Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[N:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.OC1C=CC=C2C=1N=CC=C2.Cl.[NH2:38][OH:39].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:24]([NH:38][OH:39])=[NH:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: NO
Reactant: N#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CCO
Solvent: O
Product: N=C(NO)c1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Yield: 92 %

Procedure:
To a suspension of 7-chloro-1-oxo-2-[4-(trifluoromethoxy)benzyl]isoindoline-5-carbonitrile (500 mg, 1.36 mmol) in ethanol (2 ml), 8-hydroxyquinoline (495 mg, 3.41 mmol) was added, followed by a solution of hydroxylamine hydrochloride (199 mg, 2.86 mmol) in water (1 ml) and a solution of sodium carbonate (230 mg, 2.2 mmol) in water (1 ml). The resulting mixture was refluxed for 4 hours. After removal of solvents, the residue was loaded to a flash chromatography. The product was purified (20% EtOAc/hexanes to 2% ammonia in MeOH/EtOAc) and obtained a 500 mg of greenish foam (90%). 1H NMR (300 MHz, CDCl3): δ 10.04 (s, 1H) 7.48-7.61 (m, 2H), 7.28-7.36 (m, 2H), 7.17-7.21 (m, 2H), 6.04 (br, 1H), 4.77 (s, 2H), 4.22 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Cl[CH2:10][CH:11]=O>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: Nc1ccc(I)cn1
Reactant: O=CCCl
Solvent: CCO
Product: Ic1ccc2nccn2c1
Temperature: 85 °C

Procedure:
To a solution of the product (480 mg, 2.18 mmol) from Step A in ethanol (12 mL) was added chloroacetaldehyde (50 wt. % in water, 0.336 mL) and the mixture was heated at 85° C. for 3 h. After cooling to room temperature, the solution was concentrated under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic phase was separated, dried (magnesium sulfate) and concentrated in vacuo to yield the product as light-brown solid which was used without further purification. LC/MS 244.8 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:24]COC)=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[N+:21]([O-:23])=[O:22])[CH:14]=[N:13][CH:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[C:5]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][C:19]=3[N+:21]([O-:23])=[O:22])[CH:14]=[N:13][CH:12]=2)[C:4]=1[OH:24]
Reactant: COCOc1c(-c2cncc3cccc([N+](=O)[O-])c23)ccc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(-c2cncc3cccc([N+](=O)[O-])c23)c(O)c1OC
Reaction time: 4 h

Procedure:
After dissolving isoquinoline 4a (5.285 g, 0.014 mol) in 200 ml of methanol by gentle heating, p-toluenesulfonic acid monohydrate (8.15 g; 0.043 mol) was added in several portions. Stirring was continued for four hours at room temperature. After completion of the reaction, the solution was made basic by adding saturated sodium bicarbonate. The product was then extracted with dichlormethane (3×250 ml), dried (Na2SO4), and concentrated. The resulting yellow solid (4.65 g; 98%) was used directly in the next reaction. An analytical sample was recrystallized from methanol: mp 170-174° C.; 1H NMR: (300 MHz, CDCl3): 9.33 (s, 1H); 8.62 (s, 1H); 8.24 (dd, 1H, J=7.2, 0.9 Hz); 7.99 (dd, 1H, J=6.3, 1.2 Hz); 7.67 (t, 1H, J=7.8 Hz); 6.96 (d, 1H, J=8.7 Hz); 6.59 (d, 1H, J=8.7 Hz); 5.88 (bs, 1H); 3.94 (s, 3H); 3.92 (s, 3H). CIMS m/z: 327 (M+H+, 100%). Anal Calc'd for C17H14N2O5: C, 62.57; H, 4.32; N, 8.58. Found: C, 62.18; H, 4.38; N, 8.35.
Reaction SMILES: IC1C=NC(N)=C2OC(C3C4C(=CN=CC=4)N(C)N=3)=CC=12.I[C:23]1[CH:28]=[N:27][C:26]([NH2:29])=[C:25]2[O:30][C:31]([C:33]3[N:34]([CH3:42])[N:35]=[C:36]4[C:41]=3[CH:40]=[CH:39][N:38]=[CH:37]4)=[CH:32][C:24]=12.CC1(C)C(C)(C)OB([C:51]2[CH:52]=[N:53][N:54]([CH:56]3[CH2:61][CH2:60][N:59]([C:62](=[O:64])[CH3:63])[CH2:58][CH2:57]3)[CH:55]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:29][C:26]1[N:27]=[CH:28][C:23]([C:51]2[CH:52]=[N:53][N:54]([CH:56]3[CH2:57][CH2:58][N:59]([C:62](=[O:64])[CH3:63])[CH2:60][CH2:61]3)[CH:55]=2)=[C:24]2[CH:32]=[C:31]([C:33]3[N:34]([CH3:42])[N:35]=[C:36]4[C:41]=3[CH:40]=[CH:39][N:38]=[CH:37]4)[O:30][C:25]=12
Reactant: CC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cn1nc2cnccc2c1-c1cc2c(I)cnc(N)c2o1
Agent: Cn1nc(-c2cc3c(I)cnc(N)c3o2)c2ccncc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5c6ccncc6nn5C)cc34)cn2)CC1
Temperature: 80 °C
Yield: 16.1 %

Procedure:
A 2:1 mixture of 4-iodo-2-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-7-amine and 4-iodo-2-(2-methyl-2H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-7-amine (0.042 g, 0.102 mmol) and 1-{4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidin-1-yl}ethanone (0.041 g, 0.13 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.8 mL). The mixture was degassed with nitrogen for 10 min. To this mixture was added potassium carbonate (0.0530 g, 0.383 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride dichloromethane adduct (0.0104 g, 0.0128 mmol), and the mixture was heated to 80° C. for 5 h. Purification of the residue by MDP afforded 0.0143 g (29%) of 1-(4-{4-[7-amino-2-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}piperidin-1-yl)pethanone as a yellow gum (Ex. 363), and 0.0075 g (30%) 1-(4-{4-[7-amino-2-(2-methyl-2H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}piperidin-1-yl)ethanone as a yellow gum (Ex. 364). 1-(4-{4-[7-amino-2-(1-methyl-1H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}piperidin-1-yl)ethanone: 1H NMR (400 MHz, CD3OD): δ 9.77 (s, 1 H), 9.11 (d, J=5.8 Hz, 1 H), 8.60 (d, J=6.3 Hz, 1 H), 8.35 (s, 1 H), 8.03 (d, J=0.5 Hz, 1 H), 7.97 (s, 1 H), 7.89 (s, 1 H), 4.76-4.67 (m, 1 H), 4.61 (tt, J=4.1, 11.4 Hz, 1 H), 4.51 (s, 3 H), 4.18-4.09 (m, 1 H), 3.44-3.35 (m, 1 H), 2.90 (dt, J=2.5, 13.0 Hz, 1 H), 2.33-2.21 (m, 2 H), 2.20 (s, 3 H), 2.18-2.10 (m, 1 H), 2.10-1.98 (m, 1 H); MS (ESI): 457.37 [M+H]+; HPLC tR=2.23 min. 1-(4-{4-[7-amino-2-(2-methyl-2H-pyrazolo[3,4-c]pyridin-3-yl)furo[2,3-c]pyridin-4-yl]-1H-pyrazol-1-yl}piperidin-1-yl)ethanone: 1H NMR (400 MHz, CD3OD): δ 9.85 (s, 1 H), 8.90 (d, J=6.6 Hz, 1 H), 8.39 (d, J=6.8 Hz, 1 H), 8.35 (s, 1 H), 8.07 (s, 1 H), 7.97 (s, 1 H), 7.91 (s, 1 H), 4.83 (s, 3 H), 4.73-4.65 (m, 1 H), 4.59 (tt, J=4.2, 11.4 Hz, 1 H), 4.16-4.07 (m, 1 H), 3.41-3.32 (m, 1 H), 2.88 (dt, J=2.5, 12.9 Hz, 1 H), 2.29-2.18 (m, 2 H), 2.17 (s, 3 H), 2.16-2.08 (m, 1 H), 2.08-1.95 (m, 1 H); MS (ESI): 457.37 [M+H]+; HPLC tR=2.14 min.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[C:11]([Cl:12])=[C:10]([O:13][CH:14]([F:16])[F:15])[N:9]([CH3:17])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].N([O-])=O.[Na+].[BrH:24]>O>[Br:24][C:2]1[N:6]([C:7]2[C:11]([Cl:12])=[C:10]([O:13][CH:14]([F:16])[F:15])[N:9]([CH3:17])[N:8]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: Cn1nc(-n2ncc(C#N)c2N)c(Cl)c1OC(F)F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Cn1nc(-n2ncc(C#N)c2Br)c(Cl)c1OC(F)F
Temperature: -6 °C
Reaction time: 0.25 h

Procedure:
5.68 g (19.7 mmol) 5-Amino-1-(4-chloro-5-difluoromethoxy-1-methyl-3-pyrazolyl)-4-pyrazolecarbonitrile was dissolved in 66.3 ml hydrobromic acid (47%) and the mixture cooled to -6° C. Under a nitrogen atmosphere, 2.36 g (34.2 mmol) sodium nitrite in 5.9 ml water was added dropwise. The mixture was stirred for 15 minutes at this temperature and heated to room temperature. 200 ml water was then added and the mixture extracted 4 times with methylene chloride. The organic phase was washed with saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([S:17](Cl)(=[O:19])=[O:18])=[CH:9][CH:8]=1)=[O:5].[N:25]([CH:28]([CH3:30])C)=[C:26]=[O:27]>C(N(CC)CC)C>[C:26]([N:25]1[CH2:28][CH2:30][CH:4]([NH:6][S:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:7]([NH:6][C:4](=[O:5])[C:3]3[CH:21]=[CH:22][CH:23]=[CH:24][C:2]=3[Cl:1])=[CH:8][CH:9]=2)(=[O:19])=[O:18])[CH2:3][CH2:2]1)(=[O:27])[CH2:8][CH2:7][CH3:16]
Reactant: CC(C)N=C=O
Reactant: O=C(Nc1ccc(S(=O)(=O)Cl)c2ccccc12)c1ccccc1Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3Cl)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-chloro-benzoylamino)-naphthalene-1-sulfonyl chloride, and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.86 (s, 1H), 8.68 (d, 1H), 8.35 (d, 1H), 8.25 (d, 1H), 8.13 (d, 1H), 8.0 (m, 1H), 7.74 (m, 3H), 7.64 (m, 3H), 4.00 (d, 1H), 3.60 (d, 1H), 3.26 (m, 1H), 2.93 (t, 1H), 2.59 (m, 2H), 2.17 (t, 2H), 1.46 (m, 2H), 1.43 (q, 2H), 1.17 (m, 1H), 0.82 (t, 3H); LC/MS m/z 512 (M−H)−, 514 (M+H)+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[Cl:19][C:20]1[CH:21]=[C:22]2[CH:28]=[C:27]([C:29](OC)=[O:30])[N:26]([CH3:33])[C:23]2=[N:24][CH:25]=1>O1CCCC1>[Cl:19][C:20]1[CH:21]=[C:22]2[CH:28]=[C:27]([C:29]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([B:10]4[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]4)=[CH:9][C:3]=3[O:2][CH3:1])=[O:30])[N:26]([CH3:33])[C:23]2=[N:24][CH:25]=1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N
Reactant: COC(=O)c1cc2cc(Cl)cnc2n1C
Solvent: C1CCOC1
Product: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2cc(Cl)cnc2n1C
Temperature: 25 °C
Yield: 84 %

Procedure:
To 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.073 g, 8.32 mmol) in tetrahydrofuran (dry) (20 ml) under a nitrogen atmosphere was added 2-Methylmagnesium chloride in tetrahydrofuran (4.16 ml, 8.32 mmol) and the mixture was heated at reflux for one hour. To the warm reaction mixture was added methyl 5-chloro-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (0.89 g, 3.96 mmol) in tetrahydrofuran (10 ml) and the resulting mixture was heated overnight. Then the reaction was cooled to room temperature and the solvent was evaporated. The residue was taken up in ethyl acetate and washed four times with 0.5 N hydrochloric acid. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography (silica gel; gradient of heptane to heptane/ethyl acetate 1/1) to give 5-chloro-N-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (1.47 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]#[N:13].[H-].[Na+].C([Li])(CC)C.C1CCCCC1.Cl.[C:28](=O)(O)[O-:29].[Na+]>CN(C)C=O.O1CCCC1>[CH:28]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12]#[N:13])=[O:29]
Reactant: Cc1cc(Br)cc2c(C#N)c[nH]c12
Reactant: O=C([O-])O
Agent: Cl
Agent: [H-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: C1CCCCC1
Product: Cc1cc(C=O)cc2c(C#N)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14 %

Procedure:
5-Bromo-7-methyl-1H-indole-3-carbonitrile (0.58 g, 2.46 mmol) and sodium hydride (68 mg, 2.7 mmol) were weighed into a flame-dried round-bottom flask containing a magnetic stir bar. Under a nitrogen atmosphere at room temperature, dry tetrahydrofuran (9 mL) was added. The mixture was stirred at room temperature for 15 min, during which time it became homogeneous. The stirred mixture was cooled to −78° C. and a solution of sec-butyllithium in cyclohexane (1.4M, 3.8 mL, 2.2 equiv) was added over several minutes. After 1 h at −78° C., dimethylformamide (0.9 mL) was slowly added and the mixture allowed to warm to room temperature overnight. The solution was cooled to 0° C. and carefully treated with 1N hydrochloric acid. After a few minutes, solid sodium bicarbonate was added until a pH of 9-10 was attained. The two layers were separated and the aqueous phase washed twice with ethyl acetate. The combined organic layers were washed with water (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography gave 60 mg (14%) of desired product and 0.4 g of unreacted starting material. LC/MS: tR=1.21 min, 185.10 (MH)+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl.[CH3:50][O:51][C:52]1[N:57]=[C:56]2[S:58][C:59]([NH2:61])=[N:60][C:55]2=[CH:54][CH:53]=1>C(Cl)Cl.CN(C=O)C.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([NH:61][C:59]2[S:58][C:56]3[C:55]([N:60]=2)=[CH:54][CH:53]=[C:52]([O:51][CH3:50])[N:57]=3)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc2nc(N)sc2n1
Reactant: CN1CCN(S(=O)(=O)c2ccc(C(CC3CCCC3)C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COc1ccc2nc(NC(=O)C(CC3CCCC3)c3ccc(S(=O)(=O)N4CCN(C)CC4)cc3)sc2n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
A solution of the title E compound, 3-cyclopentyl-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionic acid (5 g, 0.013 mol) in DCM (250 mL) is cooled to 0° C. and then charged HOBt hydrate (2.66 g, 0.019 mol), followed by EDCI hydrochloride (6 g, 0.031 mol). The reaction mixture is stirred at 0° C. for 5 h. After that the solution of the title F compound, 5-methoxy-thiazolo[5,4-b]pyridin-2-ylamine (2.36 g, 0.013 mol) and D1EA (8 mL, 0.046 mol) in a mixture of DCM (60 mL) and DMF (20 mL) is added dropwise over 30 min. Reaction temperature is maintained at 0° C. for 3 h, then at RT (28° C.) for 3 days. Reaction is diluted with (60 mL) of water and the organic layer is separated and washed with saturated sodium bicarbonate solution (2×50 mL) followed by water washing (2×50 mL) and saturated sodium chloride aqueous solution (1×150 mL). Finally the organic layer is dried over sodium sulfate, filtered, and evaporated under vacuo. The crude product is purified using column chromatography over silica gel (60-120 mesh), using 40% ethyl acetate in hexane as an eluent to afford 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methyl-piperazine-1-sulfonyl)-phenyl]-propionamide as a white solid: 1H NMR (400 MHz, CDCl3) δ 0.9-2.1 (m, 11H), 2.2 (s, 3H), 2.5 (br s, 4H), 3.1 (br s, 4H), 3.7 (m, 1H), 4.0 (s, 3H), 6.8 (d, J=8.8, 1H), 7.5 (d, J=8.3, 2H), 7.7 (d, J=8.3, 2H), 7.8 (d, J=8.8, 1H), 8.6 (s, 1H); MS 617 [M+1]+.
Reaction SMILES: [N:1](OC(C)(C)C)=O.[CH3:8][C:9]1[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][C:10]=1[NH:16]C(C)=O>C1(C)C=CC=CC=1>[Br:15][C:13]1[CH:14]=[C:9]2[C:10](=[CH:11][CH:12]=1)[NH:16][N:1]=[CH:8]2
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)Nc1ccc(Br)cc1C
Solvent: Cc1ccccc1
Product: Brc1ccc2[nH]ncc2c1
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 38.8 %

Procedure:
tert-Butyl nitrite (8.34 g, 0.081 mol) was added dropwise, over 30 minutes, to a suspension of 4-bromo-2-methylacetanilide (12.3 g) in toluene (300 ml) at 65° C. and the mixture was stirred at 65° C. for 45 minutes and then at 90° C. for 3 hours. The mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2:1 diethyl ether:hexane to give 5-bromoindazole (4.12 g), as a sand-coloured solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].C([Li])CCC.[C:13]([S@@:17](/[N:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36]([NH2:38])=[O:37])=[CH:35][C:30]=2[O:29][N:28]=1)=[O:18])([CH3:16])([CH3:15])[CH3:14].[Cl-].[NH4+]>O1CCCC1>[CH3:15][C:13]([CH3:16])([S@@:17]([NH:19][C@H:20]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36]([NH2:38])=[O:37])=[CH:35][C:30]=2[O:29][N:28]=1)[CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:18])[CH3:14]
Reactant: Cc1ccccn1
Reactant: CC(C)(C)[S@](=O)/N=C/c1ccccc1-c1noc2cc(C(N)=O)ccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)N[C@@H](Cc1ccccn1)c1ccccc1-c1noc2cc(C(N)=O)ccc12
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 48.7 %

Procedure:
To a solution of 2-picoline (22.6 mL, 21.3 g) in tetrahydrofuran (280 mL) cooled under nitrogen to −72° C. was added a 2.5M in hexanes solution of n-butyl lithium (98 mL) dropwise over 40 min keeping the internal temperature less than −70° C. The mixture was stirred at this temp for 45 min then a solution of 3-(2-((E)-((S)-tert-butylsulfinylimino)methyl)phenyl)benzo[d]isoxazole-6-carboxamide (Compound 10) (28.2 g) in tetrahydrofuran (280 mL) was added dropwise over 45 min (the internal temperature less than −70° C.) then stirred at this temp for 30 min. Reaction mixture allowed to warm to −30° C. and saturated aqueous ammonium chloride (500 mL) added. The layers were separated and aqueous layer washed with ether (3×300 mL). The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate and the solvents removed. Flash chromatography on silica eluting with ethyl acetate then 1 to 5% methanol in ethyl acetate gave three fractions of product that were crystallised from the minimum of ethyl acetate to give the title product (17.2 g).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[N:9]=[CH:8][C:7]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=1.[SH:16][C:17]1[CH:18]=[C:19]([C:23]2([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[CH3:30][O:29][C:23]1([C:19]2[CH:18]=[C:17]([S:16][C:4]3[N:9]=[CH:8][C:7]([N:10]([CH3:15])[S:11]([CH3:14])(=[O:13])=[O:12])=[CH:6][CH:5]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1
Reactant: CN(c1ccc(Cl)nc1)S(C)(=O)=O
Reactant: COC1(c2cccc(S)c2)CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2cccc(Sc3ccc(N(C)S(C)(=O)=O)cn3)c2)CCOCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (79 mg, 50% dispersion in mineral oil, 1.65 mmol) was added to a solution of N-(6-chloropyrid-3-yl)-N-methylmethanesulphonamide (0.33 g) and 4-(3-mercaptophenyl)-4-methoxytetrahydropyran (0.34 g) in DMF (10 ml). The mixture was stirred at ambient temperature for 15 minutes and heated at 140° C. for 1.5 hours. After cooling, it was partitioned between water (75 ml) and ethyl acetate (75 ml). The organic phase was washed with brine (50 ml), dried (MgSO4) and the solvent evaporated. The product was purified by column chromatography to give N-{6-[3-(4-methoxytetrahydropyran-4-yl)phenylthio]pyrid-3-yl}-N-methylmethanesulphonamide as a gum (0.25) g, 41%).
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[N:38]1([C:45](=O)[CH2:46]Cl)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:45][CH2:46][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: O=C(CCl)N1CCCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCCCC3)cc2)c1
Yield: 65.5 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azepan-1-yl-2-chloroethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (6.9 mg) was obtained.
Reaction SMILES: FC(F)(F)C([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][CH:8]([CH:13]1[C:26]3[CH:25]=[CH:24][C:23]([C:27]4[NH:31][N:30]=[N:29][N:28]=4)=[CH:22][C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=O.[OH-].[Na+]>CO>[NH:31]1[C:27]([C:23]2[CH:24]=[CH:25][C:26]3[CH:13]([CH:8]4[CH2:9][CH:10]5[NH:5][CH:6]([CH2:12][CH2:11]5)[CH2:7]4)[C:14]4[C:19]([O:20][C:21]=3[CH:22]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:28][N:29]=[N:30]1
Reactant: O=C(N1C2CCC1CC(C1c3ccccc3Oc3cc(-c4nnn[nH]4)ccc31)C2)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc2c(c1)Oc1cc(-c3nnn[nH]3)ccc1C2C1CC2CCC(C1)N2
Temperature: 25 °C
Yield: 64 %

Procedure:
To a solution of 2,2,2-trifluoro-1-{3-[3-(1H-tetrazol-5-yl)-9H-xanthen-9-yl]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone, 4j (0.33 g, 0.724 mmol) in methanol (10 mL) was added a 1N NaOH solution (2.17 mmol, 2.17 mL), and the mixture was heated to reflux for 1 h. The mixture was allowed to cool to rt and evaporated. The residue was purified via reverse phase HPLC (eluent gradient: CH3CN in H2O containing 0.1% TFA) to yield 0.22 g (64%) of title compound 3-[3-(1H-tetrazol-5-yl)-9H-xanthen-9-yl]-8-aza-bicyclo[3.2.1]octane, 5j as a TFA salt. MS m/z (MH+) 360.1.
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]([CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:13]=[C:14]3[C:19]=2[C:18](=[O:20])[N:17]([CH3:21])[C:16](=[O:22])[N:15]3[CH3:23])[CH:8]=[CH:9][CH:10]=1)#[N:4].O>C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:13]=[C:14]3[C:19]=2[C:18](=[O:20])[N:17]([CH3:21])[C:16](=[O:22])[N:15]3[CH3:23])[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)CCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCC(=O)O)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Lithium hydroxide (965 mg, 23.0 mmol) was added to a suspension of methyl 4-(5-(3-cyanophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)butanoate (Step 5) (1.75 g, 4.6 mmol) in THF (9 mL)/water (9 mL). The mixture was stirred at room temperature for 4 hours. The organic solvent was largely removed under vacuum, the residue was acidified to pH 1, using 2M HCl. The resulting slurry was diluted with water (100 mL). The mixture was reduced under vacuum to give a white solid, which was further dried under vacuum at 50° C. overnight.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH:12]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[F:26][C:23]([F:24])([F:25])[C:19]1[CH:18]=[C:17]([C:13]2[CH:12]=[C:11]([O:10][C:7]3[CH:6]=[CH:5][C:4]([NH2:1])=[N:9][CH:8]=3)[CH:16]=[CH:15][N:14]=2)[CH:22]=[CH:21][N:20]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc(-c3ccnc(C(F)(F)F)c3)c2)cn1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(Oc2ccnc(-c3ccnc(C(F)(F)F)c3)c2)cn1
Yield: 32.9 %

Procedure:
A solution of 4-((6-nitropyridin-3-yl)oxy)-2′-(trifluoromethyl)-2,4′-bipyridine (0.139 g, 0.384 mmol) in MeOH (10 mL) was treated with 10% Pd/C (50% wet, 0.041 g, 0.038 mmol) and hydrogenated (1 atm) for 5 h. The solids were removed via filtration through diatomaceous earth, the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/EtOAc) to afford 5-((2′-(trifluoromethyl)-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-amine (42 mg, 33%). 1H NMR (400 MHz, DMSO-d6): δ 8.87 (d, J=5.1 Hz, 1H), 8.59 (d, J=5.7 Hz, 1H), 8.49 (s, 1H), 8.35-8.33 (m, 1H), 7.87 (d, J=2.4 Hz, 1H), 7.85 (d, J=2.9 Hz, 1H), 7.33 (dd, J=8.9, 3.0 Hz, 1H), 6.91 (dd, J=5.7, 2.4 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.05 (s, 2H); MS (ESI) m/z: 333.1 (M+H+).