Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([SH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Br>>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:14]([CH2:15][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:13]=1
Reactant: Fc1cccc(CBr)c1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Product: O=[N+]([O-])c1ccc(SCc2cccc(F)c2)cc1
Yield: 54 %

Procedure:
Prepared in analogy to example 8 from 4-nitrothiophenol and 3-fluoro-benzylbromide. Yellowish solid. Yield=54%.
Reaction SMILES: Br[Si](C)(C)C.C[Si]([CH:10]1[CH2:14][CH:13](Br)[O:12][C:11]1([Si](C)(C)C)[P:16]([OH:19])([OH:18])=[O:17])(C)C.[P:24]([O:33]C(C)C)([O:29]C(C)C)[O:25]C(C)C.C[Si](OP(C1CCC(P(OC(C)C)(OC(C)C)=O)O1)(O[Si](C)(C)C)=O)(C)C>>[P:16]([C:11]1([P:24]([OH:33])([OH:29])=[O:25])[CH2:10][CH2:14][CH2:13][O:12]1)([OH:19])([OH:18])=[O:17]
Reactant: CC(C)OP(OC(C)C)OC(C)C
Reactant: C[Si](C)(C)C1CC(Br)OC1([Si](C)(C)C)P(=O)(O)O
Agent: CC(C)OP(=O)(OC(C)C)C1CCC(P(=O)(O[Si](C)(C)C)O[Si](C)(C)C)O1
Agent: C[Si](C)(C)Br
Product: O=P(O)(O)C1(P(=O)(O)O)CCCO1

Procedure:
To make 2,5-diphosphonotetrahydrofuran (i.e. n is 2), step (a) is suitably accomplished by adding dimethyl phosphite to a cool slurry of sodium hydride in 2,5-dimethoxytetrahydrofuran under an inert atmosphere such as nitrogen or argon and heating the resulting reaction mixture to form 2-phosphono-5-methoxytetrahydrofuran as a first intermediate. Step (b) is suitably accomplished by adding bromotrimethyl silane to said first intermediate and stirring the resulting mixture under an inert atmosphere such as nitrogen or argon, thereby forming di-(trimethylsilyl)2-phosphono-5-bromotetrahydrofuran as a second intermediate. Step (c) is suitably accomplished by adding triisopropyl phosphite to said second intermediate and heating the mixture under an inert atmosphere such as nitrogen or argon, thereby forming 2-(di-(trimethyl silyl)phosphono)-5-(diisopropylphosphono)-tetrahydrofuran. Diphosphonotetrahydrofuran may be produced by adding a concentrated acid, such as hydrochloric acid to the 2-(di-(trimethyl silyl)phosphono)-5-(diisopropylphosphono)-tetrahydrofuran and refluxing the acid solution. 2,6-Diphosphonotetrahydropyran (i.e. n is 3) and 2,7-Diphosphonooxepane (i.e. n is 4) may be produced in similar fashion, respectively using 2,6-dimethoxytetrahydropyran and 2,7-dimethoxyoxepane rather than 2,5-dimethoxytetrahydrofuran as a starting material.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=C)=[CH:4][CH:3]=1.C[O:31]C1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:27][CH2:26][CH:25]([O:28][CH3:29])[CH2:24][CH2:23]3)[C:8]2([NH:16][S:17]([C:19]([CH3:21])([CH3:22])[CH3:20])=[O:18])[C:11]([O:13][CH2:14][CH3:15])=[O:31])=[CH:4][CH:3]=1
Reactant: C=C(OCC)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)C1(NS(=O)C(C)(C)C)c2cc(Br)ccc2CC12CCC(OC)CC2
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 29.1 %

Procedure:
A suspension of compound 5 (400 mg, 0.99 mmol) and Lawesson's Reagent (402 mg, 0.99 mmol) in anhydrous 1,4-dioxane (15 mL) was stirred at 150° C. for 30 min in a CEM microware reactor. The mixture was concentrated in vacuo, and the residue was purified by prep-TLC to give compound 6 (140 mg, 34%) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][S:2]([N:6]1[CH2:10][CH2:9][CH:8]([O:11][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCNC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
Methanesulphonyl chloride (1.95 ml, 25.3 mmol) was added dropwise to an ice-cooled, stirred solution of 3(R,S)-pyrrolidinol (1.0 g, 11.5 mmol), triethylamine (3.5 ml, 25.3 mmol) and 4-dimethylaminopyridine (70 mg, 0.575 mmol) in dichloromethane (10 ml) under nitrogen. The resulting slurry was stirred at room temperature for 24 hours, then diluted with dichloromethane (50 ml), washed successively with saturated aqueous sodium bicarbonate solution (50 ml) and water 50 ml), dried (Na2SO4) and filtered. Dilution of the filtrate with ethyl acetate provided the title compound (1.67 g) as a white crystalline solid. Rf 0.84 (SS 1). Found: C,29.89; H,5.12; N,5.74. C6H13NO5S2 requires C,29.62; H,5.39; N,5.76%.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.CC(C)([O-])C.[K+].O1CCCC1.[C:24]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])#[N:25].C(O)(=O)C>>[C:30]([O:29][C:27](=[O:28])[CH:26]([C:24]#[N:25])[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1cc(C(C#N)C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 50 %

Procedure:
Into a seal vessel, 4-Fluoro-2-methoxy-1-nitro-benzene (15.00 g, 87.65 mmol), 1.00 M of Potassium tert-Butoxide in Tetrahydrofuran (193 mL, 193 mmol), and t-Butyl cyanoacetate (24.7 g, 175 mmol) were added. The reaction mixture was heated at 80° C. for 4 hours. The reaction was cooled to room temperature. Acetic acid (10.96 mL, 192.8 mmol) was added. The reaction was partitioned with water and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc. The reaction mixture was purified via ISCO column chromatography with hexane and EtOAc. The collected fractions afforded an orange collected fractions afforded Cyano-(3-methoxy-4-nitro-phenyl)-acetic acid tert-butyl ester as an orange solid (12.8 g, 49%).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]2[CH2:18][CH2:17][CH:16]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[F:27].O.[OH-].[Li+]>O1CCCC1>[C:23]([O:22][C:20]([NH:19][CH:16]1[CH2:15][CH2:14][N:13]([S:10]([C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([F:27])[CH:6]=2)(=[O:12])=[O:11])[CH2:18][CH2:17]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)c1ccc(S(=O)(=O)N2CCC(NC(=O)OC(C)(C)C)CC2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(S(=O)(=O)c2ccc(C(=O)O)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.9 %

Procedure:
4-(4-Tert-Butoxycarbonylamino-piperidine-1-sulfonyl)-2-fluoro-benzoic acid methyl ester (0.8 g, 2.0 mmol) was added to a 1:1 mixture of water and tetrahydrofuran (20 ml) containing lithium hydroxide (0.8 g, 20.4 mmol) and the mixture was stirred at room temperature for 2 hours. After this time the mixture was concentrated to half the original volume and the remaining solution was acidified to pH 1 with 1M HCl. The resulting precipitate was collected by filtration, washed with water (10 ml) and dried under vacuum to give the title compound (0.82 g, 99% yield) as a white solid. Tr=1.80 min m/z (ES+) (M+Na+) 425.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[C:5](=O)[CH2:6][C:7](=O)[CH3:8])[CH3:2].[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=1[NH:20][NH2:21].C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([CH3:8])[N:20]([C:14]2[C:13]([Cl:12])=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:19])[N:21]=1)=[O:11])[CH3:2]
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CCOC(=O)C(=O)CC(C)=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(C)n(-c2c(Cl)cccc2Cl)n1
Temperature: 80 °C
Yield: 66.7 %

Procedure:
Into a 2000 mL flask was weighed 35.33 g (223.5 mmol) of 2,4-dioxopentanoic acid ethyl ester, 50 g (234.7 mmol) of 2,6 dichlorophenyl hydrazine, 400 mL of acetic acid and 400 mL of ethanol. The resulting solution was heated at 80° C. for 18 h and was then cooled and was washed into a separatory funnel with 1.0 M aq. NaOH and ethyl acetate. The organic layer was separated, washed with sat. aq. NaHCO3, brine, dried over Na2SO4, and was concentrated in vacuo. The residue was recrystallized from EtOH-heptanes to afford 1-(2,6-dichlorophenyl)-5-methyl-1H-pyrazole-3-carboxylic acid ethyl ester (44.6 g, 60%); 1H NMR (400 MHz, DMSO-d6): δ 7.67 (d J=7.67 Hz, 2H), 7.57 (m, 1H), 4.17 (q, J=7.07 Hz 2H), 1.97 (s, 3H); 1.18 (t, J=7.07 Hz 3H), MS (ES): 321 [M+Na]+.
Reaction SMILES: [S:1](Cl)(Cl)(=[O:3])=[O:2].[OH:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:13][C:11]1[CH:10]=[CH:9][C:8]2[N:14]([S:15]([C:18]3[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=3)(=[O:17])=[O:16])[S:1](=[O:3])(=[O:2])[O:6][C:7]=2[CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C)cc2O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2c3ccc(C)cc3OS2(=O)=O)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
At −78° C., a solution of sulfuryl chloride (450 μl, 5.41 mmol) in CH2Cl2 (10 ml) is slowly added dropwise to a solution of N-(2-hydroxy-4-methylphenyl)-4-methylbenzenesulfonamide (1.5 g, 5.41 mmol) and triethylamine (1.5 ml), and the mixture is stirred at −78° C. for one hour. After thawing to RT, the solvent is distilled off under reduced pressure and the residue is purified by RP chromatography.
Reaction SMILES: [CH3:1][O:2][CH:3]([C:8]([O-:10])=O)[C:4]([O:6][CH3:7])=[O:5].[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]=[C:21]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>>[CH3:35][C:33]([CH3:36])([O:32][C:31]([NH:30][C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:8](=[O:10])[CH:3]([O:2][CH3:1])[C:4]([O:6][CH3:7])=[O:5])=[N:22][C:23]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:29])=[O:37])[CH3:34]
Reactant: COC(=O)C(OC)C(=O)[O-]
Reactant: CC(C)(C)OC(=O)NC(=NCCCCCCCCN)NC(=O)OC(C)(C)C
Product: COC(=O)C(OC)C(=O)NCCCCCCCCNC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Yield: 91.9 %

Procedure:
By following a procedure analogous to the method of Preparation 18, using 3.5 g (23.65.10-3 mol) of methyl 2-methoxypropanedioate and 7 g (18.1.10-3 mol) of bis(1,1-dimethylethyl) [[(8-aminooctyl)imino]methylene]biscarbamate as the starting materials, 8.6 g (yield=95%) of the expected product are obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: Cc1cccc(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1F
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(C)c3F)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 71.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-3-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (35 mg, 0.074 mmol) obtained in step 2 and ethanesulfonamide (33 mg, 0.30 mmol), the title compound (30 mg, 73%) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10](O)(=[O:14])[C:11]([CH3:13])=[CH2:12]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[CH3:9][O:8][C:3]1[CH:4]=[C:5]2[C:6](=[CH:7][C:2]=1[CH3:1])[C:10](=[O:14])[CH:11]([CH3:13])[CH2:12]2
Reactant: C=C(C)C(=O)O
Reactant: COc1ccccc1C
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1cc2c(cc1C)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-methylanisole (30 g, 0.25 mol) and methacrylic acid (27 g, 0.31 mol) was added at 60° C. to a well stirred Eaton reagent (69 g P2O5 and 350 mL of methanesulfonic acid). After 30 min of stirring the reaction mixture was cooled, poured into ice water, and filtered. The residue was recrystallized from hexane/benzene (10:1). Yield=22 g (46%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[CH:11]([C:16]([OH:18])=[O:17])[CH:12](O)[CH2:13][S:14][C@H:9]12)=[O:6].C(OC(=O)C)(=O)C.C([O-])(=O)C.[Na+].Cl>O1CCCC1>[CH3:1][O:2][N:3]=[C:4]([C:21](=[O:24])[CH2:22][Br:23])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[O:17])=[CH:12][CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
7-(2-Methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 10 g.) was added to dry tetrahydrofuran (100 ml.) at 30° C. To the solution was added acetic anhydride (10 ml.) and stirred at the same temperature for 30 minutes. Sodium acetate (3 g.) was added to the solution and stirred at 30° C. for 4 hours. 6 N Hydrochloric acid (10 ml) was dropwise added to the reaction mixture under ice-cooling and the solvent was evaporated in vacuo below 30° C. After adding water into the residue, the mixture was stirred at 20° to 25° C. for 30 minutes. The precipitates were collected by filtration, washed with water and dried to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 7 g.).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.Br[CH2:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH3:32][C:31]([CH3:34])([CH3:33])[C:30](=[O:35])[CH2:29][N:7]1[C:6](=[O:8])[CH:5]=[C:4]([O:9][CH2:10][CH2:11][CH3:12])[N:3]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:2]1=[O:1]
Reactant: CCCOc1cc(=O)[nH]c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1cc(=O)n(CC(=O)C(C)(C)C)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.9 %

Procedure:
To a mixture of 4′-[(2,4-dioxo-6-propoxy-3,4-dihydropyrimidin-1(2H)-yl)methyl]-biphenyl-2-carbonitrile (1 g), 1-bromo-3,3-dimethylbutan-2-one (0.59 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.17 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.8 g, 26%).
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH2:4]([N:8]1[C:12]([C:13](OCC)=[O:14])=[C:11]([CH:18]=O)[N:10]=[C:9]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[C:5]#[C:6][CH3:7]>C(O)C>[CH2:4]([N:8]1[C:12]2[C:13](=[O:14])[N:2]([CH3:1])[N:3]=[CH:18][C:11]=2[N:10]=[C:9]1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:22][CH2:21]1)[C:5]#[C:6][CH3:7]
Reactant: CNN
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(C=O)c1C(=O)OCC
Solvent: CCO
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cnn(C)c(=O)c21
Temperature: 80 °C
Reaction time: 15 h

Procedure:
0.05 ml of methylhydrazine was added to a 2.5-ml ethanol solution of 0.055 g of t-butyl 4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate. The mixture was stirred at 80° C. for 15 hours, and then heated at 130° C. for 14 hours. The reaction solution was concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography. Thus, 0.035 g of the title compound was obtained from the fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[C:40]([O:48]CC2C=CC=CC=2)[CH:39]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.C1COCC1.[Pd]>[C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[C:11]2([CH2:18][CH2:17][N:16]([S:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([O:32][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:31])=[CH:26][C:25]=3[CH3:37])(=[O:21])=[O:20])[CH2:15][CH2:14]2)[N:10]=[C:9]1[C:38]1[CH:43]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:41]=[C:40]([OH:48])[CH:39]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(OCc3ccccc3)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(O)cc(C(F)(F)F)c1)N(C(=O)OC(C)(C)C)C2=O

Procedure:
2-(3-Benzyloxy-5-trifluoromethyl-phenyl)-8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester (1.11 g, 1.41 mmol) was dissolved in ethyl acetate (45.0 ml)-THF (15.0 ml). Pd—C (222 mg) was added and the mixture was stirred at room temperature and for one hour in a hydrogen atmosphere. After completion of the reaction, the black solid was filtered off through celite, and the filtrate was concentrated under reduced pressure to give 8-[2-(4-tert-butoxycarbonyl-2-methyl-phenyl)-ethanesulfonyl]-2-(3-hydroxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-3-carboxylic acid tert-butyl ester as an amorphous (1.01 g, 100%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[CH3:28][C:29]1[CH:33]=[C:32]([CH2:34][C:35](O)=[O:36])[O:31][N:30]=1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:35](=[O:36])[CH2:34][C:32]5[O:31][N:30]=[C:29]([CH3:28])[CH:33]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: Cc1cc(CC(=O)O)on1
Agent: Cl
Product: Cc1cc(CC(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4CCO5)CC3)CC2)on1

Procedure:
The title compound, white solid (68 mg, 75%), MS (ISP) m/z=454.4 [(M+H)+], mp 172.5° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (88 mg, 0.2 mmol) and 2-(3-methylisoxazol-5-yl)-acetic acid.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([C:10]2[C:18]3[C:17](O)=[N:16][CH:15]=[N:14][C:13]=3[NH:12][CH:11]=2)=[O:9])=[C:6]([F:20])[CH:5]=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH3:33])=[CH:27][CH:26]=1)(=[O:24])=[O:23].P(Cl)(Cl)([Cl:36])=O>>[Cl:36][C:17]1[C:18]2[C:10]([C:8]([C:7]3[C:2]([F:1])=[C:3]([NH:21][S:22]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH3:33])=[CH:27][CH:26]=4)(=[O:24])=[O:23])[CH:4]=[CH:5][C:6]=3[F:20])=[O:9])=[CH:11][NH:12][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(O)c34)c2F)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2ccc(F)c(C(=O)c3c[nH]c4ncnc(Cl)c34)c2F)cc1
Temperature: 100 °C
Yield: 87.8 %

Procedure:
To N-[2,4-difluoro-3-(4-hydroxy-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-phenyl]-4-propyl-benzenesulfonamide (P-1030, 239 mg, 0.506 mmol), phosphoryl chloride (4.0 mL, 43 mmol) is added and the suspension is heated in an oil bath at 100° C. for one hour. The reaction is allowed to cool, then poured onto ice. The resulting solid is collected by vacuum filtration and dried to provide the desired compound (P-1030, 218 mg). MS (ESI) [M+H+]+=490.9.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[CH:17][C:18]([C:21](O)=[O:22])=[N:19][CH:20]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:21](=[O:22])[C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:24])([F:13])[F:25])=[CH:20][N:19]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cn1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
TEA (0.61 mL, 4.35 mmol) was added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H), 5-(trifluoromethyl)picolinic acid (200 mg, 1.04 mmol) and BOP—Cl (330 mg, 1.30 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 1 hour, and then a LiOH solution (3 mL, 2N) was added. The mixture was stirred for 30 minutes, and water (10 mL) was added. The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethyl)picolinamide (195 mg, 55% yield) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](=[O:23])[N:18]([CH3:24])[CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH:47]2[CH2:50][O:49][CH2:48]2)(=O)=O)=CC=1>CN(C=O)C>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH:47]2[CH2:50][O:49][CH2:48]2)[S:12]([CH3:15])(=[O:13])=[O:14])=[CH:7][C:6]=1[C:16]1[CH:21]=[C:20]([CH3:22])[C:19](=[O:23])[N:18]([CH3:24])[CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC2COC2)cc1
Reactant: Cc1cc(-c2cc(NS(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2cc(N(C3COC3)S(C)(=O)=O)ccc2Oc2ccc(F)cc2F)cn(C)c1=O
Reaction time: 2 h
Yield: 36.4 %

Procedure:
The title compound of Example 102 (46 mg, 0.11 mmol), Cs2CO3 (150 mg, 0.46 mmol), KI (10 mg, 0.06 mmol) and oxetan-3-yl 4-methylbenzenesulfonate (30 mg, 0.13 mmol) in DMF (0.9 mL) were microwaved at 130° C. for 2 h. Additional oxetan-3-yl 4-methylbenzenesulfonate (65 mg, 0.29 mmol) and Cs2CO3 (126 mg, 0.39 mmol) were added and microwave resumed at 130° C. for 2 h more. The mixture was purified by silica gel chromatography (EA) to give the title compound (20 mg, 0.04 mmol) as cream solids in 38% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03 (s, 3H) 2.98 (s, 3H) 3.50 (s, 3H) 4.41 (t, J=6.82 Hz, 2H) 4.58 (t, J=6.95 Hz, 2H) 5.30 (quin, J=7.01 Hz, 1H) 6.83 (d, J=8.84 Hz, 1H) 7.06-7.20 (m, 1H) 7.22-7.35 (m, 2H) 7.39 (d, J=2.53 Hz, 1H) 7.43-7.57 (m, 1H) 7.60 (s, 1H) 7.83 (d, J=2.27 Hz, 1H). LCMS (M+H)+ 477