Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[S:26][C:25]([C@@:27]3([OH:39])[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[C:29]([CH3:38])([CH3:37])[CH2:28]3)=[N:24][CH:23]=2)[CH:8]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][N:13]=2)[CH:10]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[NH2:1][CH2:4][C:5]1[CH:6]=[C:7]([C:22]2[S:26][C:25]([C@@:27]3([OH:39])[CH2:32][CH2:31][C@H:30]([C:33]([O:35][CH3:36])=[O:34])[C:29]([CH3:37])([CH3:38])[CH2:28]3)=[N:24][CH:23]=2)[CH:8]=[C:9]([NH:11][C:12]2[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][N:13]=2)[CH:10]=1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CN=[N+]=[N-])cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CN)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 23 °C
Reaction time: 18 h
Yield: 26.2 %

Procedure:
To a solution of the product from Step 2 (220 mg, 0.392 mmol) in THE (4 ml) and water (2 ml), was added resin-bound triphenylphosphine (154 mg, 0.588 mmol, 1.5 equiv). The resulting mixture was stirred at 23° C. for 18 h. The resin-bound triphenylphosphine was removed by filtration, and the residual bi-phasic, orange-maroon mixture was partitioned between EtOAc (45 ml) and water (55 ml). The separated organic layer was dried over Na2SO4, filtered and concentrated. The crude orange oil was purified via reverse-phase HPLC (acetonitrile/water gradient with 0.1% TFA present). The TFA salt was converted to the free base by partitioning between EtOAc (40 ml) and saturated aqueous NaHCO3 (45 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The organic layer was filtered and concentrated, yielding methyl (1S,4R)-4-{5-[3-(aminomethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-4-hydroxy-2,2-dimethylcyclohexanecarboxylate (55 mg, 25%), as an orange oil. MS ESI: [M+H]+ m/z 536.2
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:39]=[CH:38][C:25]([CH2:26][N:27]5[CH2:30][CH:29]([C:31]([O:33]C(C)(C)C)=[O:32])[CH2:28]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1>FC(F)(F)C(O)=O>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:39]=[CH:38][C:25]([CH2:26][N:27]5[CH2:28][CH:29]([C:31]([OH:33])=[O:32])[CH2:30]5)=[CH:24][CH:23]=4)[N:18]=3)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(CCC4(c5cccc(C(F)(F)F)c5)CCOCC4)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C1CN(Cc2ccc(-c3noc(CCC4(c5cccc(C(F)(F)F)c5)CCOCC4)n3)cc2)C1
Yield: 60.6 %

Procedure:
A solution of tert-butyl 1-(4-(5-(2-(4-(3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-yl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (46 mg, 80 μmol) in trifluoroacetic acid (1.5 mL) was stirred at room temperature for 75 min. Trifluoroacetic acid was removed under reduced pressure, followed by co-evaporation with ether. The crude product was purified by reversed-phase autoprep HPLC (Phenomenex S10 30×100 mm, 40 min gradient time, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.1% TFA; Final solvent: 90% aq. MeOH—0.1% TFA) to obtain 1-(4-(5-(2-(4-(3-(trifluoromethyl)phenyl)tetrahydro-2H-pyran-4-yl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl) azetidine-3-carboxylic acid (25 mg, 47% yield) as a white solid. LC/MS: m/e 516.19 (M+H)+. 1H NMR (400 MHz, CD3OD): δ ppm 8.09 (d, J=8.28 Hz, 2H), 7.66-7.75 (m, 2H), 7.62 (d, J=8.28 Hz, 2H), 7.49-7.59 (m, 2H), 4.50 (s, 2H), 4.29-4.42 (m, 4H), 3.87 (ddd, J=11.73, 5.46, 3.64 Hz, 2H), 3.72 (dt, J=16.75, 8.31 Hz, 1H), 3.45-3.63 (m, 2H), 2.60-2.79 (m, 2H), 2.32-2.36 (m, 2H), 2.27-2.32 (m, 2H), 1.90-2.08 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([NH:14][C:15]2[C:16]3[N:17]([CH:24]=[C:25]([C:27](O)=[O:28])[CH:26]=3)[N:18]=[CH:19][C:20]=2[C:21](=[O:23])[NH2:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.ON1C2C=CC=CC=2N=N1.O/[N:45]=[C:46](\[NH2:48])/[CH3:47]>CN(C=O)C>[C:21]([C:20]1[CH:19]=[N:18][N:17]2[CH:24]=[C:25]([C:27]3[O:28][N:48]=[C:46]([CH3:47])[N:45]=3)[CH:26]=[C:16]2[C:15]=1[NH:14][C@H:10]1[C@@H:11]([CH3:13])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:9]1)(=[O:23])[NH2:22]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(C(=O)O)cc12
Reactant: C/C(N)=N/O
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1noc(-c2cc3c(N[C@@H]4CN(C(=O)OC(C)(C)C)C[C@@H]4C)c(C(N)=O)cnn3c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A mixture of 4-(((3S,4S)-1-(tert-butoxycarbonyl)-4-methylpyrrolidin-3-yl)amino)-3-carbamoylpyrrolo[1,2-b]pyridazine-6-carboxylic acid (120 mg, 0.297 mmol), EDC (68.4 mg, 0.357 mmol) and 1-hydroxybenzotriazole (54.7 mg, 0.357 mmol) in DMF (2 mL) was stirred at rt for 30 minutes. (Z)—N′-hydroxyacetimidamide (48.5 mg, 0.654 mmol) was added and the reaction mixture was stirred for 30 min at rt and 3 hr at 125° C. for 5 hr. After cooling to rt, The reaction mixture was partitioned between EtOAc (30 ml) and saturated NaHCO3 solution (30 ml). The organic layer was washed with saturated NaHCO3 solution (30 ml), 10% LiCl solution (2×30 ml) and brine (30 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to a yellow oil that was chromatographed on a 12 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-methylpyrrolidine-1-carboxylate (50 mg, 0.110 mmol, 36.9% yield) as an off-white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.27 (s, 2H), 7.48 (s, 1H), 3.88-3.50 (m, 4H), 3.21 (td, J=10.3, 4.4 Hz, 1H), 2.72 (d, J=6.4 Hz, 1H), 2.43 (s, 3H), 1.45 (d, J=13.6 Hz, 9H), 1.18 (d, J=6.8 Hz, 3H). MS (ES+) m/z: 442.2 (M+H); LC retention time: 2.991 min (analytical HPLC Method O).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:14]=[O:15]>[OH-].[Na+]>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:14][OH:15]
Reactant: C=O
Reactant: COc1ccc2nccc(O)c2c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2ncc(CO)c(O)c2c1
Reaction time: 18 h

Procedure:
4-Hydroxy-6-methoxyquinoline was reacted with formaldehyde in aqueous sodium hydroxide (initially at 40°-50°, then kept at 60° for 18 hours) to give the novel compound 4-hydroxy-3-hydroxymethyl-6-methoxyquinoline, m.p. 327°-334°.
Reaction SMILES: CS([C:5]1[S:9][C:8]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=[C:13]3[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[N:27]=2)=[N:7][N:6]=1)(=O)=O.[BH4-].[Na+].CC(O)=O>CCO>[O:35]1[CH2:36][CH2:37][N:32]([C:28]2[N:27]=[C:26]([C:13]3[C:12]4[C:16](=[CH:17][CH:18]=[C:10]([C:8]5[S:9][CH:5]=[N:6][N:7]=5)[CH:11]=4)[N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:14]=3)[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nnc(S(C)(=O)=O)s3)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1cc(-c2cccc(N3CCOCC3)n2)c2cc(-c3nncs3)ccc21
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 5-(5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl)-3-(6-morpholinopyridin-2-yl)-1H-indole-1-carboxylate (100 mg, 0.185 mmol) in EtOH was added sodium borohydride (20.95 mg, 0.554 mmol). The reaction was stirred for 2 h, neutralized with HOAc then the solvent was removed to give the crude material. MS (ESI, pos. ion) m/z: 464 (M+1).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccncc3)c(-c3ccccc3)[nH]2)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1ccc(-c2cc(-c3ccncc3)c(-c3ccccc3)[nH]2)cc1
Reaction time: 2 h

Procedure:
To a suspension of 55 mg (0.161 mmol) 2-phenyl-3-(4-pyridyl)-5-[(4-nitro)phenyl]-1H-pyrrole (prepared according to Example 33) in 1.5 ml ethyl acetate and 1.5 ml ethanol was added 10 mg platinum (IV) oxide. The mixture was stirred under H2 for 2 hours. The contents of flask were centrifuged, and the catalyst washed with ethyl acetate three times. The solvents were evaporated in vacuo to afford the desired product as a pale orange solid, homogeneous by TLC (5% MeOH/CH2Cl2). FAB ms: Calc.: 312 for C21H17N3 ; Obs.: 313 (M+ +1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4O[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:23]=1[NH2:24].C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[CH:10]=[C:9]([C:15]4[N:24]([C:23]5[CH:25]=[CH:26][C:27]([F:29])=[CH:28][C:22]=5[Cl:21])[CH:17]=[N:18][N:19]=4)[S:8][C:7]=3[C:6]=2[CH:20]=1
Reactant: Brc1ccc2c(c1)-c1sc(-c3nnco3)cc1CCO2
Reactant: Nc1ccc(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-n2cnnc2-c2cc3c(s2)-c2cc(Br)ccc2OCC3)c(Cl)c1
Temperature: 160 °C
Yield: 67.6 %

Procedure:
A microwave tube was charged with 2-(9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulen-2-yl)-[1,3,4]oxadiazole (0.64 g; 1.83 mmol), 2-chloro-4-fluoroaniline (0.44 ml; 3.68 mmol), TFA (0.27 ml; 3.63 mmol) and toluene (5 ml). The mixture was heated in a microwave at 160° C. for 30 min., diluted with EtOAc (150 ml) and washed with satd. NaHCO3. The organic layer was dried (MgSO4), concentrated and purified by ISCO to give 267 as a cream-coloured solid (0.59 g; 68%). δH (400 MHz, CDCl3) 3.14 (t, J=5.2, 2H), 4.29 (t, J=5.2, 2H), 6.91 (d, J=8.4, 1H), 6.93 (s, 1H), 7.22-7.27 (m, 2H), 7.43-7.51 (m, 2H), 7.65 (d, J=2.4, 1H), 8.22 (s, 1H). [M+H]+: 478
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=1)=O.[Cl:21][C:22]1[CH:23]=[C:24]([CH2:28][CH:29]=O)[CH:25]=[CH:26][CH:27]=1>>[Cl:21][C:22]1[CH:23]=[C:24]([C:28]2[CH:29]=[N:1][C:2]3[C:3]([C:12]=2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([F:11])([F:10])[F:9])[CH:25]=[CH:26][CH:27]=1
Reactant: Nc1c(C(=O)c2cccc(O)c2)cccc1C(F)(F)F
Reactant: O=CCc1cccc(Cl)c1
Product: Oc1cccc(-c2c(-c3cccc(Cl)c3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [2-amino-3-(trifluoromethyl)phenyl]-(3-hydroxy-phenyl)methanone and (3-chloro-phenyl)-acetaldehyde following the procedure of Example 457: MS (ES) m/z 397.9; HRMS: calcd for C22H13ClF3NO+H+, 400.07105; found (ESI, [M+H]+), 400.0697.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=1)\[CH2:4][C@H:5]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](O)=[O:21])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].[NH2:30][CH2:31][CH2:32][OH:33].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:33][CH2:32][CH2:31][NH:30][C:20](=[O:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH3:12])[CH2:4]/[C:3](=[N:2]\[OH:1])/[C:23]2[CH:28]=[CH:27][N:26]=[C:25]([CH3:29])[CH:24]=2)=[CH:14][CH:15]=1
Reactant: Cc1cc(/C(C[C@H](c2ccc(CC(=O)O)cc2)c2ccccc2C)=N/O)ccn1
Reactant: NCCO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1cc(/C(C[C@H](c2ccc(CC(=O)NCCO)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 207, step 2, {4-[(R)-3-[(E)-hydroxyimino]-3-(2-methyl-pyridin-4-yl)-1-o-tolyl-propyl]-phenyl}-acetic acid (example 288) was coupled with 2-aminoethanol using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as a colourless oil, MS (ESI+): m/z=432.3 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.C(N(CC)CC)C.[C:24]([C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29])#[CH:25]>O1CCCC1.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>[CH:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:25]#[C:24][C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])=[CH:3][C:4]=1[N+:14]([O-:16])=[O:15])(=[O:10])=[O:9])([CH3:13])[CH3:12]
Reactant: C#Cc1cccc(N)c1
Reactant: CC(C)S(=O)(=O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccc(C#Cc2cccc(N)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
4-Bromo-1-(isopropylsulfonyl)-2-nitrobenzene (390 mg, 1.3 mmol), bis(triphenylphosphine)palladium(II) chloride (60 mg, 0.08 mmol) and copper(I) iodide (20 mg, 0.1 mmol) were stirred in tetrahydrofuran (5 mL) with triethylamine (250 μL, 1.8 mmol). 3-Ethynylaniline (100 μL, 1.0 mmol) was added and the mixture was stirred at rt for 1.5 hours. The mixture was evaporated, diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extracts were dried over sodium sulfate, filtered and evaporated to give the desired compound (250 mg, 60%). LCMS for C17H17N2O4S (M+H)+: m/z=345.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:13])[CH:9]2[CH2:12][NH:11][CH2:10]2)=[C:4]([CH3:14])[CH:3]=1.C(N(CC)CC)C.Cl[C:23]1[N:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>O1CCCC1.CO>[Cl:33][C:30]1[CH:31]=[N:32][C:23]([N:11]2[CH2:12][CH:9]([N:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[CH3:14])[CH3:13])[CH2:10]2)=[C:24]([CH:29]=1)[C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: Cc1cc(F)ccc1N(C)C1CNC1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(Cl)cnc1N1CC(N(C)c2ccc(F)cc2C)C1
Temperature: 75 °C
Yield: 82.6 %

Procedure:
To mixture of N-methyl-N-(2-methyl-4-fluoro-phenyl)azetidin-3-amine (D56) (110 mg, 0.566 mmol) and triethylamine (0.18 ml, 0.849 mmol) in tetrahydrofuran/methanol (3/1 ml) Methyl 2,5-dichloronicotinate (116.82 mg, 0.566 mmol) was added and the mixture was heated at 75° C. for 12 hours. Solvents were evaporated and the residue was purified by SNAP-Si cartridge (10 g) eluting with cyclohexane/ethyl acetate from 100/0 to 90/10. Collected fractions after solvent evaporation afforded the title compound (D87) (170 mg)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]2=[O:16].[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28](F)=[CH:27][CH:26]=1)(=[O:24])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH2:17]([N:6]1[CH2:5][CH2:4][C:3]2[C:8](=[CH:9][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]=2[O:1][C:28]2[CH:29]=[CH:30][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][CH:27]=2)[C:7]1=[O:16])[CH:18]([CH3:20])[CH3:19]
Reactant: CS(=O)(=O)c1ccc(F)cc1
Reactant: COC(=O)c1cc(O)c2c(c1)C(=O)N(CC(C)C)CC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)C(=O)N(CC(C)C)CC2
Temperature: 100 °C

Procedure:
A mixture of methyl 5-hydroxy-2-isobutyl-1-oxo-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (250 mg, 0.90 mmol), 4-fluorophenyl methyl sulfone (236 mg, 1.35 mmol), Cs2CO3 (441 mg, 1.35 mmol) and CuI (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via column chromatography on silica gel eluted with 10-30% EtOAc in hexanes to afford the ether (312 mg, 78%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.97 (d, J=6.78 Hz, 6 H) 1.94-2.16 (m, 1 H) 2.94 (t, J=6.59 Hz, 2 H) 3.04-3.16 (m, 3 H) 3.41 (d, J=7.54 Hz, 2 H) 3.55 (t, J=6.59 Hz, 2 H) 3.87-4.01 (m, 3 H) 7.00-7.11 (m, 2 H) 7.80 (d, J=1.70 Hz, 1 H) 7.88-8.00 (m, 2H) 8.66 (d, J=1.51 Hz, 1 H); MS (ESI, pos): 432.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH2:25])[CH:16]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1CCC(OC2C=C(C(F)(F)F)C=C(N[C:51]([C:53]3[C:54]([F:59])=[N:55][CH:56]=[CH:57][CH:58]=3)=[O:52])C=2)CC1)(OC(C)(C)C)=O>>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH:25][C:51]([C:53]2[C:54]([F:59])=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:52])[CH:16]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(NC(=O)c3cccnc3F)cc(C(F)(F)F)c2)CC1
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cc(N)cc(C(F)(F)F)c1
Product: CC(C)(C)OC(=O)N1CCCC1COc1cc(NC(=O)c2cccnc2F)cc(C(F)(F)F)c1

Procedure:
1-Boc-2-{3-[(2-Fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-pyrrolidine was prepared from 1-Boc-2-(3-amino-5-trifluoromethyl-phenoxymethyl)-pyrrolidine by a procedure similar to that described in the preparation of 1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7]([NH2:10])(=[O:9])=[O:8])=[N:3]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:60]1[CH:65]=[C:64]([CH3:66])[N:63]=[C:62]2[N:67]([CH3:81])[CH:68]=[C:69]([C:70]3[CH:75]=[CH:74][CH:73]=[C:72]([N:76]4[CH2:80][CH2:79][CH2:78][CH2:77]4)[CH:71]=3)[C:61]=12>O1CCOCC1.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:81][N:67]1[C:62]2=[N:63][C:64]([CH3:66])=[CH:65][C:60]([NH:10][S:7]([C:4]3[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=3)(=[O:9])=[O:8])=[C:61]2[C:69]([C:70]2[CH:75]=[CH:74][CH:73]=[C:72]([N:76]3[CH2:80][CH2:79][CH2:78][CH2:77]3)[CH:71]=2)=[CH:68]1
Reactant: Cc1cc(Cl)c2c(-c3cccc(N4CCCC4)c3)cn(C)c2n1
Reactant: Cn1ccc(S(N)(=O)=O)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cc(NS(=O)(=O)c2ccn(C)n2)c2c(-c3cccc(N4CCCC4)c3)cn(C)c2n1
Temperature: 150 °C
Yield: 20.7 %

Procedure:
A microwave vial was charged with 1-methyl-1H-pyrazole-3-sulfonamide (D94) (134 mg, 0.829 mmol), palladium(II) acetate (9.30 mg, 0.041 mmol), xantphos (47.9 mg, 0.083 mmol) and cesium carbonate (270 mg, 0.829 mmol). To this was added 4-chloro-1,6-dimethyl-3-(3-(pyrrolidin-1-yl)phenyl)-1H-pyrrolo[2,3-b]pyridine (D14) (135 mg, 0.414 mmol) dissolved in 1,4-dioxane (2.5 mL). The reaction mixture was heated at 150° C. in the microwave for 30 mins. The crude was purified on normal phase chromatography eluting with ethyl acetate in cyclohexane (0-80%) twice to give an impure material. The material was then dissolved in MeOH and passed through a SCX cartridge eluting with MeOH followed by 2M ammonia in MeOH to give a solid which was triturated with diethyl ether to give the title compound (38.7 mg). LCMS (A): m/z (M+H)+ 451, C23H26N6O2S requires 450 (acidic).
Reaction SMILES: O.O.O.[F-].[CH2:5]([N+](CCCC)(CCCC)CCCC)CCC.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][Si](C(C)C)(C(C)C)C(C)C)=[C:25]([F:40])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CI>C1COCC1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:5])=[C:25]([F:40])[CH:24]=1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: CC(C)[Si](Sc1ccc(Br)cc1F)(C(C)C)C(C)C
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: C1CCOC1
Product: CSc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Add tetrabutylammonium fluoride trihydrate (546 mg, 1.73 mmol) to a mixture of (4-bromo-2-fluoro-phenylsulfanyl)-triisopropyl-silane (570 mg, 1.57 mmol) and potassium carbonate (650 mg, 4.71 mmol) in 20 mL THF and stir at r.t. for 1 h. Add methyl iodide, stir for 1 h and concentrate to remove THF. Add 20 mL water, extract with diethylether, dry the combined organic extracts over sodium sulfate, filtrate and concentrate under reduced pressure to obtain 4-bromo-2-fluoro-1-methylsulfanyl-benzene (347 mg) as a colorless liquid, which was used for following conversions without further purifications. MS (m/e): 220 [(79Br)M], 222 [(81Br)M].
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[Br:13]NC(=O)CCC(N)=O>ClCCl.CN(C)C=O>[NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[Br:13]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1ccc(N)c(O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(O)c(N)c(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
To a solution of methyl 4-amino-3-hydroxybenzoate (2.5 g, 15.0 mmol) in dichloromethane (71 mL) and N,N-dimethylformamide (3.6 mL) was added N-bromosuccinamide (2.93 g, 16.5 mmol). The mixture was stirred at ambient temperature. After 15 min, the mixture was quenched with sat. sodium sulfite. Hydrochloric acid (1.0 M) was added and the mixture was extracted with dichloromethane (3×). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→100% ethyl acetate) gave the title compound (1.2 g). LC-MS [M]=246.0.
Reaction SMILES: [N:1]#[C:2]Br.C(=O)(O)[O-].[Na+].[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][NH:16]2)=[CH:12][CH:11]=1.O>CS(C)=O>[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([C:14]([CH:19]3[CH2:24][CH2:23][N:22]([C:2]#[N:1])[CH2:21][CH2:20]3)=[N:15][NH:16]2)=[CH:12][CH:11]=1
Reactant: N#CBr
Reactant: Clc1ccc2c(C3CCNCC3)n[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CN1CCC(c2n[nH]c3cc(Cl)ccc23)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a stirred mixture of cyanogen bromide (1.8 g, 0.017 mol), sodium bicarbonate (2.80 g) and dimethyl sulfoxide (DMSO) (40 ml) was added dropwise 6-chloro-3-(4-piperidinyl)-1H-indazole (4.0 g, 0.017 mol) of Example 52 dissolved in DMSO (50 ml). The reaction was stirred at ambient temperature for 1 hour and poured into water. The resulting solid was collected, dried and weighed 4.0 g. Recrystallization from toluene-hexane afforded 3.1 g (70%) of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carbonitrile, m.p. 180°-188° C. To a stirred mixture of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carbonitrile (3.0 g., 0.015 mol) in methanol (30 ml) was added a solution of 25% sodium methoxide in methanol (2.5 ml). The reaction was warmed on a steam bath to effect solution and then stirred at ambient temperature for 16 hours. Most of the methanol was removed in vacuo and the residue was diluted with water. An initial oil solidified and 3.5 g of a solid was collected. This was recrystallized from methanol-water to yield 2.9 g (66%) of 4-(6-chloro-1H-indazol-3-yl)piperidine-1-carboximidic acid methyl ester, mp 173°-175° C.