Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:18]([C:19]#[C:20][C:21]([C:24]2[CH:28]=[C:27]([CH:29]=O)[O:26][N:25]=2)([OH:23])[CH3:22])=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.Cl.NO.C([N:36](CC)CC)C.CCN(CC)CC.CC(O)=O>CN(C)C=O.C(Cl)Cl>[C:29]([C:27]1[O:26][N:25]=[C:24]([C:21]([OH:23])([CH3:22])[C:20]#[C:19][C:18]2[C:2]([F:1])=[CH:3][C:4]3[O:10][CH2:9][CH2:8][N:7]4[CH:11]=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=[C:6]4[C:5]=3[CH:17]=2)[CH:28]=1)#[N:36]
Reactant: CCN(CC)CC
Reactant: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(C=O)on1
Agent: Cl
Agent: NO
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(O)(C#Cc1cc2c(cc1F)OCCn1cc(C(N)=O)nc1-2)c1cc(C#N)on1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 6 %

Procedure:
A solution of 9-fluoro-10-(3-(5-formylisoxazol-3-yl)-3-hydroxybut-1-yn-1-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (90 mg, 0.22 mmol, 1.00 equiv), hydroxylamine hydrochloride (15 mg, 0.22 mmol, 1.00 equiv) in N,N-dimethylformamide (3 mL) was heated at 140° C. for 1 h. To this was added triethylamine (90 mg, 0.89 mmol, 4.00 equiv) at 0° C. To the mixture was added TEAA (70 mg, 1.50 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 12 h at 120° C. The reaction solution was diluted with DCM and washed with water. The crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-005(Waters)): Column, XBridge Shield RP18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 10 mmolNH4HCO3 and CH3CN (15% CH3CN up to 70% in 10 min, up to 95% in 1 min, hold 95% in 1 min, down to 15% in 2 min); Detector, UV 254/220 nm. This gave the titled compound (5.4 mg, 6%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]2[CH2:18][C:17](=O)[CH2:16][S:15]2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.Cl.[OH:24][NH2:25].C([O-])(=O)C.[Na+]>O>[CH2:1]([N:8]1[C:12]([CH3:13])=[C:11]([CH:14]2[CH2:18][C:17](=[N:25][OH:24])[CH2:16][S:15]2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C2CC(=O)CS2)ncn1Cc1ccccc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1c(C2CC(=NO)CS2)ncn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1-Benzyl-5-methyl-4-imidazolyl)-4-oxotetrahydrothiophene (0.14 g., 0.5 mole) is dissolved in 1 ml. of ethanol and 1 ml. of water is added. Then hydroxyamine hydrochloride (38 mg., 0.55 mole) and sodium acetate (45 mg., 0.55 mole) are added. The mixture is stirred at room temperature overnight. The reaction mixture is concentrated in vacuo. The residue is triturated with chloroform and the mixture is filtered. The chloroform extract is dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude oxime, 2-(1-benzyl-5-methyl-4-imidazolyl)-4-oxotetrahydrothiophene oxime, is a brown viscous oil (0.15 g.).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[F:12][C:13]([F:22])([F:21])/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CS(C)=O>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[O:1][CH:14]([C:13]([F:12])([F:22])[F:21])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4]2
Reactant: COc1cccc(C=O)c1O
Reactant: CCOC(=O)/C=C/C(F)(F)F
Solvent: CS(C)=O
Product: CCOC(=O)C1=Cc2cccc(OC)c2OC1C(F)(F)F
Temperature: 70 °C

Procedure:
The 2-hydroxy-3-methoxybenzaldehyde (3.05 g, 20mmol) was dissolved in DMSO (9 mL). TEA (4.09 g, 40 mmol) and ethyl 4,4,4-trifluorocrotonate (6.93 g, 40 mmol) were added to above solution. The reaction was heated to 70° C. and monitored by TLC and GCMS until done. The reaction was quenched with 10% HCl. The compound was extracted with EtOAc and washed with water and NH4Cl. The organic was dried over MgSO4. After concentrated, the crude compound was purified by flash column with 20% EtOAc in hexane. This ester was of suitable purity to use without further purification.
Reaction SMILES: C([Mg]Cl)(C)C.[CH3:6][O:7][C:8]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:9]=1[CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH:13]([C:17]([O-:19])=O)[CH2:12]1.[CH3:26][O:27][NH:28][CH3:29].O>C1COCC1>[CH3:6][O:7][C:8]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:9]=1[CH2:10][N:11]1[C:15](=[O:16])[CH2:14][CH:13]([C:17]([N:28]([O:27][CH3:26])[CH3:29])=[O:19])[CH2:12]1
Reactant: CNOC
Reactant: COc1ccc(CN2CC(C(=O)[O-])CC2=O)c(OC)c1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CC(C(=O)N(C)OC)CC2=O)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isopropylmagnesium chloride (15.3 mL, 30.6 mmol) was added to a solution of 1-(2,4-dimethoxybenzyl)-5-oxopyrrolidine-3-carboxylate (3.0 g, 10 mmol) and O,N-dimethyl-hydroxylamine (1.5 g, 15 mmol) in THF (100 mL) at −10° C. The mixture was stirred at 0° C. for 1 hour then the mixture was added to water and concentrated under reduced pressure to afford 1-(2,4-dimethoxybenzyl)-N-methoxy-N-methyl-5-oxopyrrolidine-3-carboxamide. 1H NMR (400 MHz, CDCl3) δ 7.13-7.15 (m, 1H), 6.43-6.45 (m, 2H), 4.41-4.42 (m, 2H), 3.79-3.82 (m, 6H), 3.67 (s, 3H), 3.46-3.49 (m, 3H), 3.18 (s, 3H), 2.70-2.77 (m, 1H), 2.57-2.63 (m, 1H). MS ESI calc'd. for C16H23N2O5 [M+H]+ 323. found 323.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]#[N:32])[CH:26]=1>>[C:31]([C:27]1[CH:26]=[C:25]([N:20]2[CH2:21][CH2:22][CH2:23][C@H:18]([NH:17][C@@H:12]3[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]3[NH:10][C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:9])[CH2:19]2)[CH:30]=[CH:29][N:28]=1)#[N:32]
Reactant: N#Cc1cc(Cl)ccn1
Reactant: O=C(Nc1ccccc1)N[C@@H]1CCCC[C@H]1NC1CCCNC1
Product: N#Cc1cc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)Nc3ccccc3)C2)ccn1

Procedure:
1-((1R,2R)-2-((S)-1-(2-Cyanopyridin-4-yl)piperidin-3-ylamino)cyclohexyl)-3-phenylurea was synthesized using 1-phenyl-3-((1R,2R)-2-(piperidin-3-ylamino)cyclohexyl)urea (from intermediate C, Example 1) (100 mg, 0.32 mmol) and 4-chloropicolinonitrile (44 mg, 0.15 mmol) according to General Procedure A to give 29.3 mg (22.1%) of pale brown oil. Anal. Calcd. for C24H30N6O m/z 418.2, found: 419.2 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.89 (d, J=6.5 Hz, 1H), 7.35 (d, J=2.7 Hz, 1H), 7.25 (m, 4H), 7.04 (m, 2H), 4.08 (m, 1H), 3.72 (m, 2H), 3.60 (m, 1H), 3.51 (m, 1H), 3.25 (m, 2H), 2.31 (m, 1H), 2.15-2.05 (m, 4H), 1.98-1.88 (m, 3H), 1.63-1.42 (m, 5H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[C:11]([F:13])[C:10]([O:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:9][C:5]=1[C:6](O)=[O:7])#[N:2].[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1>>[F:13][C:11]1[CH:12]=[C:4]2[C:5](=[CH:9][C:10]=1[O:14][CH2:15][CH2:16][O:17][CH3:18])[C:6](=[O:7])[NH:2][C:1]([NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=1)=[CH:3]2
Reactant: COCCOc1cc(C(=O)O)c(CC#N)cc1F
Reactant: Cc1cc(N)n[nH]1
Product: COCCOc1cc2c(=O)[nH]c(Nc3cc(C)[nH]n3)cc2cc1F

Procedure:
Similar procedure as described in example 2c was used, starting from 2-Cyanomethyl-4-fluoro-5-(2-methoxy-ethoxy)-benzoic acid and 3-amino-5-methylpyrazole to give 6-Fluoro-7-(2-methoxy-ethoxy)-3-(5-methyl-1H-pyrazol-3-ylamino)-2H-isoquinolin-1-one. LC-MS: m/e 333 (MH+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])/[C:7](=[CH:10]/[C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[C:28]([F:31])([F:30])[F:29])[N:15]=[CH:14]3)/[S:6][C:5]1=[O:32].[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][N:16]2[C:17]3[C:13](=[CH:12][C:11](/[CH:10]=[C:7]4/[C:8](=[O:9])[N:4]([CH2:3][CH2:2][NH:1][S:39]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)(=[O:41])=[O:40])[C:5](=[O:32])[S:6]/4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[C:22]([C:28]([F:30])([F:29])[F:31])[CH:23]=1
Reactant: NCCN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCNS(=O)(=O)c1ccccc1

Procedure:
N-{2-[(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]ethyl}benzenesulfonamide was prepared from 3-(2-aminoethyl)-(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-1,3-thiazolidine-2,4-dione (from Example 49) and benzenesulfonyl chloride following General Procedure U.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([N:8]2[CH2:11][CH:10](OS(C)(=O)=O)[CH2:9]2)[S:6][CH:7]=1)#[N:2].[C:17]([O-:20])(=[S:19])[CH3:18].[K+]>CN(C)C=O>[C:17]([S:19][CH:10]1[CH2:9][N:8]([C:5]2[S:6][CH:7]=[C:3]([C:1]#[N:2])[N:4]=2)[CH2:11]1)(=[O:20])[CH3:18]
Reactant: CS(=O)(=O)OC1CN(c2nc(C#N)cs2)C1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C#N)cs2)C1
Temperature: 80 °C
Reaction time: 4 h
Yield: 74.2 %

Procedure:
To a solution of 1-(4-cyano-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (1.12 g, 4.32 mmol) (obtained as described in Reference Example 4(3)) in dimethylformamide (56 ml) was added potassium thioacetate (3.89 g, 27.0 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (2:1) as the eluant to afford 3-acetylthio-1-(4-cyano-1,3-thiazol-2-yl)azetidine (0.767 g, yield 75%) as a pale brown solid.
Reaction SMILES: COC1C=CC(C[N:8]2[CH2:17][C:16]([CH3:19])([CH3:18])[C:15]3[C:10](=[CH:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][CH:14]=3)[C:9]2=[O:23])=CC=1.O.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>CC#N>[CH3:18][C:16]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([N+:20]([O-:22])=[O:21])=[CH:13][CH:14]=2)[C:9](=[O:23])[NH:8][CH2:17]1
Reactant: COc1ccc(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: CC1(C)CNC(=O)c2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-(4-Methoxy-benzyl)-4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (2.0 g) was dissolved in CH3CN (100 mL) and H2O (50 mL) and cooled to 0° C. CAN (9.64 g) was added and the reaction was stirred at 0° C. for 30 min, then warmed to RT and stirred for 6 h. The mixture was extracted with CH2Cl2 (2×300 mL) washed with sat'd NH4Cl, dried over MgSO4, filtered and concentrated. The crude material was recrystallized in CH2Cl2/EtOAc (1:1) to give 4,4-dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one as a white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH2:14]([NH:16][CH2:17][CH2:18][CH3:19])[CH3:15]>C(O)C>[CH2:1]([O:5][C:6]1[N:7]=[CH:8][N:9]=[C:10]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15])[C:11]=1[F:12])[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: CCCNCC
Solvent: CCO
Product: CC#CCOc1ncnc(N(CC)CCC)c1F
Temperature: 25 °C
Yield: 119.7 %

Procedure:
To 0.5 ml of ethanol ware added 0.1 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine and 0.11 g of N-ethylpropylamine, followed by heating under reflux for 10 hours. The reaction mixture was then left for cooling to room temperature and concentrated under reduced pressure. The residue was added water and extracted three times with t-butyl methyl ether. The organic layers were combined, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.15 g of 6-(2-butynyloxy)-4-(N-ethylpropylamino)-5-fluoropyrimidine (the present compound (185)).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[O:13])=[CH:6][CH:5]=1.[OH-].[Li+].[Cl-].[NH4+].C(OCC)(=O)C>O1CCCC1>[CH3:20][C:16]1[CH:15]=[C:14]([C:12](=[O:13])[CH2:11][C@H:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:28])=[O:2])=[CH:9][CH:8]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH:19]=[CH:18][N:17]=1
Reactant: COC(=O)c1ccc([C@@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)C[C@H](c2ccc(C(=O)O)cc2)c2ccccc2C)ccn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid methyl ester (98 mg) in tetrahydrofuran (3 mL) was added 1 M aq. lithium hydroxide solution (2.62 mL). The reaction mixture was stirred at room temperature for 4 h. A saturated aq. solution of ammonium chloride and ethyl acetate were added, the phases were separated and the inorganic one was extracted with ethyl acetate (2×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield 4-[(R)-3-(2-methyl-pyridin-4-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid as a white solid. This was reacted in analogy to example 132, step 6 with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to afford the title compound as a white solid (98 mg, 60%), MS (ESI−): m/z=372.9 ([M−H]−).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:30]=[CH:29][C:21]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:31](OC(=O)C)(=[O:33])[CH3:32].Cl>N1C=CC=CC=1>[CH2:1]([N:17]([C:18]1[CH:19]=[CH:20][C:21]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:29][CH:30]=1)[C:31](=[O:33])[CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCNc1ccc(CCC(=O)OCC)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(CCC(=O)OCC)cc1

Procedure:
A mixture of 10.0 g. of ethyl 4-(hexadecylamino)hydrocinnamate, 50 ml. of pyridine and 25 ml. of acetic anhydride is heated on a steam bath for 15 hours. The solution is poured onto ice and adjusted to pH 6 with concentrated hydrochloric acid. The mixture is filtered and the crystals washed with water. The solid is recrystallized from ethanol, yielding ethyl 4-(N-hexadecylacetamido)hydrocinnamate.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].O=[CH:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([S:24]([NH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>O1CCCC1>[CH3:1][O:2][C:3](=[O:4])/[CH:5]=[CH:15]/[C:16]#[C:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([S:24](=[O:26])(=[O:25])[NH:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:19]=1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: O=CC#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)/C=C/C#Cc1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a solution of trimethyl phosphonoacetate (0.81 g, 4.5 mmol) in dry tetrahydrofuran (20 ml) under an argon atmosphere at 15-20° C. sodium hydride (0.12 g, 5.0 mmol) was added. The mixture was stirred at ambient temperature for 1 hour, and a solution of 3-(3-oxoprop-1-ynyl)-N-phenylbenzenesulfonamide (54a) (0.44 g, 1.5 mmol) in dry tetrahydrofuran (20 ml) was added dropwise at 15-20° C. The reaction mixture was stirred at ambient temperature for 1 hour and quenched by 3% HCl (20 ml). The product was extracted with ethyl acetate (50 ml), the extract was washed with 5% NaHCO3, water and dried (Na2SO4). The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with ethyl acetate-hexane (1:2, v/v) as eluent to give the title compound (0.39 g, 74%) as a white solid. M.p. 134-136° C. 1H NMR (DMSO-d6, HMDSO) δ: 3.73 (3H, s, CH3); 6.49 (1H, d, J=15.5 Hz, CH); 7.03 (1H, d, J=15.5 Hz, CH); 7.01-7.38 (5H, m, C6H5); 7.41-7.89 (4H, m, C6H4); 10.34 (1H, s, NH).
Reaction SMILES: [OH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][Cl:23]>C(#N)C.CCOC(C)=O>[Cl:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][O:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: ClCCCCCBr
Reactant: Oc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: ClCCCCCOc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-hydroxybenzothiazole (0.2 g, 1.32 mmol) in 10 mL of acetonitrile was added K2CO3 (0.274 g, 1.98 mmol), followed by stirring at 50˜55° C. for 30 min. Then, 1-bromo-5-chloropentane (0.245 g, 1.32 mmol) was added to and reacted with the solution of 2-hydroxybenzothiazole at 80˜90° C. for 3 hours. The reaction was cooled to room temperature, diluted with 10 mL of EtOAc, and washed with distilled water and a saturated NaCl aqueous solution. It was dried over MgSO4 and the solvent was removed by concentration under reduced pressure to afford K23 (0.333 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5](O)=[O:6].C(N(C(C)C)CC)(C)C.C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:11])[CH:10]=1)[C:5]([N:35]=[N+:36]=[N-:37])=[O:6]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc(Br)cc(I)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: [N-]=[N+]=NC(=O)c1cc(Br)cc(I)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.7 %

Procedure:
To a stirred solution of 3-bromo-5-iodo benzoic acid (5.0 g, 15 mmol) in methanol (30 mL) was added diisopropylethylamine (2.9 mL, 16.8 mmol) and diphenylphosphoryl azide (3.6 mL, 16.8 mmol). The reaction mixture was stirred for 12 hours at room temperature and then quenched with the addition of 100 mL water. A solid precipitated out. The solid was filtered, washed with water and dried to give 5.0 g (96%) of 3-bromo-5-iodo-benzoyl azide.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:4]=O.[N+](=[C:17](P(=O)(OC)OC)C(=O)C)=[N-].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][CH:2]([CH3:14])[CH:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[C:4]#[CH:17]
Reactant: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Reactant: CC(C)C(C=O)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC(NC(=O)OC(C)(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.4 %

Procedure:
To a solution of 1.25 g of tert-butyl 3-methyl-1-oxobutan-2-ylcarbamate (Formula 21) and 1.79 g of dimethyl 1-diazo-2-oxopropylphosphonate (Formula 15) in 80 mL of methanol at 0° C. was added 1.72 g of potassium carbonate. The mixture was stirred at room temperature for 16 hours then quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Column chromatography (15% ethyl acetate/hexane) gave 1.01 g of tert-butyl 4-methylpent-1-yn-3-ylcarbamate (Formula 22) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.98-1.00 (m, 6H), 1.45 (s, 9H), 1.87-1.93 (m, 1H), 2.24-2.25 (m, 1H), 4.32 (br, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:18]([C:20]1[N:24]([CH3:25])[C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:18]([C:20]1[N:24]([CH3:25])[C:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:22][CH:21]=1)#[N:19]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: O=S(=O)(NC1CCCCC1)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)NC2CCCCC2)cc1
Reaction time: 16 h
Yield: 1.5 %

Procedure:
According to general procedure B, 4-bromo-N-cyclohexylbenzenesulfonamide (127 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-cyclohexylbenzenesulfonamide (2 mg, 1%) was provided after purification. MS (ESI) m/z 343. HPLC purity 99.1% at 210-370 nm, 11.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=2.Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1>>[C:32]([O:31][C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])=[CH:18][CH:19]=1)=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: COC(=O)c1ccc2[nH]c(C)cc2c1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Product: COC(=O)c1ccc2c(c1)cc(C)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 2, Example 38, using the methyl 2-methyl-1H-indole-5-carboxylate instead of the methyl 1H-indole-5-carboxylate, and the tert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate instead of the 1-bromo-4-(bromomethyl)benzene. ESI-MS (m/z): 456 [M+H]+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:16])([CH3:15])[C:7]2=[O:17])[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:38]1[S:39][C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[S:39]1[C:40]2[CH:46]=[CH:45][CH:44]=[CH:43][C:41]=2[N:42]=[C:38]1[O:1][C@H:2]1[CH2:5][C@H:4]([N:6]2[C:10]3=[N:11][CH:12]=[CH:13][N:14]=[C:9]3[C:8]([CH3:15])([CH3:16])[C:7]2=[O:17])[CH2:3]1
Reactant: Oc1nc2ccccc2s1
Reactant: CC1(C)C(=O)N([C@H]2C[C@@H](O)C2)c2nccnc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)C(=O)N([C@H]2C[C@H](Oc3nc4ccccc4s3)C2)c2nccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 5-(cis-3-hydroxycyclobutyl)-7,7-dimethyl-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one (0.022 g, 0.094 mmol), triphenylphosphine (0.030 g, 0.113 mmol), 2-hydroxybenzothiazole (0.017 g, 0.113 mmol) in THF (2 mL) at 0° C. was added DIAD (0.028 mL, 0.141 mmol). The reaction mixture was stirred at room temperature overnight, concentrated, purified by reverse phase HPLC. The pure fractions were concentrated to minimal H2O, neutralized with saturated aqueous NaHCO3, and the off white solid was collected and dried (18.5 mg, 53.5%). MS (M+1):367.1. 1H NMR (400 MHz, MeOH) δ ppm 8.20 (1 H, d, J=3.1 Hz), 8.15 (1 H, d, J=3.1 Hz), 7.76 (1 H, dd, J=7.9, 0.7 Hz), 7.66 (1 H, d, J=7.6 Hz), 7.39 (1 H, td, J=7.8, 1.3 Hz), 7.19-7.34 (1 H, m), 5.79 (1 H, dt, J=7.0, 3.5 Hz), 5.25-5.42 (1 H, m), 3.40-3.56 (2 H, m), 2.68-2.86 (2 H, m), 1.38-1.50 (6 H, m). MS (M+1):367.1.