Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>C(Cl)Cl>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:2]([NH:1][S:33]([CH:30]2[CH2:32][CH2:31]2)(=[O:35])=[O:34])[CH2:3][CH2:4]3)[CH:16]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC1CCc2cc(Cn3cc(CO)c(C(F)(F)F)n3)ccc21)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1-((1-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.096 mmol, 30 mg) and triethylamine (0.193 mmol, 0.027 mL, 19.50 mg) in DCM (0.9 mL) was added cyclopropanesulfonyl chloride (0.096 mmol, 13.55 mg) and the whole stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue purified by RP-HPLC to give the desired product as a clear film (12.0 mg, 0.029 mmol, 30%). MS (ESI): m/z [M+H]− 417.0.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C[O:45][C:46](=[O:52])[C@@H:47]1[CH2:51][CH2:50][CH2:49][NH:48]1>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([N:48]3[CH2:49][CH2:50][CH2:51][C@H:47]3[C:46]([OH:45])=[O:52])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)N3CCC[C@H]3C(=O)O)cc2)cc1

Procedure:
The product from Example 234B and L-proline methyl ester hydrochloride were processed as described in Example 251A and B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ11.95-13.15 (br.s, 1 H), 8.94 (s, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.95 (m, 6 H), 6.82 (d, 2 H), 4.21 (dd, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.93 (m, 2 H), 3.52 (m, 2 H), 2.91 (s, 3 H), 2.39 (s, 3 H), 2.34 (t, 2 H), 1.99-2.27 (m, 2 H), 1.87 (m, 2 H), 1.68 (m, 4 H; MS (ESI+) m/z 686 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])=[O:4].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:47]1([CH3:57])[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=1>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[N:8]([S:53]([C:50]2[CH:51]=[CH:52][C:47]([CH3:57])=[CH:48][CH:49]=2)(=[O:55])=[O:54])[C:7](=[O:9])[C@H:6]1[CH2:10][CH2:11][CH2:12][NH:13][C:14]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])=[N:15][C:16]([O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:17])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)[C@@H]1NC(=O)[C@H]1CCCNC(=NC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)[C@H]1[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)C(=O)N1S(=O)(=O)c1ccc(C)cc1
Temperature: -20 °C
Reaction time: 48 h
Yield: 48.2 %

Procedure:
To a -78° C. THF (5 mL) solution of compound 7 (4.36 mg, 0.67 mmol) was added 1N THF solution of sodium bis(trimethylsilyl)amide (0.67 mL, 0.67 mmol), and the resultant solution was stirred for 15 min. p-Toluenesulfonyl chloride (134 mg, 0.70 mmol) was added, and the mixture was stirred at -78° C. for 4 h and at -20° C. for 21/2 days. The reaction mixture was partitioned between EtOAc and H2O. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (Et2O:hexane/3:2) to afford 210 mg (48%) of the title product.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13](=[C:14]([O:20][CH3:21])[C:15]([F:19])=[CH:16][CH:17]=3)[C:12]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:11]2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[OH-].[K+].C([O:43][C:44]([CH3:49])([CH3:48])[C:45](Cl)=[O:46])(=O)C>ClCCl>[Cl:31][C:28]1[S:27][C:26]([S:23]([NH:22][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[C:15]([F:19])[C:14]=3[O:20][CH3:21])[N:10]([CH2:9][C:5]3[CH:4]=[C:3]([CH2:2][NH:1][C:45](=[O:46])[C:44]([OH:43])([CH3:49])[CH3:48])[CH:8]=[CH:7][CH:6]=3)[N:11]=2)(=[O:25])=[O:24])=[CH:30][CH:29]=1
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(F)ccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(=O)C(C)(C)O)c1
Reaction time: 2.5 h
Yield: 49 %

Procedure:
A suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-5-fluoro-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide (for a preparation see Intermediate 61) (100 mg, 0.208 mmol) in dichloromethane (0.5 mL), pyridine (0.5 mL) and potassium hydroxide (11.67 mg, 0.208 mmol) was treated with 2-chloro-1,1-dimethyl-2-oxoethyl acetate (0.054 mL, 0.37 mmol) and the mixture was stirred for 2.5 h. The reaction mixture was concentrated in vacuo and the orange residue was dissolved in 1:1 MeOH-DMSO (1 mL) and purified by Mass Directed AutoPrep on Sunfire C18 column using Acetonitrile Water with a TFA modifier (Method B). The solvent was evaporated in vacuo to give the title compound (58 mg, 49%). LCMS (System A) RT=1.04 min, ES+ve m/z 567/569 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1.[C:16](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:16][O:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=[O:14])[CH:3]=1
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cc(C(=O)O)nn1-c1ccccc1
Reaction time: 8 h
Yield: 38 %

Procedure:
600 mg (2.94 mmol) of 5-hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid were dissolved in 30 ml of DMF, 1.92 (5.9 mmol) of cesium carbonate and 1.04 g (7.35 mmol) of iodomethane were added, and the resulting mixture was heated for 4 h to 80° C. The mixture was filtrated and the solvent removed in vacuo. The residue was dissolved in 20 ml of MOH and 5.9 ml of an aqueous 1 M solution of sodium hydroxide. After stirring overnight the reaction was complete. The solvent was removed and the residue subjected to preparative HPLC to give the title compound in a yield of 38%.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]1[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=1)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])(C1C=CC(C)=CC=1)(=O)=O.C(=O)(O)[O-].[Na+].[N-:48]=[N+:49]=[N-:50].[Na+]>CN(C)C=O.O>[N:48]([CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]1[CH:28]=[C:29]([CH:40]=[CH:41][CH:42]=1)[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])=[N+:49]=[N-:50]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOCCOCCOCC#Cc2cccc(C(=O)OCc3ccccc3)c2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOCCOCCOCCOCC#Cc1cccc(C(=O)OCc2ccccc2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 1000-mL round-bottom flask, was placed a solution of benzyl 3-(1-(tosyloxy)-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate (35.4 g, 59.30 mmol, 1.00 equiv) in N,N-dimethylformamide (400 mL), sodium bicarbonate (10 g, 119.05 mmol, 2.00 equiv), sodium azide (11 g, 169.23 mmol, 3.00 equiv). The resulting solution was stirred overnight at 80° C. The resulting solution was diluted with 200 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×100 mL of NaHCO3 aq. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 25 g (90%) of benzyl 3-(1-azido-3,6,9,12-tetraoxapentadec-14-yn-15-yl)benzoate as brown oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][CH:6]=1.[C:13](OC)(=[O:21])[C:14]1[C:15](=[CH:17][CH:18]=[CH:19][CH:20]=1)[SH:16].C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:10]=[C:9]([C:11]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[C:13](=[O:21])[N:12]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: N#Cc1cccc(CCCO)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(CCCO)n2)sc2ccccc12
Yield: 15 %

Procedure:
6-(3-Hydroxypropyl)-2-pyridinecarbonitrile (2.2 g, 13.6 mmol) and methyl thiosalicylate (3.7 g, 22.0 mmol) were dissolved in toluene (15 ml), and triethylamine (3.0 ml, 21.7 mmol) was added thereto. The reaction mixture was refluxed for 30 hrs and subjected to a silica gel (170 g) column chromatography. The fractions eluted with ethyl acetate were collected and concentrated to give the titled compound (0.61 g, 15%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:24])[CH2:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35]I>COCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2([C:25]3[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=3[F:32])[CH2:12][CH2:13][CH:14]([CH2:17][C:18](=[O:24])[CH:19]([S:20]([CH3:23])(=[O:22])=[O:21])[CH3:35])[CH2:15][CH2:16]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)CC(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C(=O)CC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(Cl)cc2)CC1)S(C)(=O)=O
Reaction time: 1.5 h
Yield: 44.7 %

Procedure:
The product from Example 134 (28 mg, 0.056 mmol) in 1,2-dimethoxyethane (3 mL) was treated with sodium hydride (60% dispersion in mineral oil, 2 mg, 0.056 mmol) at room temperature. After stirring for 1.5 hours, methyl iodide (6 μL, 0.056 mmol) was added and the reaction stirred for 18 hours, then quenched with saturated aqueous ammonium chloride solution. The reaction was then extracted into ethyl acetate, dried (MgSO4) and evaporated to a white solid which was purified by column chromatography on silica eluting with 35% ethyl acetate/iso-hexane to yield the desired product as a white solid (13 mg).
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[F:39][C:40]1[CH:41]=[CH:42][C:43]([C:49]([F:52])([F:51])[F:50])=[C:44](B(O)O)[CH:45]=1>>[NH2:30][C:29]1[S:28][C:27]([C:44]2[CH:45]=[C:40]([F:39])[CH:41]=[CH:42][C:43]=2[C:49]([F:50])([F:51])[F:52])=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:14][CH2:15][CH:10]([CH2:9][NH2:8])[CH2:11][CH2:12]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: OB(O)c1cc(F)ccc1C(F)(F)F
Product: Cn1ncc(NC(=O)c2nc(-c3cc(F)ccc3C(F)(F)F)sc2N)c1N1CCC(CN)CC1
Yield: 55 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 5-fluoro-2-(trifluoromethyl)phenylboronic acid gave 279 as a brown solid (54 mg, 55% over two steps). 1H NMR (400 MHz, d4-MeOD) 7.94 (dd, J=8.9, 5.4 Hz, 1H), 7.60-7.50 (m, 2H), 7.40 (td, J=8.3, 2.6 Hz, 1H), 3.73 (s, 3H), 3.21-3.09 (m, 4H), 2.63 (d, J=6.6 Hz, 2H), 1.84 (d, J=12.5 Hz, 2H), 1.57-1.48 (m, 1H), 1.38 (qd, J=11.8, 4.7 Hz, 2H). LCMS (ES+) m/z 498 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:39])[CH3:38]>ClCCl>[CH3:29][O:28][C:20]1[CH:19]=[C:18]([NH:17][C:14]2[O:15][C:16]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:39])[CH3:38])=[CH:3][CH:4]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[C:21]=1[O:26][CH3:27]
Reactant: CC(=O)Cl
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(N)cc4)c3o2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Nc2nc3cccc(-c4ccc(NC(C)=O)cc4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.075 g (0.1927 mmol) [7-(4-amino-phenyl)-benzooxazol-2-yl]-(3,4,5-trimethoxy-phenyl)-amine (example 11), 0.027 ml triethylamine and 0.016 g (0.199 mmol) acetyl chloride in 4 ml dichloromethane is stirred for 1 h at room temperature. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with water and saturated NaCl solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography (silicagel, EtOAc) to afford the title compound as orange crystals. Rt=2.16 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 434 (M+1)+; m.p. 265-270° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[N:7][O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:27]=[C:26](F)[C:25]([F:29])=[CH:24][C:23]=1[C:30](=[O:32])[CH3:31].CCN(C(C)C)C(C)C>CS(C)=O>[CH:18]([O:17][C:15]([N:12]1[CH2:11][CH2:10][CH:9]([O:8][N:7]=[C:4]2[CH2:3][CH2:2][N:1]([C:26]3[CH:27]=[C:22]([F:21])[C:23]([C:30](=[O:32])[CH3:31])=[CH:24][C:25]=3[F:29])[CH2:6][CH2:5]2)[CH2:14][CH2:13]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(=O)c1cc(F)c(F)cc1F
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCNCC2)CC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(F)c(N2CCC(=NOC3CCN(C(=O)OC(C)C)CC3)CC2)cc1F
Temperature: 130 °C
Yield: 62 %

Procedure:
Compound 2d (0.22 g, 0.78 mmol), 1-(2,4,5-trifluoro-phenyl)-ethanone (0.22 mL), DIEA (0.22 mL, 1.33 mmol), and DMSO (2 mL) were combined and heated at 130° C. for 20 h. The mixture was cooled to room temperature and purified by flash chromatography (eluent: 10 to 40% EtOAc+0.1% triethylamine in hexane) to afford 211 mg (62% yield) of 4-[1-(4-acetyl-2,5-difluoro-phenyl)-piperidin-4-ylideneaminooxy]-piperidine-1-carboxylic acid isopropyl ester 50a: LC-MS 438.0 (MH+).
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[F:66][C:67]([F:71])([F:70])[CH2:68][NH2:69]>CN(C=O)C>[F:66][C:67]([F:71])([F:70])[CH2:68][NH:69][C:6]([CH:4]1[CH2:5][C:2]([F:1])([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:22])([F:23])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:3]1)=[O:8]
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reactant: NCC(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(F)(F)F)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.9 %

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 7, 0.1 g, 0.200 mmol) in DMF (3 mL) was added HOBt (0.026 g, 0.200 mmol), DIPEA (0.050 g, 0.392 mmol) followed by addition of EDCl.HCl (0.056 g, 0.294 mmol, 1.5 eq.) and 2,2,2-trifluoro-ethylamine hydrochloride (0.026 g, 0.200 mmol) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×20 mL). Combined organic layer was washed with water (5×30 mL), brine (50 mL), saturated NaHCO3 (50 mL), dried over sodium sulphate and evaporated in vacuo to get crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 1% methanol in DCM to afford sticky mass, which was crystallized with pentane to afford white solid (0.065 g, 56%). 1H-NMR (400 MHz, CDCl3) δ: 2.77-2.83 (m, 3H), 2.96-3.08 (m, 2H), 3.68 (d, 1H, J=17.2 Hz), 3.92-4.00 (m, 2H), 4.08 (d, 1H, J=17.2 Hz), 5.70 (t, 1H, J=6.3 Hz), 7.52 (d, 2H, J=8.2 Hz), 7.64 (s, 2H), 7.70 (d, 2H, J=8.12 Hz); LC-MS (m/z): [M−H] 588.60.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][N:67]([CH:69]([CH3:71])[CH3:70])[CH3:68])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][N:67]([CH:69]([CH3:71])[CH3:70])[CH3:68])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Reactant: CC(C)N(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Product: CC(C)N(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=549, obsd.=549).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][C:11]1[C:15](B(O)O)=[C:14]([CH3:19])[O:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:10][C:11]1[C:15]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)=[C:14]([CH3:19])[O:13][N:12]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: Cc1oc(Br)cc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1noc(C)c1-c1cc(C=O)c(C)o1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 3,5-dimethylisoxazole-4-boronic acid (1.7 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (9 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 30% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.4 g, 69%) as a yellow crystal.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[CH2:4][CH2:5][OH:6].[F:9][C:10]([F:17])([F:16])[CH2:11][S:12](Cl)(=[O:14])=[O:13].C(OCC)(=O)C>C(Cl)Cl>[F:9][C:10]([F:17])([F:16])[CH2:11][S:12]([O:6][CH2:5][CH2:4][C:3]([O:2][CH3:1])([CH3:8])[CH3:7])(=[O:14])=[O:13]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: COC(C)(C)CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(C)(C)CCOS(=O)(=O)CC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a solution of 3-methoxy-3-methylbutane-1-ol (0.4 g, 3.4 mmol) and TEA (0.2 g, 2 mmol) in CH2Cl2 (6 mL) was added 2,2,2-trifluoroethanesulfonyl chloride (0.12 g, 0.66 mmol). The solution was stirred at rt for 1 h. The organics were extracted with CH2Cl2 (25 mL) and washed with 0.1 M HCl (3×20 mL), saturated aqueous NaHCO3 (1×20 mL) and saturated aqueous NaCl (1×20 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product as an oil (0.086 g, 50%). 1H NMR (400 MHz CDCl3) δ 4.41 (t, 2H, J=7.3 Hz), 3.87 (q, 2H, J=8.8 Hz), 3.14 (s, 3H), 1.94 (t, 2H, J=7.3), 1.16 (s, 6H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.Cl[S:13]([C:16]1[CH:17]=[CH:18][C:19]2[O:28][C:27]3[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][C:22]=3[C:20]=2[CH:21]=1)(=[O:15])=[O:14]>C1COCC1>[N:3]1([S:13]([C:16]2[CH:17]=[CH:18][C:19]3[O:28][C:27]4[CH2:26][CH2:25][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:23][C:22]=4[C:20]=3[CH:21]=2)(=[O:15])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)Cl)cc3c2C1
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2oc3ccc(S(=O)(=O)n4ccc5ccccc54)cc3c2C1
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
Sodium hydride (60% suspension in mineral oil, 19 mg, 0.484 mmol) was added to a solution of indole (42 mg, 0.363 mmol) in THF (1.5 mL) under N2 at room temperature, and the reaction stirred for 30 min. The product of step B (90 mg, 0.242 mmol) was then added and the reaction held for 2 h. It was quenched with H2O (10 mL), diluted with ether (10 mL) and the organic phase removed. The aqueous phase was extracted with ether (2×10 mL) and the combined organic phases dried over Na2SO2 and concentrated. Purification by combiflash (silica gel, hexane/ethyl acetate, 100:0 to 40:60) provided tert-butyl 8-(1H-indol-1-yl-sulfonyl)-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (28 mg, 25%) as a clear oil. 1H NMR (CDCl3, 300 MHz) δ 8.02 (d, J=9.0 Hz, 2H), 7.76 (dd, J=9.1, 2.2 Hz, 1H), 7.60 (d, J=4.0 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.33 (t, J=1.4 Hz, 1H), 7.28 (t, J=1.4 Hz, 1H), 6.66 (d, J=3.6 Hz, 1H), 4.53 (br s, 2H), 3.80 (t, J=6.2 Hz, 2H), 2.82 (t, J=6.2 Hz, 2H), 1.52 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](O)=[O:15])=[CH:10][C:9]=2[OH:17])[N:3]=1.Cl.[CH3:19][N:20](C)[CH2:21]CCN=C=NCC.ON1C2C=CC=CC=2N=N1.CNC>CN(C=O)C.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([N:20]([CH3:21])[CH3:19])=[O:15])=[CH:10][C:9]=2[OH:17])[N:3]=1
Reactant: Cc1cc(C)n(-c2ccc(C(=O)O)cc2O)n1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C)n(-c2ccc(C(=O)N(C)C)cc2O)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 28.4 %

Procedure:
36 mg of 4-(3,5-dimethyl-1H-pyrazol-1-yl)-3-hydroxybenzene carboxylic acid was dissolved in 0.4 ml of DMF, and 36 mg of 1-(3-dimethylamino propyl)-3-ethylcarbodiimide hydrochloride, 25 mg of 1-hydroxybenzotriazole, and 93 μl of dimethylamine (2.0M THF solution) were added and stirred at room temperature for 4 hours. To the reaction mixture was added 10 ml of water, and extracted with 15 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using a preparative thin-layer silica gel column chromatography (ethyl acetate) to yield 11.4 mg of the title compound.