Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C@H:17]2[O:21][C:20]([CH3:23])([CH3:22])[N:19]([C:24]([O:26][C@H:27]3[C@H:34]4[C@H:30]([O:31][CH2:32][CH2:33]4)[O:29][CH2:28]3)=[O:25])[C@H:18]2[CH2:35][C:36]2[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:50][C:51]1[CH:52]=[C:53]([CH:56]=[CH:57][CH:58]=1)[C:54]#[N:55].CCOCC>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:16][C@H:17]2[O:21][C:20]([CH3:22])([CH3:23])[N:19]([C:24]([O:26][C@H:27]3[C@H:34]4[C@H:30]([O:31][CH2:32][CH2:33]4)[O:29][CH2:28]3)=[O:25])[C@H:18]2[CH2:35][C:36]2[CH:37]=[CH:38][C:39]([O:42][CH2:50][C:51]3[CH:58]=[CH:57][CH:56]=[C:53]([C:54]#[N:55])[CH:52]=3)=[CH:40][CH:41]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(O)cc1)S(=O)(=O)c1ccc(N)cc1
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)CN(C[C@H]1OC(C)(C)N(C(=O)O[C@@H]2CO[C@H]3OCC[C@H]32)[C@H]1Cc1ccc(OCc2cccc(C#N)c2)cc1)S(=O)(=O)c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a stirred mixture of (3S,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (4S,5R)-5-{[[(4-aminophenyl)sulfonyl](isobutyl)amino]methyl}-4-(4-hydroxybenzyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (40 mg, 0.07 mmol) and cesium carbonate (22 mg, 0.07 mmol) in 1.5 mL of N,N-dimethylformamide was added 3-bromomethylbenzonitrile (13 mg, 0.07 mmol). The mixture was stirred at room temperature for 12 hours followed by dilution with 25 mL of ether. The ether was extracted with water (5×15 mL). The organic phase was dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified on silica gel using ethyl acetate-hexanes (8.5:1.5) as eluent to provide 41 mg (85%) of the title compound. 1H-NMR (DMSO-d6): δ 0.80-0.86 (6H,dd), 1.37 (3H,s), 1.48,1.55 (3H,s)*, 1.75 (2H,m), 1.94 (1H,m), 2.58-2.78 (6H,m), 2.92-3.09 (2H,m), 3.15-3.21 (1H,m), 3.61 (2H,m), 3.81 (1H,m), 4.14 (1H,m), 4.74 (1H,q), 5.17 (2H,s), 5.53,5.57 (1H,d)*, 5.99 (2H,s,b), 6.58 (2H,d), 6.95 (2H,d), 7.11,7.14 (2H,d)*, 7.22,7.28 (2H,d)*, 7.60 (1H,t), 7.80 (2H,m,b), 7.91 (1H,s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C.[I:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=1.Cl>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([NH:59][C:58]2[CH:60]=[CH:61][C:55]([I:54])=[CH:56][CH:57]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: Nc1ccc(I)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CC(=O)Nc2ccc(I)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.2 %

Procedure:
A mixture of 3-methoxy-4-[3-(2-methylphenyl)ureido]phenylacetic acid (2.9 g, Reference Example 31), 1-hydroxybenzotriazole (2.13 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.67 g) and diisopropylethylamine (3.6 g) in anhydrous dimethylformamide (30 ml) was treated with 4-iodoaniline (2.43 g). After stirring at ambient temperature for 18 hours the reaction mixture was poured into a mixture of ethyl acetate (50 ml) and hydrochloric acid (50 ml, 1M). The resultant solid was filtered and then washed sequentially with 50 ml portions of saturated aqueous sodium bicarbonate solution, water and diethyl ether. The residue was dried under vacuum to give the title compound (4.05 g) as a light brown solid, m.p. >200° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[O:10][CH2:11][C:12](=[O:19])[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][N:27]=2)[C:22]([CH:29]=O)=[CH:21]1.N1CCCCC1>C(O)C>[NH:20]1[C:28]2=[N:27][CH:26]=[CH:25][CH:24]=[C:23]2[C:22]([CH:29]=[C:11]2[O:10][C:9]([NH:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]2=[O:19])=[CH:21]1
Reactant: CCOC(=O)C1=C(Nc2ccccc2O)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)C1=C(Nc2ccccc2O)OC(=Cc2c[nH]c3ncccc23)C1=O
Yield: 12.8 %

Procedure:
To a solution of ethyl 2-[(2-hydroxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.050 g, 0.19 mmol) which similarly prepared according to the procedure described in the Example 4 and 7-azaindole-3-carboxaldehyde (0.023 g, 0.16 mmol) in ethanol (1.0 mL), piperidine (0.0010 mL, 0.010 mmol) was added at ambient temperature. The mixture was refluxed for 2 days. The precipitate was collected by filtration, washed with hot ethanol. The solid was washed hexane then dried to afford the titled compound (0.008 g, y. 11%).
Reaction SMILES: Cl[CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4].[CH2:8]([NH2:10])[CH3:9]>C1(C)C=CC=CC=1>[CH2:8]([NH:10][CH:2]([CH2:5][O:6][CH3:7])[CH:3]=[O:4])[CH3:9]
Reactant: CCN
Reactant: COCC(Cl)C=O
Solvent: Cc1ccccc1
Product: CCNC(C=O)COC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The dimethyl acetal of 2-chloro-3-methoxypropionaldehyde (0.1 mole) and toluene (75 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Ethylamine (0.22 mole) is added to the reaction mixture with stirring at room temperature. Stirring is continued for a period of about 15 minutes. After this time the reaction mixture is heated at reflux for a period of about 1 hour. The reaction mixture is then cooled to room temperature and filtered. The filtrate is stripped of toluene and unreacted starting material under reduced pressure to yield the desired product the dimethyl acetal of 2-ethylamino-3-methoxypropionaldehyde as the residue.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10]O)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].P(Br)(Br)[Br:13].CCOC(C)=O.C([O-])(O)=O.[Na+]>COCCOC>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[N:6][CH:5]=[C:4]([CH2:10][Br:13])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: COc1ncc(CO)cc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ncc(CBr)cc1Br
Reaction time: 0.25 h

Procedure:
To (5-bromo-6-methoxy-pyridin-3-yl)-methanol (2.86 g, 13.1 mmol) in DME (30 mL) was added phosphorus tribromide (1.9 mL, 19.7 mmol), and the reaction was stirred for 15 minutes. The mixture was worked up with EtOAc and saturated aqueous NaHCO3, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give 3-bromo-5-bromomethyl-2-methoxy-pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](NC)[CH2:6][CH2:5]2.[CH2:13]([N:15](CC)CC)C.[C:20]([O:24]C(=O)CC)(=O)[CH2:21][CH3:22]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([CH2:13][NH:15][C:20](=[O:24])[CH2:21][CH3:22])[CH2:6][CH2:5]2
Reactant: CNC1CCc2cc(Br)ccc21
Reactant: CCN(CC)CC
Reactant: CCC(=O)OC(=O)CC
Solvent: C1CCOC1
Product: CCC(=O)NCC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.4 %

Procedure:
A solution of (5-bromo-indan-1-yl)-methylamine (240 mg, 0.91 mmol) and triethylamine (363 mg, 3.60 mmol) in THF (5 mL) was stirred at 5° C. and propionic anhydride (125 mg, 0.96 mmol) added dropwise. After the mixture was stirred for 18 h at room temperature, the solvent was removed and ethyl acetate/water were added. The organic layer was washed with water and dried over MgSO4. The filtrate was concentrated to give a white solid (250 mg, 97%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[O:12][CH3:13].[B-](F)(F)(F)[CH:15]=[CH2:16].[K+].ClCCl.C(N(CC)CC)C>C(O)C>[CH3:13][O:12][C:3]1[C:4]2[CH2:8][O:7][C:6](=[O:9])[C:5]=2[CH:10]=[CH:11][C:2]=1[CH:15]=[CH2:16]
Reactant: C=C[B-](F)(F)F
Reactant: COc1c(Br)ccc2c1COC2=O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: C=Cc1ccc2c(c1OC)COC2=O

Procedure:
To a 100 mL round bottom flask was added 5-Bromo-4-methoxy-2-benzofuran-1(3H)-one (430 mg, 1.8 mmol, 1.0 eq), potassium trifluoro(vinyl)borate (474 g, 3.5 mmol, 2.0 eq), [1,1′-bis(diphenylposphino)-ferrocene]dichloropalladium(II) complex with dichloromethane(1:1) (144 mg, 0.2 mmol, 0.1 eq) and triethylamine (493 μL, 3.5 mmol, 2.0 eq). To above mixture was added ethanol (12 mL). The flask was degassed and filled with nitrogen. The reaction was heated to reflux for 12 hr. The mixture was then diluted with EtOAc, filtered through a pad of celite and washed with brine. The organic phase was dried over Na2SO4, filtered and purified by flash column chromatography using biotage and the solvent systems (0-50% EtOAc/Hexane). The fractions containing desired product were collected and concentrated to 4-methoxy-5-vinyl-2-benzofuran-1(3H)-one.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]([CH2:18]C)[CH2:14][CH2:15][O:16][CH3:17])=[N:10][C:9]=2[C:20]2[C:21]([F:36])=[C:22]([NH:26][S:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)(=[O:29])=[O:28])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1.[NH4+:37].[OH-]>O.Cl.C(Cl)Cl>[NH2:37][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:20]2[C:21]([F:36])=[C:22]([NH:26][S:27]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)(=[O:28])=[O:29])[CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CCN(CCOC)c1nc(-c2cccc(NS(=O)(=O)C3CCCCC3)c2F)c(-c2ccnc(Cl)n2)s1
Agent: Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cccc(NS(=O)(=O)C3CCCCC3)c2F)n1
Temperature: 120 °C
Yield: 41 %

Procedure:
N-[3-(5-(2-Chloro-4-pyrimidinyl)-2-{ethyl[2-(methyloxy)ethyl]amino}-1,3-thiazol-4-yl)-2-fluorophenyl]cyclohexanesulfonamide (148 mg, 0.275 mmol) was suspended in NH4OH (4 mL) and heated in microwave reactor at 120° C. for 48 min. The reaction was diluted with water and neutralized with 5% aqueous HCl and solid formed. A solid was diluted with DCM and water. The organic layer was dried over Na2SO4, filtered, added silica gel and concentrated. The crude product was chromatographed on silica gel eluting with 100% DCM to 1:1 [DCM:(9:1 EtOAC:MeOH)]. The clean fractions were combined and concentrated. The product was triturated in diethyl ether and filtered to obtain the title compound as a yellow powder (58 mg, 41% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.67 (s, 1H), 7.87 (d, J=5.3 Hz, 1H), 7.43-7.62 (m, 1H), 7.09-7.41 (m, 2H), 6.35-6.74 (m, 2H), 5.80 (d, J=5.3 Hz, 1H), 3.68 (t, J=4.6 Hz, 4H), 3.43 (t, J=4.6 Hz, 4H), 2.81-3.02 (m, 1H), 1.69 (d, J=12.5 Hz, 2H), 1.51 (br. s., 1H), 1.33 (qd, J=12.1, 2.2 Hz, 2H), 0.89-1.22 (m, 5H). MS (ESI): 518.9 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].N1C=CN=C1.C([Si](C)(C)Cl)(C)(C)C.C(N(CC)CC)C.[N:30]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl.C(Cl)(Cl)Cl>[OH:8][CH2:7][CH:5]([NH:6][C:36]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)=[O:37])[C:4]([O:3][CH3:2])=[O:9]
Reactant: O=C(Cl)N1CCCCC1
Reactant: COC(=O)[C@@H](N)CO
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(CO)NC(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.00 g (6.43 mmol) of serine methyl ester hydrochloride and 960 mg (14.1 mmol) of imidazole were dissolved in 10 ml of dichloromethane. 10 ml of a solution of 1.07 g (7.07 mmol) of t-butyldimethylchlorosilane in dichloromethane was added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature for 1 hour. After concentrating under reduced pressure, ethyl acetate was added to the residue. The reaction mixture was washed with saturated aqueous ammonium chloride solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 10 ml of dichloromethane. 1.35 ml (9.65 mmol) of triethylamine and 0.97 ml (7.72 mmol) of 1-piperidinecarbonyl chloride were added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. 20 ml of chloroform was added to the reaction mixture, and they were stirred at 50° C. for 3 hours and then concentrated under reduced pressure. The residue was dissolved in 15 ml of methanol. 10 ml of 2 N hydrochloric acid was added dropwise to the obtained solution under cooling with ice, and they were stirred at room temperature for 2 hours. After the concentration under reduced pressure, ethyl acetate was added to the residue. The product was washed with 1 N aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by the silica gel chromatography (dichloromethane:methanol=1:0 to 9:1) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:11]([NH:12][C:13](=O)[CH2:14][O:15][CH3:16])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C(C)=CC=CC=1>[CH3:16][O:15][CH2:14][C:13]1[S:27][C:2]2[C:11]([N:12]=1)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2
Reactant: COCC(=O)Nc1cc(C(=O)OC)cnc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1C
Product: COCc1nc2cc(C(=O)OC)cnc2s1

Procedure:
A mixture of 0.53 g (2.05 mmol) of methyl 6-chloro-5-methoxyacetamidonicotinate and 0.42 g (1.0 mmol) of Lawesson's reagent was refluxed for 16 hours in 25 mL of xylene. After the solvent had been removed in vacuo, the crude product obtained was purified by flash chromatography (silica gel; methylene chloride/ethanol=100:1) and evaporated down again in vacuo. Yield: 0.33 g (67% of theory) of yellow amorphous solid; Rf value: 0.52 (silica gel; ethyl acetate/petroleum ether=1:4).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C1(C)C=CC=CC=1>[C:16]1([NH:15][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccc1Cl
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, and acondenser, 31.3 g (0.2 mol) of 2-chlorobenzoic acid and 180 g of toluene are placed. To the above mixture in the flask, 25.0 g (0.21 mol) of thionyl chloride is added dropwise over 30 minutes while stirring at a temperature of from 60° to 65° C. to be allowed to react with each other for about 30 minutes. To the above reaction mixture, a solution containing 27.9 g (0.3 mol) of aniline dissolved in 100 g of toluene is dropwise added to be allowed to react with each other at a temperature of from 70° to 75° C. for 30 minutes. After completion of the reaction, the reaction mixture is cooled to room temperature, and 70 g of a 5% by weight hydrochloric acid solution is added to the above mixture. The mixture is vigorously shaken and kept standing for separation of the toluene layer from the aqueous layer. Afterseparation of the toluene layer, it is condensed to precipitate white crystals, followed by recrystallization (in a water/methanol mixture of 3/7), to give 43.1 g of N-phenyl-2-chlorobenzamide (melting point: 116° to 117° C.). The yield of the product against 2-chlorobenzoic acid is 93%.
Reaction SMILES: [CH2:1]([O:8][N:9]([C:12]1[N:17]=[C:16]([NH:18][CH2:19][CH2:20][CH3:21])[N:15]=[C:14]([NH:22][CH2:23][CH2:24][CH3:25])[N:13]=1)[CH2:10]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:26][S:27]([OH:30])(=[O:29])=[O:28]>>[S:27]([OH:30])([OH:29])(=[O:28])=[O:26].[CH2:1]([O:8][N:9]([C:12]1[N:13]=[C:14]([NH:22][CH2:23][CH2:24][CH3:25])[N:15]=[C:16]([NH:18][CH2:19][CH2:20][CH3:21])[N:17]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCNc1nc(NCCC)nc(N(CC)OCc2ccccc2)n1
Agent: O=S(=O)(O)O
Product: CCCNc1nc(NCCC)nc(N(C)OCc2ccccc2)n1

Procedure:
O-Benzyl-N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N-ethyl-hydroxylamine (LXVIII) was reacted with 95% H2SO4 as described in Example 9 to yield O-benzyl-N-(4,6-bis-n-propylamino-[1,3,5]triazin-2-yl)-N-methyl-hydroxylamine hydrogen sulfate (LXIX) in quantitative yield. 400 MHz 1H NMR (DMSO-d6, ppm) 12.0-11.0 (1H, br s), 8.7-8.0 (1H, m), 7.57-7.30 (5H, m), 5.07-4.95 (2H, m), 3.89-3.68 (2H, m), 3.39-3.14 (4H, m), 1.63-1.42 (4H, m), 1.23-1.07 (3H, m), 0.94-0.77 (6H, m). ESI-MS (m/z): 345 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[N:3]1.[Li]CCCC.[O:12]=[CH:13][CH2:14][C@@:15]1([C:28]([N:30]2[CH2:39][CH2:38][C:37]3[N:36]=[CH:35][C:34]([C:40]([F:43])([F:42])[F:41])=[CH:33][C:32]=3[CH2:31]2)=[O:29])[CH2:19][C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:16]1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[OH:12][CH:13]([C:6]1[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=1)[CH2:14][C@@:15]1([C:28]([N:30]2[CH2:39][CH2:38][C:37]3[N:36]=[CH:35][C:34]([C:40]([F:43])([F:42])[F:41])=[CH:33][C:32]=3[CH2:31]2)=[O:29])[CH2:19][C@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:16]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@](CC=O)(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: Cn1cccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cn1nccc1C(O)C[C@]1(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
To a solution of 1-methylpyrazole (0.165 mmol, 1.98 mmol, 3 eq) in THF (8 mL) at −78° C. under Ar was added n-BuLi (0.77 mL of a 2.5 M solution in hexane, 1.92 mmol, 2.9 eq) and the solution stirred 1 hr. Then a solution of the product of Example 10, Step A (300 mg, 0.66 mmol, 1 eq) in THF (8 mL) was added over 5 min. After 1 hr, saturated NH4Cl was added, the solution extracted with ethyl acetate, the organics combined, dried over MgSO4 and concentrated. Purification by chromatography (12 g column) eluting with 50 to 100% EtOAc/heptane to 5 to 10% methanol/DCM afforded the title compound of Step A as a mix of diastereomers. 1H NMR (CHLOROFORM-d) δ: 8.70 (s, 1H), 7.62-7.80 (m, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.19-6.49 (m, 1H), 6.09 (br. s., 1H), 5.87 (dd, J=17.9, 5.6 Hz, 1H), 4.54-5.03 (m, 5H), 3.74-3.96 (m, 4H), 3.48 (s, 1H), 2.90-3.23 (m, 2H), 2.46-2.87 (m, 2H), 2.06-2.39 (m, 2H), 1.73-1.98 (m, 1H), 1.43 (br. s., 9H). Calculated for C27H34F3N5O4: 558.2 (M+23). found: 558.2.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=O)[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[F:40][C:41]1[CH:56]=[CH:55][CH:54]=[CH:53][C:42]=1[CH2:43][C:44]1([O:51][CH3:52])[CH2:49][CH2:48][CH2:47][CH:46]([NH2:50])[CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:40][C:41]1[CH:56]=[CH:55][CH:54]=[CH:53][C:42]=1[CH2:43][C:44]1([O:51][CH3:52])[CH2:49][CH2:48][CH2:47][CH:46]([NH:50][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:19])[CH2:45]1
Reactant: COC1(Cc2ccccc2F)CCCC(N)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC1(Cc2ccccc2F)CCCC(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.025 mmol, 12.4 mg), HCl salt of 3-(2-fluorobenzyl)-3-methoxycyclohexanamine (0.025 mmol, 6.8 mg), HATU (0.025 mmol, 9.5 mg) and DIEA (0.1 mL) in DMA (0.5 mL) was stirred at room temperature for overnight. The product, N-(3-(2-fluorobenzyl)-3-methoxycyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[F:27])=[CH:14][CH:15]=1)=[O:5])C.[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=1.C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH3:28][C:29]1([CH3:44])[CH2:34][N:33]([CH3:35])[CH2:32][CH2:31][N:30]1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([NH:43][C:4]([C:6]2[C:7]3[N:8]=[CH:9][CH:10]=[N:11][C:12]=3[C:13]([C:16]3[C:17]([F:27])=[C:18]([O:25][CH3:26])[CH:19]=[C:20]([O:23][CH3:24])[C:21]=3[F:22])=[CH:14][CH:15]=2)=[O:5])=[N:41][CH:42]=1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2F)c2nccnc12
Reactant: CN1CCN(Cc2ccc(N)nc2)C(C)(C)C1
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4(C)C)cn3)c3nccnc23)c1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
The title compound was prepared in analogy to the procedures described in Example 115 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 124.1), 5-(2,2,4-trimethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Step 110.1), 1.5 equiv of trimethyl aluminum, stirring the reaction mixture for 6 h at 80° C. and pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 563.1 [M+H]+; tR=3.55 min (System 1); TLC: Rf=0.08 (DCM/MeOH, 95:5).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](I)[CH:13]=2)[O:9][N:8]=1.C(N(CC)CC)C.[CH2:28]([OH:31])[C:29]#[CH:30]>CN(C)C=O.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>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([C:30]#[C:29][CH2:28][OH:31])[CH:13]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(I)cc(-c2nc(-c3ccccn3)no2)c1
Reactant: C#CCO
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1cc(C#CCO)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 17.7 %

Procedure:
A mixture of the 3-(2-pyridyl)-5-(5-cyano-3-iodophenyl)-1,2,4-oxadiazole (140 mg, 0.374 mmol), Pd(PPh3)4 (10 mg, 0.009), and Cul (30 mg, 0.158 mmol) in N,N-dimethylformamide (3 mL) was treated with triethylamine (1 mL, 726 mg, 7 mmol). The reaction mixture was cooled to 0° C. and treated with propargyl alcohol (56 mg, 1 mmol). The mixture was stirred at ambient temperature 5 hours and then filtered through a short plug of silica gel, washing with ethyl acetate. The organic solution was concentrated in vacuo. Silica gel chromatography afforded 20 mg (18%) of 3-(2-pyridyl)-5-(5-cyano-3-[3-hydroxypropyn-1-yl]phenyl)-1,2,4-oxadiazole: 1H-NMR (MeOH-d4), δ ppm: 8.80 (d, 1H), 8.60 (s, 1H), 8.58 (s, 1H), 8.30 (d, 1H), 8.10 (m, 2H), 7.60 (m, 1H), 4.5 (s, 2H).