Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([OH:24])[CH:6]=1)(=[O:3])[CH3:2].N1C=CC=CC=1.FC(F)(F)S([O-])(=O)=O.[F:39][C:40]([I+]C1C=CC=CC=1)([F:48])[C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43]>ClCCl>[C:1]([NH:4][C:5]1[N:9]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][C:18]([F:19])([F:20])[F:21])[C:13]([CH3:22])=[CH:12][C:11]=2[F:23])[N:8]=[C:7]([O:24][C:40]([F:48])([F:39])[C:41]([F:47])([F:46])[C:42]([F:45])([F:44])[F:43])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(O)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Reactant: FC(F)(F)C(F)(F)C(F)(F)[I+]c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(OC(F)(F)C(F)(F)C(F)(F)F)nn1-c1cc(SCC(F)(F)F)c(C)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.3 %

Procedure:
2.1 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-hydroxypyrazole was dissolved in 60 mL of dichloromethane, and 0.51 g of pyridine was added. To the obtained solution, 3.0 g of (perfluoro-n-propyl)phenyliodonium trifluoromethanesulfonate was slowly added, followed by stirring at room temperature for 1 hour. The solvent was distilled off under reduced pressure, a saturated salt solution was added, extraction with ethyl acetate was carried out, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.10 g of 5-acetylamino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(1,1,2,2,3,3,3-heptafluoropropoxy)pyrazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Li].C([Li])(C)(C)C.CN(C)[CH:33]=[O:34]>O.CCOCC>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[CH:33]=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(C=O)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3.3 g (0.01 mol) 2,5-bis-tert.-butyloxycarbonylaminobromobenzene from step A are dissolved in 100 ml of water-free tetrahydrofuran under argon. 17 ml of a 1.6 molar etheric methyl lithium solution (0.03 mol) are gradually added. The reaction mixture is cooled to −20° C., 7 ml of a 1.5 molar tert.-butyl lithium solution (0.01 mol) are gradually added. After the addition has ended the solution is stirred for 30 minutes at the given temperature. Subsequently 1.2 g of dimethyl formamide (0.02 mol) are added and the reaction mixture is stirred for one hour at −20° C. After slowly heating to room temperature the reaction mixture is hydrolyzed with water and then poured into ether, the aqueous phase is extracted with ether and then the organic phase is dried over magnesium sulfate. The solvent is distilled away in a rotary evaporator and the residue is purified on silica gel with a petroleum ether/ethyl acetate solvent (9/1).
Reaction SMILES: [F:1][C:2]([F:16])([C:6]([F:15])([F:14])[C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])[CH2:3][CH2:4][OH:5].N1C=CC=CC=1.[Cl-].[C:24]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]CC)(=[O:30])/[CH:25]=[CH:26]\[C:27]([O-])=[O:28].C(OCC)(=O)C>C(Cl)(Cl)Cl>[C:24]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])(=[O:30])/[CH:25]=[CH:26]\[C:27]([O:5][CH2:4][CH2:3][C:2]([F:16])([F:1])[C:6]([F:14])([F:15])[C:7]([F:12])([F:13])[C:8]([F:9])([F:10])[F:11])=[O:28]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCCCCCCOC(=O)/C=C\C(=O)[O-]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCCCCCCCCCOC(=O)/C=C\C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 17 %

Procedure:
3,3,4,4,5,5,6,6,6-Nonafluorohexanol (164.6 g, 623 mmol) and pyridine (49.3 mL, 623 mmol) were dissolved in chloroform (280 mL), and the mixture was added dropwise with monododecyl maleate chloride (155.8 g, 566 mmol), while the internal temperature was kept at 20° C. or lower on an ice bath. After completion or the addition, the mixture was stirred for 1 hour and added with ethyl acetate. The organic phase was washed with 1 mol/L aqueous hydrochloric acid and a saturated sodium chloride aqueous solution. Then, the organic layer was collected, and the organic solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/chloroform=10/0 to 7/3 (v/v)) to obtain the target compound (48.2 g, yield: 18%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([O:20][CH3:21])=[CH:13][N:12]=1.C([O-])(=O)C.[K+]>CCO.O>[F:10][C:11]1[C:16]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=2)=[CH:15][C:14]([O:20][CH3:21])=[CH:13][N:12]=1
Reactant: COc1cnc(F)c(B(O)O)c1
Reactant: Cc1nc(N)nc(Cl)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Temperature: 100 °C

Procedure:
To a 20 mL microwave reaction tube was added 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9, 1.02 g, 7.05 mmol), 2-fluoro-5-methoxypyridin-3-ylboronic acid (1.67 g, 9.77 mmol), Am-Phos (Aldrich, 0.255 g, 0.360 mmol) and potassium acetate (Aldrich, 2.11 g, 21.5 mmol) in EtOH (10 mL) and water (1 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 20 min. The reaction mixture was partitioned between water (200 mL) and EtOAc (200 mL). Layers were separated and insoluble material was collected (precipitate 1). The aqueous phase was further extracted with 10% isopropanol in chloroform (3×100 mL). Each organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Upon addition of DCM to the crude product, precipitate came out and the solid was collected via filtration. The first precipitate (precipitate 1) and the solid from extraction were all desired product (1.17 g, 70.3%). 1H NMR (400 MHz,CDCl3) δ ppm 8.08 (dd, J=7.53, 3.23 Hz, 1H) 7.97 (dd, J=3.03, 1.86 Hz, 1H) 5.47 (br. s., 2H) 3.92 (s, 3H) 2.54 (s, 3H). m/z (ESI, positive ion): 236.0 (M+H)+.
Reaction SMILES: O.O[N:3]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([NH:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])([C:37](O)=[O:38])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].[OH-].[NH4+]>CN(C=O)C.[Cl-].[Na+].O.O>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([NH:40][C:41]([O:43][C:44]([CH3:45])([CH3:47])[CH3:46])=[O:42])([C:37](=[O:38])[NH2:3])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(C(N)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.33 h
Yield: 97.7 %

Procedure:
1-Hydroxybenzotriazole hydrate (150 mg, 1.1 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (214 mg, 1.1 mmol) were added to a stirred solution of 4-tert-butoxycarbonylamino-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (149 mg, 0.44 mmol) in DMF (9 mL). The reaction mixture was stirred for 80 minutes, and ammonium hydroxide (1.2 mL, ammonia sol. aq.) was added. After stirring for a further 20 hours at room temperature, brine (18 mL) and water (3 mL) were added to the reaction mixture. The aqueous phase was extracted with ethyl acetate (2×12 mL) and the combined organic phases were dried (Mg2SO4), filtered and concentrated to give 4-tert-butoxycarbonylamino-4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (147 mg, 0.43 mmol, 97%). LC-MS (LCT2) m/z 366 [M+Na+], Rt 6.63 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][C:36]([F:39])([F:38])[F:37])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][C:36]([F:39])([F:37])[F:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH3:33])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:34])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1OC(F)(F)F

Procedure:
155 mg (0.23 mmol) of tert-butyl 4-[(2-{4-[5-chloro-2-(trifluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}propanoyl)amino]benzoate were hydrolysed with TFA according to General Method 2. Yield: 67 mg (purity 94%, 54% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH:20]=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27].S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-]>C(OCC)(=O)C.CCCCCC.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([F:19])[CH:15]=2)[N:10]=[C:9]1[CH2:20][NH:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27]
Reactant: O=Cc1nc2ccc(F)cc2c(=O)n1-c1ccccc1Cl
Reactant: N#Cc1cccc(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(NCc2nc3ccc(F)cc3c(=O)n2-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.2 %

Procedure:
A mixture of 3-(2-chloro-phenyl)-6-fluoro-3,4-dihydro-quinazolin-4-one-2-carboxaldehyde (0.150 g, 0.50 mmol), glacial acetic acid (10 mL), 3-aminobenzonitrile (0.050 g, 0.42 mmol), and anhydrous sodium sulfate (0.71 g, 5 mmol) was stirred at ambient temperature overnight. Tlc indicated that the imine had formed (Rf=0.43 on silica gel tic developed with 30% ethyl acetate/hexane, UV detection). Sodium triacetoxyborohydride (0.267 g, 1.26 mmol) was added and the reaction was allowed to stir over the weekend (72 hours). The mixture was poured into saturated aqueous bicarbonate and repeatedly extracted with ethyl acetate. The combined organic layer was dried over magnesium sulfate and concentrated to afford a yellow solid. This solid was triturated with 50% ethyl ether/isopropyl ether to give 0.133 g (78%) of 3-{[3-(2-chloro-phenyl)-6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl]-amino}-benzonitrile as an off white solid which had: mp 225-228° C.; 1H NMR δ 7.93 (dd, J=3, 8 Hz, 1 H), 7.87 (dd, J=4.5, 8.5 Hz, 1 H), 7.70 (dd, J=1.5, 7.5 Hz, 1 H), 7.62-7.52 (m, 4 H), 7.40 (dd, J=1.5, 7.5 Hz, 1 H), 7.20 (t, J=8 Hz, 1 H), 6.97 (d, J=7.5 Hz, 1 H), 6.80 (dd, J=2, 8 Hz, 1 H), 6.66 (s, 1 H), 3.88 (ABq, Δv1-3=39.5 Hz, J=17 Hz, 2 H). Analysis calculated for C22H14ClFN4O.0.5 H2O: C, 63.85; H, 3.65; N, 13.54. Found: C, 63.90; H, 3.31; N, 13.46.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:6][C@H:5]2[O:7][C@H:8]([CH:10]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[OH:11])[CH2:9][C@H:4]2[O:3]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:18]([O:11][CH:10]([C@H:8]1[O:7][C@@H:5]2[O:6][C:2]([CH3:17])([CH3:1])[O:3][C@@H:4]2[CH2:9]1)[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1(C)O[C@H]2O[C@H](C(O)C3CCCC3)C[C@H]2O1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)O[C@H]2O[C@H](C(OC(=O)c3ccccc3)C3CCCC3)C[C@H]2O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.8 %

Procedure:
To a solution of [(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-cyclopentyl-methanol (compound 11a, 1.2 g, 5.0 mmol), TEA (3.2 g, 31.2 mmol) and DMAP (100 mg) in DCM (50 mL) was added benzoyl chloride (1.4 g, 10.0 mmol) slowly at 0° C. The mixture was stirred at 25° C. for 4 hours and then quenched by saturated NaHCO3 solution. The reaction mixture was extracted with EtOAc (100 mL) twice. The organic layers were combined, washed with brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with 1:20 to 1:5 EtOAc in petroleum ether) to afford 1.4 g of [[(3aR,5S,6aR)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]-cyclopentyl-methyl] benzoate (compound 11b) as a colourless oil.
Reaction SMILES: C1C2C(CO[C:16]([N:18](C)[C:19]([CH3:71])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:33]([O:65][CH3:66])[CH2:34][C:35]([N:37]3[CH2:41][CH2:40][CH2:39][C@H:38]3[C@H:42]([O:63][CH3:64])[C@@H:43]([CH3:62])[C:44]([NH:46][C@@H:47]([CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49])=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH3:20])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>ClCCl>[CH3:16][NH:18][C:19]([CH3:20])([C:21]([NH:23][C@H:24]([C:28]([N:30]([C@@H:32]([C@@H:67]([CH3:70])[CH2:68][CH3:69])[C@H:33]([O:65][CH3:66])[CH2:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[C@H:42]([O:63][CH3:64])[C@@H:43]([CH3:62])[C:44]([NH:46][C@@H:47]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:48]([O:50][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:49])=[O:45])=[O:36])[CH3:31])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])[CH3:71]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)N(C)C(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CCNCC
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC)C(C)C
Temperature: 25 °C
Yield: 81 %

Procedure:
To a stirring solution of #129 (823 mg, 0.826 mmol, 1.00 eq.) in 15 mL of dichloromethane, diethylamine (4 mL, 40 mmol, 50 eq.) was added. The reaction was allowed to stir at room temperature for ˜14½ hours. The reaction was concentrated in vacuo and azeotroped once with heptanes. Residue with diluted with dichloromethane and a small amount of methanol before being reduced down onto silica. Residue was purified by Silica Chromatography (Gradient: 0%-20% methanol in ethyl acetate) producing #130 (518 mg, 81%) as a white solid. LC-MS (Protocol Q): m/z 774.3 [M+H+] retention time=1.48 minutes. HPLC (Protocol A at 25° C.): m/z 774.5 [M+H+], retention time=7.733 minutes (purity >98%). 1H NMR (400 MHz, DMSO-d6), δ 8.36 (d). 8.14 (d), 7.81 (t), 7.14-7.25 (m), 7.01-7.07 (m), 4.87-4.94 (m), 4.78-4.85 (m), 4.67-4.76 (m), 4.46-4.65 (m), 4.29-4.40 (m), 3.93-4.03 (m), 3.70-3.81 (m), 3.49-3.60 (m), 3.38-3.47 (m), 3.29-3.36 (m), 3.15-3.28 (m), 2.98-3.13 (m), 2.94 (br s), 2.74-2.89 (m), 2.64-2.69 (m), 2.18-2.45 (m), 2.02-2.14 (m), 1.90-2.01 (m), 1.62-1.87 (m), 1.40-1.55 (m), 1.37 (d), 1.20-1.33 (m), 1.16 (d), 1.01-1.10 (m), 0.90-0.98 (m), 0.82-0.89 (m), 0.69-0.79 (m).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([Cl:21])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cl)Cc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
Dissolve 4-bromophenylacetic acid (25.39; 118.07 mmol) in ether (200 mL). Add anhydrous pyridine (1 mL) and cool the reaction to 0° C., then add oxalyl chloride (18.44 g, 12.86 mL, 145.32 mmol). After 15 minutes, allow the reaction to come to ambient temperature. At 1.5 hours, add DMF (0.4 mL) and stir for an additional hour. Concentrate to a thick amber oil. Dilute with dichloromethane (118 mL) to provide a 1 N stock solution of (4-bromo-phenyl)-acetyl chloride (118 mmol).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]([NH:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[N:7]=1)(=[O:4])=[O:3]>CO.[Pd]>[CH3:1][S:2]([O:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[N:7]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)Oc1ccc([N+](=O)[O-])c(NC2CCCCC2)n1
Agent: [Pd]
Solvent: CO
Product: CS(=O)(=O)Oc1ccc(N)c(NC2CCCCC2)n1

Procedure:
6-(Cyclohexylamino)-5-nitropyridin-2-yl methanesulfonate (1.58 g, 5.01 mmol) was dissolved in methanol (1000 mL). Palladium (5% Pd/C, 1.72 g, 0.075 mmol) was added. The reaction was flushed with nitrogen and stirred under a balloon filled with hydrogen over 3 h at room temperature. The mixture was filtered through Celite® and concentrated to give the title compound as a dark green solid which was used immediately in next step without further purification.
Reaction SMILES: [CH3:1][C:2]([C:21]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24])([CH3:20])[CH2:3][C@:4]([O:12][Si](CC)(CC)CC)([C:8]([F:11])([F:10])[F:9])[CH2:5][C:6]#[CH:7].Cl>CO>[F:30][C:27]1[CH:28]=[CH:29][C:21]([C:2]([CH3:20])([CH3:1])[CH2:3][C@:4]([OH:12])([C:8]([F:10])([F:11])[F:9])[CH2:5][C:6]#[CH:7])=[C:22]([CH:26]=1)[C:23]([NH2:25])=[O:24]
Reactant: C#CC[C@@](CC(C)(C)c1ccc(F)cc1C(N)=O)(O[Si](CC)(CC)CC)C(F)(F)F
Agent: Cl
Solvent: CO
Product: C#CC[C@](O)(CC(C)(C)c1ccc(F)cc1C(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 7.1 g of 2-((S)-1,1-dimethyl-3-triethylsilanyloxy-3-trifluoromethylhex-5-ynyl)-5-fluorobenzamide (15.7 mmol) in 80 mL of MeOH was added 400 mL of HCl (4 N in dioxane, 1.6 mol). The reaction was stirred for 2 hours at room temperature. The volatiles were concentrated in vacuo and 500 mL of water was added. The reaction mixture was then extracted with ethyl acetate, dried over sodium sulfate, and concentrated in vacuo to afford 5.2 g (100%) of 5-fluoro-2-((S)-3-hydroxy-1,1-dimethyl-3-trifluoromethylhex-5-ynyl)benzamide.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[C:4]1([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:27]=[CH:26][CH:25]=[CH:24][C:18]=2[O:19][CH2:20][CH:21]2[CH2:23][O:22]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1>[CH3:1][N:2]([CH2:23][CH:21]([OH:22])[CH2:20][O:19][C:18]1[CH:24]=[CH:25][CH:26]=[CH:27][C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:3]
Reactant: CNC
Reactant: c1ccc(CCCCCCCc2ccccc2OCC2CO2)cc1
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
1.0 ml of 50% by volume aqueous dimethylamine was added to a solution of 0.41 g of the crude compound containing 2-[2-(7-phenylheptyl)phenoxymethyl]oxirane [prepared as described in step (a) above]in 6 ml of tetrahydrofuran, and the mixture was stirred at room temperature for one day. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 19:1 by volume mixture of methylene chloride and methanol as the eluent, to give 0.32 g (yield 69%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:17]([OH:19])=O)=[N:8][C:9]=2[O:10][CH:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:22]([NH2:24])=[O:23]>>[C:22]([C@@H:21]([NH:20][C:17]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH:11]([CH3:16])[C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:19])[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])[NH2:24]
Reactant: CC(Oc1nc(C(=O)O)ccc1C1CC1)C(F)(F)F
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OC(C)C(F)(F)F)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-(1,1,1-trifluoropropan-2-yloxy)picolinic acid and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials. MS (EI): m/e=388.4 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[H-].[Na+].[N+]([C:15]1[CH:16]=[C:17]([CH3:22])[N+:18]([O-:21])=[CH:19][CH:20]=1)([O-])=O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][N+:18]([O-:21])=[C:17]([CH3:22])[CH:16]=2)=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: Cc1cc([N+](=O)[O-])cc[n+]1[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2ccc(Br)c(F)c2)cc[n+]1[O-]
Temperature: 180 °C

Procedure:
4-Bromo-3-fluorophenol (0.5 g, 2.61 mmol) was added to a solution of sodium hydride (0.115 g, 2.90 mmol) in DMF (5 ml). After stirring for 10 minutes 4-nitro-2-picoline N-oxide (0.37 g, 2.41 mmol) was added. The reaction mixture was heated at 180° C. for 1 hour under microwave irradiation. After cooling to room temperature the mixture was filtered through diatomaceous earth and this was thoroughly washed with EtOAc. The filtrate was washed with water (2×25 ml), the organic fraction was dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; 0-3% methanol/DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate D12 (0.33 g, 49%).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>COCCO>[NH:18]([C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1)[NH2:19]
Reactant: Clc1nccc2[nH]c(-c3ccccc3)nc12
Reactant: NN
Solvent: COCCO
Solvent: O
Product: NNc1nccc2[nH]c(-c3ccccc3)nc12

Procedure:
A mixture of 130 mg (0.568 mmol) of 4-chloro-2-phenyl-1H-imidazo[4,5-c]pyridine, 0.110 mL (114 mg, 2.4 mmol) of hydrazine hydrate, and 3 mL of 2-methoxyethanol was stirred at reflux for 2 days. The cooled solution was concentrated, and the residue was partitioned between ethyl acetate and water. The organic phase was dried over sodium sulfate, filtered and concentrated to yield the title compound. LC-MS 226 (M+1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:36]2[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=2)=[N:8]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3ccnc(OC)c23)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (3.20 g) obtained in Step C of Example 35 in DMF (20 mL)/water (2.0 mL) were added methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (2.87 g), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (319 mg) and potassium carbonate (2.16 g). The reaction mixture was stirred overnight at 90° C. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.75 g).