (14.2 mg, 0.0134 mmol) as a slurry in ethanol. The reaction flask was evacuated and filled with hydrogen gas three times and the reaction mixture was stirred under an atmosphere of Hydrogen for 4 h. The reaction mixture was filtered through a pad of solka Floc® and the pad was washed with 20 ml MeOH. The filtrate was concentrated to yield an oil which was placed under high vacuum yielding the desired compound as a solid (119 mg) which was used directly in the next step. 1H NMR (400 MHZ. CDCl3) δH ppm 6.66 (m, 1H), 6.53 (m, 2H), 3.34 (br. s., 4H), 2.33 (m, 2H), 2.08 (m, 1H), 1.99 (m. 2H). 1.80 (m, 1H), 1.42 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Br[CH2:10][CH:11]([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][N:3]=1
Reactant: Oc1cnc(Cl)nc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COc1cnc(Cl)nc1
Temperature: 80 °C

Procedure:
0.80 mg (6.13 mmol) 2-chloro-5-hydroxypyrimidine, 1.26 g (9.19 mmol) 1-bromo-2-methylpropane and 1.69 g (12.26 mmol) K2CO3 are added to 10 mL DMF and stirred at 80° C. over night. Afterwards the reaction is quenched by the addition of water and extracted with EtOAc. The org. layers are combined, dried over MgSO4, filtered and the solvent is removed in vacuo.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: C1CCNC1
Reactant: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CBr)cc1
Solvent: CC#N
Product: O=c1cc(OCc2ccc(Br)cn2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 90 mg (0.19 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 12.1b) in 2.0 mL acetonitrile is added at RT 63 μL (0.75 mmol) pyrrolidine. The reaction mixture is stirred for 2 h at RT and is directly transferred to a reverse HPLC for purification (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: C(OC(=O)[NH:5][C:6]1[N:15]([CH:16]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[C:20]([O:36][CH3:37])[CH:19]=2)[CH3:17])[C:9]2=[N:10][CH:11]=[C:12]([I:14])[CH:13]=[C:8]2[N:7]=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.O>[I:14][C:12]1[CH:13]=[C:8]2[N:7]=[C:6]([NH2:5])[N:15]([CH:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:28][CH:27]=4)=[C:20]([O:36][CH3:37])[CH:19]=3)[CH3:17])[C:9]2=[N:10][CH:11]=1
Reactant: CCOC(=O)Nc1nc2cc(I)cnc2n1C(C)c1ccc(OCc2ccc(C(F)(F)F)cc2)c(OC)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cc(C(C)n2c(N)nc3cc(I)cnc32)ccc1OCc1ccc(C(F)(F)F)cc1
Temperature: 160 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
To a stirred solution of ethyl(6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-yl)carbamate (1.30 g, 2.03 mmol) in ethanol (8 mL)/water (6 mL) was added potassium phosphate tribasic (1.76 g, 8.12 mmol). The mixture was heated to 160° C. in a microwave reactor. After 1 h, the reaction mixture was diluted with water (100 mL), resulting in a precipitate. The solids were isolated by filtration, washed with water (25 mL), and dried to provide 1.02 g (88%) of 6-iodo-3-(1-(3-methoxy-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)ethyl)-3H-imidazo[4,5-b]pyridin-2-amine as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=3)[N:21]=2)[N:16](COCC[Si](C)(C)C)[CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:38])([CH3:39])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]3[CH:24]=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=3)[N:21]=2)[NH:16][CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCCC2)C(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCCC4)C(C)(C)C)c3n2)cn1
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 2-(1-ethyl-1H-pyrazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide in CH2Cl2 (2.25 mL) was added TFA (0.75 mL). The reaction mixture was stirred overnight and concentrated. The residue was dissolved in a mixture of ammonium hydroxide, MeOH and CH2Cl2 (1:10:60, 3.0 ml) and stirred at room temperature for 90 min. The reaction mixture was then concentrated and the residue purified by SiO2 chromatography (0-10% MeOH/CH2Cl2) to afford 85 mg (89%) of 2-(1-ethyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide as a yellow powder. MS: (M+H)+=424.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:7]2[N:14]=[CH:15][C:16]([CH:17]=[O:18])=[C:6]2[N:5]=1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][C:4]1[CH:9]=[C:8]([NH:10][CH:11]2[CH2:13][CH2:12]2)[N:7]2[N:14]=[CH:15][C:16]([CH:17]=[O:18])=[C:6]2[N:5]=1
Reactant: [N-]=[N+]=Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(NC2CC2)n2ncc(C=O)c2n1
Reaction time: 6 h
Yield: 85 %

Procedure:
The above product 5-azido-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (1.09 g, 4.46 mmol) was subjected to hydrogenation using 10% wt palladium on carbon in ethanol. The reaction was stirred under hydrogen for 6 hours. The mixture was filtered through celite and sonicated with 1:1 mixture of ethyl acetate and hexane. The light yellow solid was filtered and dried to yield 5-amino-7-(cyclopropylamino) pyrazolo[1,5-a]pyrimidine-3-carbaldehyde as product 750 mg (85% yield). LCMS (M+1=218)
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([C:21]3[N:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[C:23]([C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=4)[N:22]=3)[CH:18]=[CH:17][N:16]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:29][CH:27]([F:28])[C:25]1[CH:24]=[C:23]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:38])([F:37])[F:39])=[CH:32][CH:31]=2)[N:22]=[C:21]([C:19]2[CH:18]=[CH:17][N:16]=[C:15]([C:11]3[CH:10]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:14]=[CH:13][CH:12]=3)[CH:20]=2)[N:26]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)F)n3)ccn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 51 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{4-[4-difluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonamide (0.37 g) in dichloromethane (5 ml) was added TFA (5 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (20 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as an off-white solid (0.17 g, 34%). MS (ISP) 507.2 [(M+H)+]; mp 233.5° C.
Reaction SMILES: NC1SC2C3C(CC=2[C:3]=1[C:14](N)=[O:15])=CC=CC=3.[NH2:17][C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:33]([NH2:35])=[O:34])=[CH:27][C:26]([O:31][CH3:32])=[CH:25][CH:24]=3>>[C:14]([NH:17][C:18]1[S:22][C:21]2[C:23]3[C:28]([CH2:29][CH2:30][C:20]=2[C:19]=1[C:33]([NH2:35])=[O:34])=[CH:27][C:26]([O:31][CH3:32])=[CH:25][CH:24]=3)(=[O:15])[CH3:3]
Reactant: COc1ccc2c(c1)CCc1c-2sc(N)c1C(N)=O
Reactant: NC(=O)c1c(N)sc2c1Cc1ccccc1-2
Product: COc1ccc2c(c1)CCc1c-2sc(NC(C)=O)c1C(N)=O

Procedure:
The title compound was prepared by the same procedure as Example 3 except that 2-amino-4H-indeno[1,2-b]thiophene-3-carboxylic acid amide was replaced with 2-amino-7-methoxy-4,5-dihydro-naphtho[1,2-b]thiophene-3-carboxylic acid amide to give the above title compound as light grey solid. ESMS m/z: 317 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.NC(N)=[S:27].C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C>[C:16]1([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=1[C:10]1[C:9]([CH3:20])=[N:8][N:7]2[C:2]3[S:27][CH2:23][CH2:22][C:3]=3[C:4]([CH3:21])=[N:5][C:6]=12
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Reactant: NC(N)=S
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCS4)c(C)c1
Reaction time: 8 h
Yield: 97.7 %

Procedure:
A solution of 7-chloro-6-(2-chloroethyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidine (500 mg, 1.38 mmol), thiourea (105 mg, 1.38 mmol) and sodium carbonate (180 mg, 1.73 mmol) in ethanol (10 mL) was heated under reflux for one hour. After overnight, water was added and the resulting crystals were collected by filtration. The crystals were washed with water, to give the title compound (436 mg) as white crystals.