Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8](=O)[CH2:9][F:10])[CH:7]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].O.CCOC(C)=O>C1COCC1.C(O[Ti](OCC)(OCC)OCC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8](=[N:19][S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH2:9][F:10])[CH:7]=1
Reactant: O=C(CF)c1cc(Br)ccc1F
Reactant: CC(C)(C)[S@](N)=O
Agent: CCO[Ti](OCC)(OCC)OCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[S@@](=O)N=C(CF)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.2 %

Procedure:
To a solution of 1-(5-bromo-2-fluorophenyl)-2-fluoroethanone (14 g, 59.6 mmol, step 1) and (R)-2-methylpropane-2-sulfinamide (14.44 g, 119 mmol, AK Scientific) in THF (120 ml) was added tetraethoxytitanium (27.2 g, 119 mmol, Aldrich). The reaction was stirred at RT for 16 hours. The reaction was poured slowly into vigorously stirring water (700 ml) and the resulting suspension was stirred for 20 minutes. EtOAc (400 ml) was added and the suspension was stirred for an additional 20 minutes. The suspension was filtered through celite and the filter cake was washed with additional EtOAc. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The material was purified via silica gel flash chromatography using a gradient of 0-25% EtOAc in Hexanes to afford the title compound as a yellow oil (15.35 g, 45.4 mmol, 76% yield). MS m/z=338.0 M+. Calculated for C12H14BrF2NOS: 338.211
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[H-].[Na+].[H][H].Cl[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:12])=[N:8][N:9]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)n[nH]c1C
Reactant: Clc1cnccn1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)nn(-c2cnccn2)c1C
Temperature: 50 °C
Reaction time: 24 h
Yield: 43.7 %

Procedure:
step 1—To a solution of 3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester (1 g, 5.95 mmol) in DMF (20 mL) cooled to 0° C. was added portionwise NaH (60% in mineral oil, 171 mg, 7.13 mmol). After hydrogen evolution ceased, 2-chloro-pyrazine (0.64 mL, 7.13 mmol) was added and the reaction was stirred at 50° C. for 24 h. The reaction mixture was cooled to RT, partitioned between EtOAc and saturated NH4Cl. The aqueous layer was extracted twice with EtOAc. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified via SiO2 chromatography eluting with hexane/EtOAc to afford 0.64 g (44%) of 3,5-dimethyl-1-pyrazin-2-yl-1H-pyrazole-4-carboxylic acid ethyl ester (124a). The ethyl ester was hydrolyzed to the corresponding acid with KOH in aqueous EtOH as described in step 2 of example 31.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH2:24][CH3:25])[CH2:22][CH3:23])=[CH:17][C:16]=4[O:26][CH2:27][CH:28]=[CH2:29])=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:30])[CH2:3]1>C(O)C.[Pd]>[CH3:31][C:2]1([CH3:1])[C:11]2[CH:10]=[C:9]3[NH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([N:21]([CH2:22][CH3:23])[CH2:24][CH3:25])=[CH:17][C:16]=4[O:26][CH2:27][CH2:28][CH3:29])=[N:14][C:8]3=[CH:7][C:6]=2[NH:5][C:4](=[O:30])[CH2:3]1
Reactant: C=CCOc1cc(N(CC)CC)ccc1-c1nc2cc3c(cc2[nH]1)C(C)(C)CC(=O)N3
Agent: [Pd]
Solvent: CCO
Product: CCCOc1cc(N(CC)CC)ccc1-c1nc2cc3c(cc2[nH]1)C(C)(C)CC(=O)N3

Procedure:
2 g. 8,8-Dimethyl-2-(4-diethylamino-2-allyloxy-phenyl)-5,6,7,8-tetrahydro-lH-imidazo[4,5-g]quinolin-6-one were hydrogenated in ethanol in the presence of palladium/charcoal. After completion of the take up of hydrogen, the catalyst was filtered off, the filtration was evaporated and the residue recrystallised from isopropanol to give 1.8 g. of the title compound; m.p. 147 -148° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1.[I-].[K+].C[N:18](C)C=O>>[NH2:18][CH2:2][CH2:3][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: CN(C)C=O
Reactant: O=C1COc2cc(CCBr)ccc2N1
Agent: [I-]
Agent: [K+]
Product: NCCc1ccc2c(c1)OCC(=O)N2

Procedure:
In a 250-cm3 ground-necked flask, 0.01 mol of 7-(2-bromoethyl)-3-oxo-2,3-dihydro-1,4-benzoxazine and 0.3 g of potassium iodide are dissolved in 30 cm3 of dimethylformamide.
Reaction SMILES: [OH:1][CH:2]([CH2:29][OH:30])[CH2:3][NH:4][C:5]1[CH:12]=[C:11]([N:13]2[C:21]3[CH2:20][C:19]([CH3:23])([CH3:22])[CH2:18][C:17](=[O:24])[C:16]=3[C:15]([C:25]([F:28])([F:27])[F:26])=[N:14]2)[CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[OH-:31].[Na+].OO>CCO.O>[OH:1][CH:2]([CH2:29][OH:30])[CH2:3][NH:4][C:5]1[CH:12]=[C:11]([N:13]2[C:21]3[CH2:20][C:19]([CH3:22])([CH3:23])[CH2:18][C:17](=[O:24])[C:16]=3[C:15]([C:25]([F:27])([F:28])[F:26])=[N:14]2)[CH:10]=[CH:9][C:6]=1[C:7]([NH2:8])=[O:31]
Reactant: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C#N)c(NCC(O)CO)c3)c2C1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C(N)=O)c(NCC(O)CO)c3)c2C1
Yield: 29.5 %

Procedure:
2-(2,3-Dihydroxy-propylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (1.7 g, 4 mmol, 1 eq), NaOH (806 mg, 20 mmol, 5 eq), and H2O2 (3 mL) were dissolved in EtOH-water (4:1) (40 mL). The mixture was microwaved at 120° C. for 15 min, then concentrated to dryness, and purified by flash chromatography, eluted by 10% MeOH in EtOAc to give pure 2-(2,3-Dihydroxy-propylamino)-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydroindazol-1-yl)-benzamide (0.52 g, 29% yield). LCMS (m/z): M+H=441.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]2[CH:26]=[CH:25][C:13]3[CH2:14][CH2:15][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:4](=[O:27])[CH:3]=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35]O)=[N:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:1][C:2]2[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C:10]3[CH:26]=[CH:25][C:13]4[CH2:14][CH2:15][N:16]([C:19](=[O:24])[C:20]([F:21])([F:22])[F:23])[CH2:17][CH2:18][C:12]=4[CH:11]=3)[C:4](=[O:27])[CH:3]=2)=[N:33][CH:34]=1
Reactant: O=C(N1CCc2ccc(CCn3ccc(O)cc3=O)cc2CC1)C(F)(F)F
Reactant: OCc1ccc(F)cn1
Product: O=C(N1CCc2ccc(CCn3ccc(OCc4ccc(F)cn4)cc3=O)cc2CC1)C(F)(F)F

Procedure:
4-(5-Fluoro-pyridin-2-ylmethoxy)-1-{2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one is prepared following example 23.9 from 500 mg (1.32 mmol) 4-hydroxy-1-{2-[3-(2,2,2-trifluoro-acetyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl]-ethyl}-1H-pyridin-2-one (preparation 21b) and 251 mg (1.97 mmol) (5-fluoro-pyridin-2-yl)-methanol.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[NH:5][CH:4]=[CH:3]1.P(Br)(Br)[Br:15].[OH-].[Na+]>CN(C=O)C>[Br:15][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: N#Cc1ccc2[nH]ccc(=O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nccc(Br)c2c1
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of quinolinone (b) (12.0 g, 70.5 mmol) in DMF (60 ml) was treated dropwise with phosphorus tribromide (8.0 ml, 84.6 mmol) over 10 minutes (exothermic). After allowing to stir and cool to room temperature, ice water (100 ml) was added and the mixture was stirred 30 minutes, then basified to pH8 by dropwise addition of 50% NaOH with cooling. The resultant solid was filterd off, washed with water and air dried to afford a tan solid (14.3 g, 87%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:3])[NH2:2].[CH2:9]=O.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[O:14]1[CH2:15][CH2:16][N:11]([CH2:9][NH:2][C:1]([NH:4][CH2:5][C:6]([OH:8])=[O:7])=[O:3])[CH2:12][CH2:13]1
Reactant: NC(=O)NCC(=O)O
Reactant: C1COCCN1
Reactant: C=O
Product: O=C(O)CNC(=O)NCN1CCOCC1

Procedure:
1 mol of N-carbamyl glycine and 1 mol of formol are mixed while stirring. This mixture is cooled with ice-bath and 1 mol of morpholine is added slowly while keeping the temperature at about 15°C during 30 feet and at about 50°C during the same time. After cooling the resulting mixture is evaporated until dry. The residue is a white colored paste. The yield of the reaction is 98 %.
Reaction SMILES: [O:1]=[C:2]([CH:4]([NH:8][C:9](=[O:13])[N:10]([CH3:12])[CH3:11])[C:5](=[O:7])[CH3:6])[CH3:3].C=C[C@@H]1[C@@H]2C[C@@H:23]([C@H:24](O)[C:25]3C=CN=[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=34)[N:18](CC2)C1.[CH3:36][CH2:37][O:38][C:39](C)=[O:40]>C(Cl)Cl>[C:2]([C:4]([NH:8][C:9]([N:10]([CH3:11])[CH3:12])=[O:13])([C:5](=[O:7])[CH3:6])[C@H:23]([NH:18][C:39](=[O:40])[O:38][CH2:37][C:36]1[CH:6]=[CH:5][CH:4]=[CH:2][CH:3]=1)/[CH:24]=[CH:25]/[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:29]=1)(=[O:1])[CH3:3]
Reactant: CC(=O)C(NC(=O)N(C)C)C(C)=O
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)C(NC(=O)N(C)C)(C(C)=O)[C@@H](/C=C/c1ccccc1)NC(=O)OCc1ccccc1
Temperature: -78 °C

Procedure:
A flame-dried 250-mL round-bottomed flask was charged with urea 2 (2.38 g, 12.28 mmol, 1.0 equiv), cinchonidine (7) (0.72 g, 2.46 mmol, 0.2 equiv), and CH2Cl2 (65 mL). The resulting suspension was cooled to −78° C. and a cold solution of imine 3 (5.1 g, 19.24 mmol, 1.5 equiv) in CH2Cl2 (35 mL) was added via cannula transfer. The reaction was warmed to −65° C. and stirred until complete consumption of urea 2 was indicated by TLC analysis, typically 14-36 h (scale-dependent). The crude reaction was filtered through a short silica plug and rinsed with EtOAc (300 mL). The filtrate was concentrated in vacuo to give a pale yellow foam with a 84:16 enantiomeric ratio. Crystalline racemic product was isolated via trituration with 60:40 (v/v) hexanes:EtOAc (300 mL). The analytically-pure white solid was removed by filtration (1.33 g, 24%) and the filtrate was concentrated in vacuo to give a yellow oil. The crude oil was purified by flash chromatography (60:40 to 50:50 hexanes:EtOAc) affording diketone 4 as a pale yellow foam (3.87 g, 70%, 97:3 er). The enantiomeric ratio (er) was determined by SFC analysis (Chiralcel, OD, 9.0% MeOH, 1.5 mL/min, 150 bar, 210 nm; tR-minor 12.8 min, tR-major 14.7 min). Analytical data: [α]D19 +16.5 (c=1.00, CHCl3); mp (racemate) 130-134° C.; 1H NMR (600 MHz, CDCl3): δ 7.37-7.21 (m, 10H), 7.07 (br d, J=6.0 Hz, 1H), 6.59 (d, J=16.2 Hz, 1H), 6.50 (s, 1H), 5.96 (dd, J=16.2 Hz, 7.2, 1H), 5.40 (t, J=7.2 Hz, 1H), 5.14 (d, J=12.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 2.97 (s, 6H), 2.28 (s, 3H), 2.14 (s, 3H); 13C NMR (150 MHz, CDCl3): δ 200.9, 200.4, 157.6, 156.7, 136.9, 136.5, 133.2, 128.7, 128.6, 128.2, 128.2, 128.1, 126.9, 124.6, 81.7, 67.0, 57.2, 36.8, 26.2, 25.4; LRMS (ESI+) Calcd. For C25H29N3O5+Na, 474.20. Found, 474.22. IR (thin film, cm−1) 3418, 2243, 1702, 1635, 1507, 1371, 1249, 1066, 912, 693; TLC (60:40 Hexanes:EtOAc): Rf=0.20.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([O:27]C)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>>[N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1

Procedure:
22.19 g (39.90 mmol) of the compound from Example 48A and 44.78 g (399.0 mmol) of potassium tert-butoxide were reacted according to the General Method 9A. Yield: 18.29 g (100% of theory).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[NH:51][C:52]([C:55]2[CH:56]=[C:57]([NH2:61])[CH:58]=[CH:59][CH:60]=2)=[CH:53][CH:54]=1>CN(C=O)C>[N:50]1[NH:51][C:52]([C:55]2[CH:56]=[C:57]([NH:61][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:58]=[CH:59][CH:60]=2)=[CH:53][CH:54]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2ccn[nH]2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4ccn[nH]4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 6.8 %

Procedure:
DIEA (0.011 mL, 0.062 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.012 g, 0.057 mmol) and HATU (0.024 g, 0.062 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(2H-pyrazol-3-yl)-phenylamine (0.009 g, 0.057 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.0014 g of product in 7% yield: LCMS (ESI) m/z 362 (MH+).
Reaction SMILES: C1(N=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12]C2)CCCCC1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][C:24]=2[CH2:34][C:35]([OH:37])=[O:36])=[CH:19][CH:18]=1.OC1CCN(C)CC1>C1COCC1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:25][C:24]=2[CH2:34][C:35]([O:37][CH:14]2[CH2:15][CH2:10][N:9]([CH3:8])[CH2:12][CH2:13]2)=[O:36])=[CH:21][CH:22]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)Cc1cnn(-c2ccccc2)c1-c1ccc(Cl)cc1
Agent: CN1CCC(O)CC1
Solvent: C1CCOC1
Product: CN1CCC(OC(=O)Cc2cnn(-c3ccccc3)c2-c2ccc(Cl)cc2)CC1
Reaction time: 0.25 h

Procedure:
A solution of 2.27 g of dicyclohexylcarbodiimide in 10 ml of dry THF is added slowly, at 5°-10°, to a solution of 3.13 g of (5-p-chlorophenyl-1-phenyl-pyrazol-4-yl)-acetic acid in 25 ml of dry THF. The mixture is stirred for 15 minutes at 5°-10°, a solution of 1.23 g of 4-hydroxy-1-methylpiperidine in 10 ml of dry THF is then added at 5°-10°, the resulting mixture is stirred for 3 hours at 20° and subjected to the customary working up, and 1-methyl-4-piperidyl (5-p-chlorophenyl-1-phenylpyrazol-4-yl)-acetate is obtained; m.p. 90°-93°. Hydrochloride, m.p. 234°-236°.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([CH:9]=1)[NH2:8].FC(F)(F)C1C=CC(OC)=C([N:22]=[C:23]=[O:24])C=1.[C:29]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([OH:31])=[O:30]>>[C:29]([C:32]1[CH:33]=[C:34]([CH:43]=[CH:44][CH:45]=1)[O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)([OH:31])=[O:30].[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([O:10][CH3:11])=[C:7]([N:8]([C:34]2[CH:43]=[CH:44][CH:45]=[C:32]([C:29]([OH:31])=[O:30])[CH:33]=2)[C:23]([NH2:22])=[O:24])[CH:9]=1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Reactant: COc1ccc(C(F)(F)F)cc1N
Agent: Nc1ccc(Oc2cccc(C(=O)O)c2)cc1
Product: COc1ccc(C(F)(F)F)cc1N(C(N)=O)c1cccc(C(=O)O)c1

Procedure:
Entry 37: 4-(3-Carboxyphenoxy)aniline was synthesized according to Method A11. 5-(Trifluoromethyl)-2-methoxyaniline was converted into 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method B1. 4-(3-Carboxyphenoxy)aniline was reacted with 5-(trifluoromethyl)-2-methoxyphenyl isocyanate according to Method C1f to afford N-(5-(trifluoromethyl)-2-methoxyphenyl)-N-(3-carboxyphenyl) urea, which was coupled with 4-(dimethylamino)aniline according to Method D1c.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=2)=[N:10]1.C1C(=O)N([Br:36])C(=O)C1.O>CN(C=O)C>[Br:36][C:16]1[C:17]2[N:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:10]=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]#[N:28])=[CH:22][CH:21]=3)[C:12]=2[C:13]([O:18][CH3:19])=[N:14][CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2-c1c(F)cccc1F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(Br)c2c1c(-c1ccc(CC#N)cc1)nn2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
To a solution of (4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)phenyl)acetonitrile (148.1 mg) obtained in Step A of Example 39 in DMF (5 mL) was added NBS (77 mg) at 0° C., and the mixture was allowed to be warmed to room temperature, and stirred overnight. The reaction mixture was poured into water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (161 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12](=[O:17])[NH:13][CH2:14][C:15]#[CH:16])[O:7]1)=[O:5])[CH3:2].[N:25]([C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)=[N+:26]=[N-:27].CCCC[Sn](OC(C)=O)(CCCC)CCCC>CC(O)(C)C.CCO.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:8]([C:9](=[O:24])[NH:10][C@@H:11]([CH2:18][C:19]2[N:20]=[CH:21][S:22][CH:23]=2)[C:12]([NH:13][CH2:14][C:15]2[N:27]=[N:26][N:25]([C:28]3[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=3)[CH:16]=2)=[O:17])[O:7]1)=[O:5])[CH3:2]
Reactant: C#CCNC(=O)[C@H](Cc1cscn1)NC(=O)[C@H]1O[C@@H]1C(=O)OCC
Reactant: [N-]=[N+]=Nc1ccc(N)cc1
Agent: [Cu+2]
Agent: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: CC(C)(C)O
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](Cc1cscn1)C(=O)NCc1cn(-c2ccc(N)cc2)nn1
Yield: 85.8 %

Procedure:
The general click procedure was used substituting the following quantities using: 37 (29.5 mg, 0.084 mmol); 4-azidoaniline (11.3 mg, 0.084 mmol); CuSO4 (3.0 mg, 0.02 mmol); NaAsc (7.0 mg, 0.03 mmol); TBTA (5.0 mg, 0.009 mmol); in t-BuOH/EtOH/H2O (2:1:0.5); afforded 48 as a white solid (35 mg, 85.9%). 1H NMR (400 MHz, CDCl3): d=8.73 (s, 1H); 8.18 (bs, 1H); 7.86 (s, 1H); 7.85-7.83 (d, 1H, J=8.17 Hz); 7.46-7.35 (d, 2H, J=8.58 Hz); 7.06 (s, 1H); 6.80-6.78 (d, 2H, J=8.62 Hz), 4.78-4.77 (q, 1H): 4.48-4.47 (d, 2H, J=5.60 Hz); 4.29-4.23 (m, 2H); 3.65-3.64 (d, 1H, J=1.59 Hz): 3.51-3.51 (d, 1H, J=1.59 Hz); 3.41-3.24 (m, 2H): 1.33-1.30 (t, 3H). 13C NMR (100 MHz, CDCl3): 169.12, 166.74, 166.14, 153.09, 151.8, 147.32, 144.44, 127.90, 121.86, 120.73, 115.77, 115.0, 62.07, 53.39, 52.23, 34.51, 34.39, 32.70, 13.6.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]1=[O:15].C([O-])([O-])=O.[K+].[K+].[CH2:22]([O:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[CH2:23][CH3:24].CC#N>O.CCOC(C)=O>[CH2:22]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]2=[O:15])[CH2:28][CH2:27]1)[CH2:23][CH3:24]
Reactant: O=c1ccc2ccccc2n1CCCCl
Reactant: CCCOC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCOC1CCN(CCCn2c(=O)ccc3ccccc32)CC1
Temperature: 50 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
A 4 mL vial was charged with 1-(3-chloropropyl)-1H-quinolin-2-one (0.069 g, 0.31 mmol), K2CO3 (0.069 g, 0.50 mmol), KI (0.083 g, 0.50 mmol), 4-propoxypiperidine (0.050 g, 0.35 mmol) and dry CH3CN (2 mL). The mixture was shaken at 50° C. for 24 h and thereafter diluted with water (25 mL) and EtOAc (25 mL). The phases were separated and the water phase was extracted with EtOAc (2×50 mL). The combined organic phase was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 4:1) followed by prep RP-HPLC to give the title compound (0.060 g, 59%). 1H NMR (CD3OD) δ 7.85 (d, J=9.4 Hz, 1H), 7.65 (brd, J=7.2 Hz, 1H), 7.63 (m, 2H), 7.29-7.22 (m, 1H), 6.62, (d, J=9.4 Hz), 4.36-4.29 (m, 1H), 3.38 (t, J=6.6 Hz, 2H), 3.34-3.24 (m, 1H), 2.78-2.69 (m, 2H), 2.48-2.41 (m, 2H), 2.18-2.09 (m, 2H), 1.94-1.82 (m, 4H), 1.59-1.47 (m, 4H), 0.90 (t, J=7.4 Hz); 13C NMR (CD3OD) δ 162.0, 140.3, 139.0, 131.1, 129.2, 122.6, 121.4, 120.3, 114.7, 74.7, 69.5, 55.4, 51.0, 40.6, 31.0, 24.9, 32.1, 9.9; HPLC-MS (ammonium acetate) [M+H]+=329.3.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][N:26]=[C:27]=[O:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C1(C)C=CC=CC=1>[N:29]1([CH2:24][CH2:25][NH:26][C:27]([N:13]2[CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8][C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:11]3[CH2:12]2)=[O:28])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: O=C=NCCBr
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: O=C(NCCN1CCOCC1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.3 %

Procedure:
Hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (0.17 g, 0.58 mmol) was dissolved in toluene (1.5 mL). 2-Bromoethyl isocyanate (0.10 g, 0.67 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate), and the fractions were collected and concentrated. The residue was dissolved in N,N-dimethylformamide (2 mL), morpholine (0.20 g, 3.9 mmol) was added thereto, and the mixture was stirred at 60° C. for 16 hours. To the reaction solution was added ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The residue was purified with amino silica gel column chromatography (ethyl acetate), and crystallized from hexane to obtain the title compound (66 mg, yield 26%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1([CH2:33][CH:34]([C:38]2[CH:43]=[CH:42][C:41]([S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])=[CH:40][CH:39]=2)[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Br:58])=[CH:54][N:53]=1>C(Cl)Cl>[Br:58][C:55]1[CH:56]=[CH:57][C:52]([NH:51][C:35](=[O:36])[CH:34]([C:38]2[CH:39]=[CH:40][C:41]([S:44]([C:47]([F:49])([F:50])[F:48])(=[O:46])=[O:45])=[CH:42][CH:43]=2)[CH2:33][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[N:53][CH:54]=1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: Nc1ccc(Br)cn1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(Br)cn1)C(CC1CCCC1)c1ccc(S(=O)(=O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63 %

Procedure:
A solution of triphenylphosphine (206 mg, 0.785 mmol) in methylene chloride (4 mL) was cooled to 0° C. and then slowly treated with N-bromosuccinimide (140 mg, 0.785 mmol). The reaction mixture was stirred at 0° C. for 10 min and then treated with 3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)propionic acid (250 mg, 0.710 mmol). The resulting reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to 25° C. where it was stirred for 30 min. The reaction mixture was then treated with 2-amino-5-bromopyridine (271 mg, 1.57 mmol). The resulting reaction mixture was stirred at 25° C. for 15 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 2/1 hexanes/ethyl acetate) afforded the pure N-(5-bromo-pyridin-2-yl)-3-cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide (226 mg, 63%) as a yellow foam: mp 130-132° C.; EI-HRMS m/e calcd for C20H20BrF3N2O3S (M+) 504.0330, found 504.0325.