Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7](N[N+]([O-])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(O)C.S(=O)(=O)(O)O.[N:22]([O-:24])=[O:23].[Na+]>C(Cl)(Cl)Cl.O>[CH:1]([C:4]1[CH:5]=[C:6]([N+:22]([O-:24])=[O:23])[CH:7]=[CH:12][CH:13]=1)([CH3:2])[CH3:3]
Reactant: O=N[O-]
Reactant: CC(C)c1ccc(N[N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.56 G. of 4-isopropylnitroaniline is dissolved in 580 ml. of ethanol and stirred. 30.4 Ml. of concentrated sulfuric acid is added dropwise. The reaction mixture is heated to reflux and a solution of 16 g. of sodium nitrite in 25 ml. of water is added dropwise over 5 minutes. Heating is continued for 1 hour and then the reaction mixture is allowed to cool to room temperature. 250 Ml. of water and 1200 ml. of chloroform is added, the layers are separated and the water layer is extracted with an additional 230 ml. of chloroform. The chloroform layers are combined, washed with 250 ml. of water, dried over sodium sulfate and the solvent is removed by distillation through a short vigreau column at atmosphere pressure. The residue is vacuum distilled at from 8.6 to 9.0 mm. of Hg. The fraction taken at 112° to 128° C. is used as is in the next step.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2.[Al+3].[Cl-].[Cl-].[Cl-].CCS>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@H:8]([C@H:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH2:7][CH2:6]2
Reactant: COC(=O)[C@@H](C)[C@@H]1CCc2cc(OC)ccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: COC(=O)[C@@H](C)[C@@H]1CCc2cc(O)ccc21
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 37.8 %

Procedure:
A solution of methyl (2S)-2-[(1S)-5methoxy-2,3-dihydro-1H-inden-1yl]propanoate (Example 11) (5.70 g, 0.024 mol) in CH2Cl2 (70 mL), under argon, was cooled to 0-5° C. and AlCl3 (16.22 g, 0.122 mol) was added portion-wise while maintaining the temperature below 10° C. To this mixture was added EtSH (9.0 mL, 0.122 mol) and the resulting mixture was stirred at 0-5° C. for 4 h. The reaction mixture was then slowly poured into vigorously stirred ice-water (200 mL) and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed with water, brine, dried (Na2SO4), filtered, and concentrated to dryness under vacuum. The resulting crude product was purified by silica gel flash chromatography (gradient of 10-40% ethyl acetate/hexanes) to give 4:2 g (80%) of the title compound. 1H NMR (400 MHz, CDCl3): δ 6.93 (d, 1H), 6.70 (s, 1H), 6.63 (dd, 1H), 3.72 (s, 3H), 3.50 (q, 1H), 2.83 (m, 3H), 2.19 (m, 1H), 1.90 (m, 1H), 1.08 (d, 3H); LC-MS: RT=8.60 min, (M+H)+ 220.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[C:6]([N:11]([CH3:20])[S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:21]1[S:22][CH:23]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:24][N:25]=1.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[F:1][C:2]1[C:10]2[C:5](=[C:6]([N:11]([CH3:20])[S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:21]1[S:22][CH:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][N:25]=1
Reactant: CCOC(=O)CC1CN=C(c2[nH]c3c(N(C)S(=O)(=O)c4cccs4)cccc3c2F)S1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN(c1cccc2c(F)c(C3=NCC(CC(=O)O)S3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of ethyl (2-{3-fluoro-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (0.1 g) in tetrahydrofuran (1 mL) and ethanol (1 mL) was added 2N aqueous sodium hydroxide solution (0.15 mL), and the mixture was stirred at room temperature for 1 hr, and then at 50° C. for 1 hr. The mixture was acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was recrystallized from ethyl acetate to give the title compound (0.080 g, yield 85%) as colorless crystals. melting point 213-214° C.
Reaction SMILES: [CH:1]1([C:7]2[N:16]3[C:10]([CH2:11][C:12](=[O:34])[N:13]([CH2:21][C:22]([N:24]([CH:31]([CH3:33])[CH3:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37]([CH:44]=O)=[CH:36]1>>[CH:1]1([C:7]2[N:16]3[C:10]([CH:11]([CH2:44][C:37]4[C:38]5[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=5)[NH:35][CH:36]=4)[C:12](=[O:34])[N:13]([CH2:21][C:22]([N:24]([CH:31]([CH3:32])[CH3:33])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=43)=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)N(C(=O)CN1C(=O)Cc2nnc(C3CCCCC3)n2-c2ccccc21)c1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Product: CC(C)N(C(=O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(C3CCCCC3)n2-c2ccccc21)c1ccccc1

Procedure:
Following the procedure described for Example 6(A), Step A; 2-(1-cyclohexyl-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl)-N-isopropyl-N-phenyl-acetamide (Preparation 8(B)) was condensed with 1H-indole-3-carbaldehyde. This intermediate was carried forward according to Example 6(A) Step B to afford 2-[1-cyclohexyl-4-(1H-indol-3-ylmethyl)-5-oxo-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-N-phenyl-acetamide. 1H NMR (CD2Cl2) δ 8.44 (s, 1H), 7.42-7.48 (m, 4H), 7.28-7.42 (m, 4H), 7.17-7.19 (m, 2H), 7.07-7.10 (m, 1H), 6.98-7.02 (m, 1H), 4.90-4.94 (m, 1H), 4.07-4.15 (m, 1H), 3.91 (d, 1H), 3.67-3.73 (m, 2H), 2.83 (br.m, 1H), 2.19 (br.m, 1H), 1.89-1.92 (m, 2H), 1.68 (br.s, 4H), 1.50-1.59 (m, 1H), 1.32-1.35 (m, 2H), 1.23 (t, 1H), 1.06 (m, 6H); MS 587 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[N:9]=[C:10]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=3)[CH:17]=[CH:16][N:15]=2)[S:11][CH:12]=1.Br[CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CN(C=O)C>[CH3:7][C:8]1[N:9]=[C:10]([NH:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=3)[O:27][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:17]=[CH:16][N:15]=2)[S:11][CH:12]=1
Reactant: Cc1csc(Nc2cc(Oc3cccc(O)c3)ccn2)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1csc(Nc2cc(Oc3cccc(OCC(=O)OC(C)(C)C)c3)ccn2)n1

Procedure:
A mixture of potassium carbonate (3.00 g, 21.7 mmol), 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)phenol (0.750 g; 2.51 mmol), and tert-butyl 2-bromoacetate (0.489 g, 2.51 mmol) was stirred in DMF (20 mL) overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water, and the ethyl acetate was washed with water and brine, dried and concentrated. The residue was purified via MPLC (Biotage) eluting with 3:2 hexane:ethyl acetate to afford the desired product as a white powder. 1H NMR (d6-DMSO) δ 11.01 (s, 1H), 8.16 (d, 1H), 7.38 (t, 1H), 6.85 (d, 1H), 6.79 (d, 1H), 6.74 (s, 1M), 6.56 (s, 1H), 6.49-6.52 (m, 2H), 4.68 (s, 2H), 2.21 (s, 3H), 0.90 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[Cl:18][C:19]1[CH:20]=[C:21]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccccc2Br)cc1
Product: COc1ccc(-c2ccccc2-c2ccc(S(C)(=O)=O)cc2)cc1Cl
Yield: 68.3 %

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 4.0 g (13 mmol) of 1-bromo-2-[4-(methylsulfonyl)phenyl]benzene (Example 4, Step 2) was reacted with 2.86 g (15.4 mmol) of 3-chloro-4-methoxyphenylboronic acid (Step 2). Purification by silica gel chromatography (Waters PrepLC500A) with ethyl acetate/hexane (35:65) and subsequent recrystallization from ethyl acetate/hexane gave 3.31 g (69%) of 2-chloro-1-methoxy-4-[2-[4-(methylsulfonyl)phenyl]phenyl]benzene as a colorless solid: mp 161.5-162.3° C.; NMR (CDCl3) δ 3.05 (s, 3H), 3.88 (s, 3H), 6.75 (d, J=9 Hz, 1H), 6.87 (dd, J=1.5, 9 Hz, 1H), 7.17 (d, J=2 Hz, 1H), 7.34 (d, J=9 Hz, 2H), 7.37-7.51 (m, 4H), 7.82 (d, J=8 Hz, 2H). MS (EI): m/e (rel intensity) 372 (100), 243 (24); HRMS Calc'd for C20H17ClO3S: 372.0587. Found: 372.0557. Anal. Calc'd for C20H17ClO3S: C, 64.43; H, 4.60; Cl, 9.51. Found: C, 64.17; H, 4.56; Cl, 9.63.
Reaction SMILES: N[C@@H]1C2C(=CC=CC=2)C[C@@H]1O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:28]([C:29](=[O:40])[C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)=[C:27]([CH:41]([CH3:43])[CH3:42])[CH:26]=[C:25]3[C:20]=2[C:21](=[O:46])[CH2:22][C:23]([CH3:45])([CH3:44])[O:24]3)=[CH:15][CH:14]=1.CO>O1CCCC1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:28]([C:29]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=3)=[O:40])=[C:27]([CH:41]([CH3:42])[CH3:43])[CH:26]=[C:25]3[C:20]=2[C@@H:21]([OH:46])[CH2:22][C:23]([CH3:44])([CH3:45])[O:24]3)=[CH:17][CH:18]=1
Reactant: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(C(F)(F)F)cc1)C(=O)CC(C)(C)O2
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)c1cc2c(c(-c3ccc(F)cc3)c1C(=O)c1ccc(C(F)(F)F)cc1)[C@@H](O)CC(C)(C)O2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
120 μl (680 μmol) of borane/N,N-diethylaniline complex are added slowly to a solution of 3.79 mg (30 μmol) of (1R,2S)-1-aminoindan-2-ol in 4 ml of tetrahydrofuran. The mixture is then cooled to 0° C., and a solution of 82 mg (170 μmol) of 5-(4-fluorophenyl)-7-isopropyl-2,2-dimethyl-6-[4-(trifluoromethyl)benzoyl]-2,3-dihydro-4H-chromen-4-one (Example 23A) in 4 ml of tetrahydrofuran is then slowly added dropwise. The mixture is allowed to thaw slowly and stirred at room temperature overnight. Methanol is then added, and the solvent is removed under reduced pressure. The residue is taken up in ethyl acetate and washed in each case twice with 1 M hydrochloric acid and saturated sodium bicarbonate solution and once with saturated sodium chloride solution. The organic phase is dried over sodium sulfate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel (mobile phase: gradient cyclohexane→cyclohexane/ethyl acetate 10:1) gives the target compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.Cl>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][N:5]([S:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][Cl:23])=[CH:33][CH:32]=1)(=[O:35])=[O:36])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: COC(=O)CNCc1ccc(OC)cc1
Reactant: O=S(=O)(Cl)c1ccc(OCCCCl)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 30.97 g (0.148 mol) of (4-methoxy-benzylamino)-acetic acid methyl ester in 200 ml of dioxane and 200 ml of H2O, 25 ml (0.178 mol) of triethylamine a solution of 43.9 g (0.163 mol) of 4-(3-chloro-propoxy)-benzenesulfonyl chloride in 100 ml of dioxane is added at 0-5° C. The mixture is allowed to warm to r.t. and stirred for 3 h. The reaction mixture is neutralized with 1N HCl and extracted with AcOEt. The combined extracts are dried over MgSO4 and concentrated under reduced pressure to give {[4-(3-chloro-propoxy)benzenesulfonyl]-(4-methoxy-benzyl)-amino}-acetic acid methyl ester; NMR (CDCl3): 2.25-2.35 (m, 2H), 3.56 (s, 3H), 3.75 (t, 2H, J=6.04 Hz), 3.79 (s, 3H), 3.9 (s, 2H), 4.2 (t, 2H, J=6.04 Hz), 4.39 (s, 2H), 6.84 (d, 2H, J=8.56 Hz), 6.99 (d, 2H, J=9.08 Hz), 7.16 (d, 2H, J=9.08 Hz), 7.83 (d, 2H, J=8.56 Hz).
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:17]([O-])([O-:19])=[O:18].[K+]>S(=O)(=O)(O)O>[CH:1]1([N:7]2[CH2:15][C:14]3[C:9](=[CH:10][C:11]([N+:17]([O-:19])=[O:18])=[CH:12][CH:13]=3)[C:8]2=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1c2ccccc2CN1C1CCCCC1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1c2cc([N+](=O)[O-])ccc2CN1C1CCCCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
The compound (50.00 g, 0.23 mol) obtained in step (b) just above was dissolved at 0° C. in concentrated sulfuric acid (413 ml). Potassium nitrate (36.63 g, 0.36 mol) was added to the solution. The mixture was stirred overnight while gradually raising the temperature from 0° C. to room temperature. The reaction solution was poured into ice water (2000 ml), and then extracted with ethyl acetate. The extract was then washed with water, a saturated aqueous NaHCO3 solution, and saturated saline in that order, and then dried over anhydrous MgSO4. The solvent was removed by distillation under the reduced pressure. The precipitated crystals were collected by suction filtration, washed with hexane, and then dried to give 49.78 g (82%) of 2-cyclohexyl-2,3-dihydro-6-nitro-1H-isoindol-1-one as a pale yellow crystalline product.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][C:32]1[C:38]([OH:39])=[CH:37][CH:36]=[CH:35][C:33]=1[OH:34]>ClCCl.O>[OH:34][C:33]1[CH:35]=[CH:36][CH:37]=[C:38]([OH:39])[C:32]=1[NH:31][C:16](=[O:18])[CH2:15][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: COc1ccc(CC(=O)O)cc1OC1CCCC1
Reactant: Nc1c(O)cccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: ClCCl
Product: COc1ccc(CC(=O)Nc2c(O)cccc2O)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A suspension of 3-cyclopentyloxy-4-methoxyphenylacetic acid (2.49 g) and 1,1′-carbonyl diimidazole (2.31 g) in dichloromethane (10 ml) was stirred at room temperature, under argon, for 2 hours. The resulting solution was added to a stirred suspension of 2-aminoresorcinol (1.62 g) in dichloromethane (15 ml) and the mixture stirred at room temperature, under argon, overnight. The reaction mixture was diluted with water (100 ml) and extracted with dichloromethane (3×50 ml). The combined organic extracts were washed with water (100 ml), 1 N HCl (100 ml) and brine (100 ml), dried over CaSO4 and evaporated in-vacuo to yield the title compound (2.122 g, 60%) as a beige solid.
Reaction SMILES: C(O)=O.OS([O-])(=O)=O.[K+].[Cl:10][C:11]1[CH:12]=[C:13]2[N:36](COCC[Si](C)(C)C)[C:35]([O:45][C@H:46]3[C@H:50]4[O:51][CH2:52][C@@H:53]([OH:54])[C@H:49]4[O:48][CH2:47]3)=[N:34][C:14]2=[N:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:27][CH:28]=2)=[CH:19][CH:18]=1.[OH-].[Na+]>O.C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]2[NH:36][C:35]([O:45][C@H:46]3[C@H:50]4[O:51][CH2:52][C@@H:53]([OH:54])[C@H:49]4[O:48][CH2:47]3)=[N:34][C:14]2=[N:15][C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[CH:24]=[N:25][C:26]([N:29]3[CH:33]=[CH:32][CH:31]=[N:30]3)=[CH:27][CH:28]=2)=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(-c4ccc(-n5cccn5)nc4)cc3)c(Cl)cc21
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=CO
Product: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2nc(-c3ccc(-c4ccc(-n5cccn5)nc4)cc3)c(Cl)cc2[nH]1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of formic acid (6 mL, 156 mmol), saturated aqueous KHSO4 (0.66 mL, 2.58 mmol), and (3R,3aR,6R,6aR)-6-[6-chloro-5-[4-(6-pyrazol-1-yl-3-pyridyl)phenyl]-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydro-furo[3,2-b]furan-3-ol (1.67 g, 2.58 mmol) was stirred at 60° C. overnight, and then cooled to 0° C. in an ice bath. The pH of the reaction mixture was adjusted to pH>11 through the addition of NaOH (6.24 g, 156 mmol) in water (5 mL). THF (10 mL) was added to the reaction mixture, and the reaction was removed from the ice bath and allowed to warm to room temperature. After 30 minutes, the pH of the reaction mixture was adjusted to pH 6 through the addition of concentrated HCl. The biphasic mixture was separated. The organic layer and the resulting white precipitate were concentrated under reduced pressure, redissolved in DMSO, and filtered before being purified by preparative HPLC Reverse phase (C-18), using a 19×100 mm Sunfire™ column and eluting with a 10%-90% acetonitrile/water+0.05% TFA gradient followed by a 90% acetonitrile/water+0.05% TFA flush. The desired fractions were combined, and evaporated under reduced pressure. The resulting residue was washed with MeOH and lyophilized from acetonitrile and water to afford the title compound as a white solid. LC-MS: calculated for C26H21ClN6O4 516.13 observed m/e: 517.22 (M+H)+ (Rt 1.16/2 min); 1H NMR δ (ppm) (CD3OD): 8.80 (d, J=2.5 Hz, 1H), 8.67 (d, J=2.0 Hz, 1H), 8.30 (dd, J=2.8 Hz, 8.5 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H), 7.81-7.83 (m, 6H), 6.84 (t, J=2.3 Hz, 1H), 5.56 (qt, J=55 Hz, 1H), 4.99 (t, J=5.3 Hz, 1H), 4.49 (t, J=5.0 Hz, 1H), 4.28-4.32 (m, 1H), 4.19 (dd, J=6.0 Hz, 10 Hz, 1H), 4.13 (dd, J=4.8 Hz, 10.3 Hz, 1H), 3.92 (dd, J=7.0 Hz, J=8.0 Hz, 1H), 3.62 (t, J=8.5 Hz, 1H).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].C1COCC1.[CH3:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15]>O>[CH3:12][O:13][C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH:2]=[O:4])[CH2:18][CH2:17]1)=[O:15]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C1CCC(=O)CC1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1CCC(C=O)CC1
Reaction time: 1 h
Yield: 79.3 %

Procedure:
To dried MTP 50.0 g (146 mmol), THF 500 ml was added, and potassium-t-butoxide 18.0 g (160 mmol) was added. The mixture was stirred for about one hour. To the reactant, a THF solution (100 ml) of 4-oxocyclohexane carboxylic acid methylester 21.9 g (140 mmol) was added dropwise, and the mixture was stirred for 2 hours. Water 500 ml was added to the reactant, the product was extracted with diethylether. The extract was washed with a sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (eluent: toluene). Such resulting purified material was stirred in mixed solvent of 2N-hydrochloric acid 500 ml and acetone 500 ml for 5 hours at room temperature, and the product was extracted with toluene. The extract was washed with a saturated sodium bicarbonate aqueous solution and then with water, and dried over anhydrous magnesium sulfate. Toluene was distilled off to obtain 4-formylcyclohexane carboxylic acid methyl ester 18.8 g (111 mmol). The yield was 79.2% from 4-oxocyclohexane carboxylic acid methylester.
Reaction SMILES: ClC(N(C)C)=C(C)C.[CH2:9]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([CH:25]=[CH:26][C:27]([OH:29])=O)[CH2:21][CH2:20]1)=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:40][N:41]1[C@@H:45]([CH3:46])[C@@H:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:43][C:42]1=[O:53]>C1COCC1.O>[CH2:9]([O:16][C:17]([N:19]1[CH2:20][CH2:21][CH:22]([CH:25]=[CH:26][C:27]([N:43]2[C@H:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C@H:45]([CH3:46])[N:41]([CH3:40])[C:42]2=[O:53])=[O:29])[CH2:23][CH2:24]1)=[O:18])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: C[C@H]1[C@@H](c2ccccc2)NC(=O)N1C
Reactant: O=C(O)C=CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)=C(Cl)N(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1[C@@H](c2ccccc2)N(C(=O)C=CC2CCN(C(=O)OCc3ccccc3)CC2)C(=O)N1C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (1.37 g) was added dropwise over 10 minutes to a solution of 3-(benzyloxycarbonylpiperidin-4-yl)propenoic acid (2.5 g) in THF (20 ml) and the mixture was stirred for 1.5 hours. Lithium bis(trimethylsilyl)amide (8.65 ml)was added to a solution of (4R,5S)-1,5dimethyl4-phenyl-2-imidazolidinone (1.64 g) in THF (20 ml) at −10° C. and the mixture was stirred at −10° C. for 10 minutes, allowed to warm to 0° C. and then cooled again to −10° C. The acid chloride solution (prepared above) was added dropwise and the mixture was allowed to warm to room temperature. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were dried, evaporated to dryness and the residue was chromatographed on a Bond-Elut column eluted with an ethyl acetate/isohexane mixture (1:1) to give the title compound, yield 3.6 g. NMR (DMSOd6): 0.6 (d, 3H) 0.95 (d, 1H) 1.2 (m, 2H) 1.55 (m, 2H) 2.4 (m, 1H) 2.3 (s, 3H) 2.8 (m, 2H) 3.95 (m, 3H) 5 (s, 2H) 5.3 (d, 1H) 6.9 (m, 1H) 7.1 (m, 2H) 7.2–7.4 (m, 8H).
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[N:23]1([CH2:28][CH2:29][O:30][C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][S:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][C:6]1[C:5]2[N:4]([N:3]=[C:2]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][CH2:29][CH2:28][N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:32][CH:33]=3)[N:22]=2)[CH:9]=[CH:8][CH:7]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Cl)nc12
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccccc1CNc1cccn2nc(Nc3ccc(OCCN4CCCC4)cc3)nc12

Procedure:
N(8)-(2-Methanesulfonyl-benzyl)-N(2)-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine-2,8-diamine was prepared from (2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-(2-methanesulfonyl-benzyl)-amine (75.0 mg, 0.223 mmol) and 4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine (51.0 mg, 0.247 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.037 g, 33%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.11 (d, J=7.8 Hz, 1H), 7.84 (d, J=6.6 Hz, 1H), 7.67-7.58 (m, 2H), 7.52 (t, J=6.9 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.8 Hz, 2H), 6.68 (t, J=7.5 Hz, 1H), 6.52 (s, 1H), 6.42 (d, J=7.6 Hz, 1H), 5.28 (t, J=6.0 Hz, 1H), 4.96 (d, J=6.2 Hz, 2H), 4.12 (t, J=5.6 Hz, 2H), 3.16 (s, 3H), 2.96-2.88 (m, 2H), 2.67 (br s, 4H), 1.89-1.76 (m, 4H). MS=507 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:17](Cl)=[O:18].[NH2:20][C:21]1[CH:22]=[C:23]([C:28]#[N:29])[C:24]([Cl:27])=[N:25][CH:26]=1.O>N1C=CC=CC=1>[Cl:27][C:24]1[N:25]=[CH:26][C:21]([NH:20][C:17]([C:3]2[CH:4]=[N:5][N:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][N:8]=3)[C:2]=2[CH3:1])=[O:18])=[CH:22][C:23]=1[C:28]#[N:29]
Reactant: Cc1c(C(=O)Cl)cnn1-c1ccc(C(F)(F)F)cn1
Reactant: N#Cc1cc(N)cnc1Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1c(C(=O)Nc2cnc(Cl)c(C#N)c2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Yield: 195.8 %

Procedure:
5-Methyl-1-(5-(trifluoro methyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid chloride (200 mg) and 5-amino-2-chloro-3-cyanopyridine (228 mg) were dissolved in pyridine (10 ml) and stirred at room temperature. After completion of the reaction, water was added to the reaction solution, the precipitated solid was collected by filtration and dried under heating and blow to give N-(6-chloro-5-cyanopyridin-3-yl)-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (550 mg) as a light brown solid.