Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+:5].[OH:6][C:7]1[CH:20]=[C:19](O)[C:18]2[C:22]3=[C:23]4[C:11](=[C:12]([S:28]([O-:31])(=[O:30])=[O:29])[CH:13]=[C:14]([S:24]([O-:27])(=[O:26])=[O:25])[C:15]4=[CH:16][CH:17]=2)[CH:10]=[CH:9][C:8]=13.[Na+].[Na+].[C:34](OC(=O)C)(=[O:36])[CH3:35]>CN(C=O)C>[Na+:5].[C:1]([O:4][C:19]1[CH:20]=[C:7]([O:6][C:34](=[O:36])[CH3:35])[C:8]2[C:22]3=[C:23]4[C:15](=[C:14]([S:24]([O-:27])(=[O:25])=[O:26])[CH:13]=[C:12]([S:28]([O-:31])(=[O:29])=[O:30])[C:11]4=[CH:10][CH:9]=2)[CH:16]=[CH:17][C:18]=13)(=[O:3])[CH3:2].[Na+:5]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: O=S(=O)([O-])c1cc(S(=O)(=O)[O-])c2ccc3c(O)cc(O)c4ccc1c2c43
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Oc1cc(OC(C)=O)c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c4ccc1c2c43
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Compound (2) was prepared by the protocol already published [D2], but modified here. The modification was that sodium acetate was used [D3]. A mixture of sodium 6,8-dihydroxypyrene-1,3-disulfonate (1) (4.452 g, 10.16 mmol), sodium acetate (83.0 mg, 1.016 mmol) and acetic anhydride (5.8 mL) in DMF (250 mL) was stirred intensively at room temperature for 48 h with the exclusion of light. The reaction mixture was filtered through a Celite-kieselguhr bed (h=0.5 cm), and DMF was stripped off on a rotary evaporator at 50° C. and 0.1 Torr. The residue was recrystallized from an ethanol/water mixture (70 ml:10 ml), washed with acetone and dried in vacuo to give a yield of 4.242 g (83%) as yellow powder (melting point 245-247° C. (decomposition)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([F:21])=[C:11]([F:20])[CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[NH:15][CH:14]2[CH3:19].C1C(=O)N([I:29])C(=O)C1>C1COCC1.CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([I:29])[CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[C:10]([F:21])=[C:11]([F:20])[CH:12]=[C:13]2[C:17]=1[C:16](=[O:18])[NH:15][CH:14]2[CH3:19]
Reactant: CC1NC(=O)c2c1cc(F)c(F)c2Nc1ccccc1Cl
Reactant: O=C1CCC(=O)N1I
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CC1NC(=O)c2c1cc(F)c(F)c2Nc1ccc(I)cc1Cl
Yield: 21.1 %

Procedure:
A solution of 7-(2-chlorophenylamino)-5,6-difluoro-3-methyl-2,3-dihydro-isoindol-1-one (18 mg, 0.059 mmol), NIS (17 mg, 0.074 mmol), and p-TsOH-H2O (24 mg, 0.12 mmol) in THF-MeOH (1 mL/1 mL) was stirred for 1 hour at room temperature. The reaction mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and water. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that was purified by silica gel flash column chromatography (100% CH2Cl2 to 1% MeOH in CH2Cl2) to afford 7-(2-chloro-4-iodophenylamino)-5,6-difluoro-3-methyl-2,3-dihydro-isoindol-1-one (5.4 mg, 21%). MS APCI (−) m/z 433, 435 (M-, Cl pattern) detected; 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.70 (d, 1H), 7.48 (dd, 1H), 6.75 (m, 2H), 6.04 (s, 1H), 4.63 (q, 1H), 1.49 (d, 3H).
Reaction SMILES: C([O:3][P:4]([C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:6]CC)=[O:5])C.C[Si](Br)(C)C>>[P:4]([C:9]#[C:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([OH:6])([OH:5])=[O:3]
Reactant: CCOP(=O)(C#Cc1ccccc1)OCC
Agent: C[Si](C)(C)Br
Product: O=P(O)(O)C#Cc1ccccc1

Procedure:
1-Diethylphosphono-2-phenylacetylene was deesterified with TMSBr as described in Step D, Example 1, to provide the title compound (no. 16.01) as a solid. HPLC Rt=3.75 min; negative ion electrospray MS M-1 found: 181.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][CH:4]=1.[Cl:14][CH:15]([CH3:19])[C:16](=O)[CH3:17]>C(O)(C)C>[ClH:14].[CH3:19][C:15]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:4][CH:5]=2)[S:8][C:16]=1[CH3:17]
Reactant: NC(=S)c1ccc(C(F)(F)F)cc1
Reactant: CC(=O)C(C)Cl
Solvent: CC(C)O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C
Product: Cl
Temperature: 50 °C
Yield: 45.6 %

Procedure:
A solution of 4-trifluoromethyl-thiobenzamide (4 g, 19.5 mmol) and 3-chloro-2-butanone (3.9 ml, 39 mmol) in isopropanol (20 ml) was heated to reflux for 30 h under an argon atmosphere. The reaction mixture was concentrated to a volume of 10 ml, cooled to 50° C. and diisopropylether (20 ml) was added dropwise. The solution was cooled to ambient temperature, the resulting crystals were filtered off, washed with ice cold diisopropylether and dried in vacuo to give 2.6 g (8.9 mmol, 45%) of the title compound as off-white crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:23]1[N:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>>[CH2:1]([N:8]1[CH2:18][CH2:17][C:11]2[N:12]=[CH:13][N:14]=[C:15]([NH:29][C:26]3[CH:27]=[N:28][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:24][CH:25]=3)[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1ccc(N)cn1
Reactant: Clc1ncnc2c1CN(Cc1ccccc1)CC2
Product: CC(C)(C)c1ccc(Nc2ncnc3c2CN(Cc2ccccc2)CC3)cn1

Procedure:
The title compound was prepared substantially according to the procedure given for Compound 1A, using 6-benzyl-4-chloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (Intermediate 2), and 6-tert-butyl-pyridin-3-ylamine to give the desired N-benzyl intermediate as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][CH2:22][O:23][CH3:24])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.[OH2:36]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][CH:10]=[CH:11][C:12]2[CH:13]=[CH:14][C:15]([O:21][CH2:22][O:23][CH3:24])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=2)(=[O:33])=[O:36])=[CH:4][CH:3]=1
Reactant: COCOc1ccc(C=CCSc2ccc(Cl)cc2)cc1[N+](=O)[O-]
Reactant: O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCOc1ccc(C=CCS(=O)(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 74 %

Procedure:
Under a current of argon, a solution of 300 mg of 5-[3-(4-chlorophenylthio)-1-propenyl]-2-methoxymethoxy nitrobenzene in 6 ml of methylene chloride and 283 mg of m-chloroperbenzoic acid added thereto as kept cooled with ice were stirred for eight hours. The reaction mixture was combined with water and extracted from ethyl acetate. The consequently separated organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated saline solution in the order mentioned and then dried with anhydrous sodium sulfate. The residue from drying was concentrated under a vacuum and the concentrate was subjected to silica gel column chromatography. From the hexane-ethyl acetate (2:1 V/V) eluate, 240 mg of 5-[3-(4-chlorophenylsulfonyl)-1-propenyl]-2-methoxymethoxy nitrobenzene was obtained in the form of yellow crystals. The yield was 74%.
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)(=O)=O.[NH2:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.CN1CCCC1=O>C(OCC)(=O)C.O>[O:18]1[CH2:19][CH2:20][CH:15]([NH:14][C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[CH:12][S:11][C:9]=3[N:10]=2)[CH2:16][CH2:17]1
Reactant: CS(=O)(=O)c1ncc2ccsc2n1
Reactant: NC1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: c1cc2cnc(NC3CCOCC3)nc2s1
Temperature: 100 °C
Reaction time: 7 h
Yield: 72.9 %

Procedure:
A mixture of 2-methanesulfonyl-thieno[2,3-d]pyrimidine (1.58 g, 7.37 mmol), 4-aminotetrahydropyran (2.24 g, 3 eq) and 1-methyl-2-pyrolidinone (2 mL) was heated to 100° C. with stirring for about 7 hours and continued heating at 80° C. overnight. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (180 mL)/water (60 mL). The layers were separated, and the organic layer was washed successively with water (4×60 mL) and brine (1×60 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated to give 1.7 g of the crude product. Purification by column chromatography on silica gel eluting with 25% ethyl acetate in hexanes afforded the title compound as a white powder (1.264 g) ((M+H)+=236, M.P.=127.0–130.0° C.).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][OH:22])[CH2:17][CH2:16]1)[CH3:14].C(N(CC)CC)C.O>CS(C)=O>[F:23][C:2]([F:1])([F:24])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]([N:15]1[CH2:16][CH2:17][CH:18]([CH:21]=[O:22])[CH2:19][CH2:20]1)[CH3:14]
Reactant: CC(c1ccc(C(F)(F)F)cc1C(F)(F)F)N1CCC(CO)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(c1ccc(C(F)(F)F)cc1C(F)(F)F)N1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 57.8 %

Procedure:
To a solution of (1-{1-[2,4-bis(trifluoromethyl)phenyl]ethyl}piperidin-4-yl)methanol (2.0 g) and triethylamine (2.35 mL) in DMSO (22.5 mL) was added sulfur trioxide pyridine complex (2.69 g). The reaction mixture was stirred at room temperature for 1.5 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by so silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.15 g).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][C:21]1=[O:26].[OH-].[Na+]>ClCCl.CN(C)C=O>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:17](=[O:19])[N:23]1[CH2:24][CH2:25][NH:20][C:21](=[O:26])[CH2:22]1)([CH3:5])([CH3:6])[CH3:7]
Reactant: O=C1CNCCN1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCNC(=O)C1

Procedure:
BOC-L-Phenylalanine (530 mg, 2 mmol) and piperazin-2-one (J. Am. Chem. Soc. 62 1202 (1940), 200 mg, 2 mmol) were coupled according to procedure A (2:1 dichloromethane/dimethylformamide reaction solvent, washed with 1 N NaOH after acid washes) and the product used without further purification. Yield 404 mg, 58%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.S1C=CC=C1.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH:16]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:17]([NH:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[O:18])[CH2:14][CH2:15]2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: O=C(NCC(F)(F)F)C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: c1ccsc1
Product: Nc1ccc(N2CCN(C(C(=O)NCC(F)(F)F)c3ccccc3)CC2)cc1
Yield: 70.8 %

Procedure:
A mixture of intermediate (3) (0.0054 mole) in methanol (150 ml) was hydrogenated with Pd/C 10% (1 g) as a catalyst in the presence of a 4% thiophene solution (1 ml). After uptake of hydrogen (2 equivalents), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 1.5 g of (±)-4-(4-aminophenyl)-α-phenyl-N-(2,2,2-trifluoroethyl)-1-piperazineacetamide (intermediate 4, melting point 136° C.).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=O.O.[NH2:18][NH2:19]>C(O)CO>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=1)=[N:18][NH2:19]
Reactant: COc1cccc(C(=O)c2sccc2Br)c1
Reactant: NN
Solvent: O
Solvent: OCCO
Product: COc1cccc(C(=NN)c2sccc2Br)c1
Temperature: 130 °C

Procedure:
A mixture of (3-bromothien-2-yl) (3-methoxyphenyl)methanone (10.0 g), hydrazine hydrate (10 ml, above 99% purity), and 75 ml of ethylene glycol was heated at 130° C. for three hours. The reaction mixture was then quenched with water and extracted with ether. The ether solution was washed three times with water and dried over anhydrous magnesium sulfate. The ether was then evaporated to give 5.5 g of an oil. This was then column chromatographed on a silica gel column packed in hexane using 15% ether/hexane as an eluent. The solid from the column was then recrystallized from ether/hexane.
Reaction SMILES: [CH2:1]([SH:4])[CH2:2][CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:16]1[N:20]([C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)[N:19]=[CH:18][C:17]=1[C:31](=[O:39])[NH:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C=O)C.C1COCC1.C(OCC)(=O)C>[CH:33]1([NH:32][C:31]([C:17]2[CH:18]=[N:19][N:20]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)[C:16]=2[S:4][CH2:1][CH2:2][CH3:3])=[O:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)NC3CCCCC3)c2Cl)cc1
Reactant: CCCS
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCSc1c(C(=O)NC2CCCCC2)cnn1-c1ccc(C(=O)OC)cc1
Reaction time: 0.25 h

Procedure:
Propane thiol (88 mg, 1.16 mmol) was dissolved in DMF (5 mL) and treated at ambient temperature with a 1M solution of NaHMDS in THF (1.16 mL). After stiffing for 15 min the clear solution was added to a suspension of methyl 4-[5-chloro-4-(cyclohexylcarbamoyl)pyrazol-1-yl]benzoate (Intermediate#15) (378 mg, 1.05 mmol) in DMF (10 mL). Stiffing was continued at ambient temperature for 2 h and then the reaction mixture was diluted with ethyl acetate (100 mL), washed with water (4×25 mL) and dried (MgSO4). Volatiles were removed by evaporation under reduced pressure to give a clear oil which was purified by chromatography on silica gel, eluting with an ethyl acetate/hexane gradient (0-50%) to give the title compound as a white solid. (363 mg, 86%)
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=O)[CH3:25])[O:19][C:18]4=[O:27])=[CH:13][C:12]=3[F:28])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:38])=CC=1>O1CCOCC1>[O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[S:38])[CH3:25])[O:19][C:18]4=[O:27])=[CH:13][C:12]=3[F:28])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Solvent: C1COCCO1
Product: CC(=S)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCO4)c(F)c2)C(=O)O1
Yield: 55 %

Procedure:
The title compound was prepared by reacting (S)—N-{3-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol, prepared as per procedure described in U.S. Pat. No. 5,668,286) with Lawesson's reagent (1.1 mmol), in dioxane (10 ml) at a temperature 65° C. for 12 hours followed by silica gel column chromatographic purification in 55% yield. Mp; 141-143° C., Mass m/z 410.1 (ES+, 100%) for C19H24FN3O4S.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)#[N:2].[NH2:9][C:10]1[S:11][C:12]([CH3:20])=[CH:13][C:14]=1[C:15](OCC)=O.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:15]1[C:14]2[CH:13]=[C:12]([CH3:20])[S:11][C:10]=2[N:9]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[N:2]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc(C)sc1N
Reactant: N#Cc1ccncc1
Product: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 477, the reaction of 4-cyanopyridine and 2-amino-5-methyl-3-ethoxycarbonyl-thiophene, and the subsequent reaction with POCl3 yields 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine
Reaction SMILES: [N:1]1(C(OCC(Cl)(Cl)[Cl:23])=O)[C:9]23[CH2:10][CH2:11][CH2:12][CH2:13][C:4]2([CH2:5][CH2:6][C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=23)[CH2:3][CH2:2]1>CO.C(O)(=O)C.[Zn]>[ClH:23].[NH:1]1[C:9]23[CH2:10][CH2:11][CH2:12][CH2:13][C:4]2([CH2:5][CH2:6][C:7]2[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=23)[CH2:3][CH2:2]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CCC23CCCCC12c1ccccc1CC3
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CO
Product: Cl
Product: c1ccc2c(c1)CCC13CCCCC21NCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A solution of the product from Example 19 (0.70 g, 1.74 mmol) in 20 mL of methanol and 0.5 mL acetic acid was treated with zinc dust (1.58 g, 320 mesh) and the resulting suspension stirred at room temperature for three hours. The reaction mixture was filtered and the filtrate concentrated. The residue was dissolved in ether (30 mL) and extracted with aqueous 1N HCl (3×15 mL). The combined acid extracts are made basic (pH=11) with potassium carbonate and the resulting aqueous solution was extracted with CH2Cl2 (5×15 mL). The combined organic extracts were dried (Na2SO4, filtered and concentrated. The residue (0.30 g) was converted to its HCl salt by dissolution in ether and treatment with a saturated solution of HCl (gas) in ether. The solid which formed was collected by filtration and dried under vacuum (100° C.) to give the title compound (0.25 g, 54%) as a white solid mp >270° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH:2]([CH3:4])[CH3:3].[Cl:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][C:8]=1[N+:16]([O-:18])=[O:17].C(N(CC)CC)C>O1CCCC1>[CH2:1]([NH:5][C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([Cl:6])=[C:8]([N+:16]([O-:18])=[O:17])[CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CN
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)CNC(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
6 ml (0.06 mol) of isobutylamine in 60 ml tetrahydrofuran are added dropwise to a solution of 13.2 g (0.06 mol) of 4-chloro-3-nitro-benzoylchloride and 6 g (0.06 mol) of triethylamine in 150 ml tetrahydrofuran and the mixture is stirred for 1 hour. The solution is evaporated down, dissolved in methylene chloride and washed with water. The combined organic extracts are dried and evaporated down. The residue is chromatographed on silica gel and eluted with methylene chloride/ethanol (98:2). The desired fractions are combined and evaporated down.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[C:9]([CH2:10][N:11]([C@@H:45]([CH3:53])[CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])[C:12](=[O:44])[C@@H:13]([NH:26]C(=O)OCC3C4C=CC=CC=4C4C3=CC=CC=4)[CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=3)=[CH:8][CH:7]=[CH:6][C:5]=12.N1CCCCC1>>[NH2:26][C@@H:13]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)[C:12]([N:11]([CH2:10][C:9]1[C:4]2[C:5](=[N:1][S:2][N:3]=2)[CH:6]=[CH:7][CH:8]=1)[C@@H:45]([CH3:53])[CH:46]([O:50][CH2:51][CH3:52])[O:47][CH2:48][CH3:49])=[O:44]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2nsnc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCNCC1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2nsnc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Yield: 139.7 %

Procedure:
According to the procedure described in the synthesis method of Compound IV-1, (9H-fluoren-9-yl)methyl(S)-1-((benzo[c][1,2,5]thiadiazol-4-ylmethyl)((S)-1,1-diethoxypropan-2-yl)amino)-3-(4-tert-butoxyphenyl)-1-oxopropan-2-ylcarbamate (Compound III-8)(509 mg, 0.69 mmol) was treated with piperidine and the obtained residue was purified by silica gel column chromatography (eluent: n-hexane:ethyl acetate=9:1, chloroform:methanol=100:0 and 8:2) to obtain the title compound (496 mg, 139%).
Reaction SMILES: [Cl:1][CH:2]([Cl:23])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:22])[CH3:21])=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.C([O-])(=O)C.[Na+].O[NH:42][C:43](=[NH:53])[CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:51])([CH3:50])[CH3:49]>CN(C)C=O.C(OC(=O)C)C.C1(C)C=CC=CC=1>[Cl:23][CH:2]([Cl:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:20]=[CH:19][C:15]([C:16]3[O:17][N:53]=[C:43]([CH2:44][NH:45][C:46](=[O:52])[O:47][C:48]([CH3:50])([CH3:49])[CH3:51])[N:42]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:22])[CH3:21])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(C(=O)O)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCC(=N)NO
Agent: CC(=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1noc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(Cl)Cl)[C@@H]3CF)cc2)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.7 %

Procedure:
To a solution of the product of Step 2, Example 8 (525 mg, 1.4 mmol) in dimethylformamide (15 mL) is added 1,1′-Carbonyldiimidazole (286 mg, 1.7 mmol). The resulting solution is stirred at room temperature for 30 minutes at which time sodium acetate (140 mg, 1.7 mmol) and commercially available tert-butyl 2-(hydroxyamino)-2-iminoethylcarbamate (325 mg, 1.7 mmol) are added. The reaction is then stirred at room temperature for 72 hours. Next, the reaction is diluted with ethylacetate (75 mL) and washed with water (3×75 mL). The organic phase is dried (Na2SO4) and concentrated under vacuum. To the residue is added toluene (15 mL) and sodium acetate (140 mg, 1.7 mmol). The resulting mixture is heated to reflux for 18 hours while stirring, then cooled to room temperature and concentrated under vacuum. The residue is chromatographed on silica gel eluting from 100% hexanes to 50:50 EtOAc:hexanes to afford the title compound (280 mg): 1H NMR (400 MHz, CDCl3) 8.19 (d, 2H, J=8.0 Hz), 7.64 (d, 2H, J=8.0 Hz), 6.33 (m, 1H), 5.16 (m, 2H) 4.88-4.52 (m, 4H), 1.75 (s, 3H), 1.59 (s, 3H), 1.50 (s, 9H). m/z (Cl) 461 [M-(CH3)2CO].
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[C:14]=2[CH:13]=[CH:12]1>>[ClH:1].[Cl:1][C:2]1[S:6][C:5]([S:7]([N:11]2[C:19]3[CH:18]=[CH:17][N:16]=[C:15]([N:20]4[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]4)[C:14]=3[CH:13]=[CH:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccc3[nH]ccc23)CC1
Product: Cl
Product: O=S(=O)(c1ccc(Cl)s1)n1ccc2c(N3CCNCC3)nccc21

Procedure:
5-Chlorothiophene-2-sulfonyl chloride (28.0 mg) was added to tert-butyl 4-(1H-pyrrolo[3,2-c]pyridin-4-yl)piperazine-1-carboxylate the title compound (7.2 mg). LC/MS RT: 1.381 (System 10 till 40% MeCN over 1.5 min, ACE C8), Purity. 97%. MS: 483 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[S:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:2]=12.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.[NH2:46][C:47]1[C:48]([F:68])=[CH:49][C:50]([F:67])=[C:51]([NH:53][C:54](=[O:66])[C:55]2[CH:60]=[CH:59][CH:58]=[C:57]([C:61]([C:64]#[N:65])([CH3:63])[CH3:62])[CH:56]=2)[CH:52]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:64]([C:61]([C:57]1[CH:56]=[C:55]([CH:60]=[CH:59][CH:58]=1)[C:54]([NH:53][C:51]1[C:50]([F:67])=[CH:49][C:48]([F:68])=[C:47]([NH:46][C:10]([C:8]2[S:7][C:3]3=[N:4][CH:5]=[CH:6][N:1]=[C:2]3[CH:9]=2)=[O:12])[CH:52]=1)=[O:66])([CH3:63])[CH3:62])#[N:65]
Reactant: O=C(O)c1cc2nccnc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(N)c(F)cc2F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cc(NC(=O)c3cc4nccnc4s3)c(F)cc2F)c1
Reaction time: 0.25 h
Yield: 20.5 %

Procedure:
A mixture of thieno[2,3-b]pyrazine-6-carboxylic acid (57.1 mg, 0.317 mmol), HATU (145 mg, 0.381 mmol) and DIPEA (0.105 mL, 0.634 mmol) in DMF (3 mL) was stirred for 15 min. N-(5-amino-2,4-difluorophenyl)-3-(2-cyanopropan-2-yl)benzamide 73 (100 mg, 0.317 mmol) was added and stirred for 2 h at 80° C. Citric acid solution (3%) was added and the resulting precipitate was collected. Purification by HPLC gave the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2,4-difluorophenyl)thieno[2,3-b]pyrazine-6-carboxamide 74 (31 mg, 20%). NMR (400 MHz, DMSO-d6) 1.76 (s, 6H), 7.61 (m, 2H), 7.79 (m, 1H), 7.85 (t, J=7.8 Hz, 1H), 7.97 (d, J=7.8 Hz, 1H), 8.10 (t, J=2.0 Hz, 1H), 8.56 (s, 1H), 8.77 (d, J=2.3 Hz, 1H), 8.89 (d, J=2.3 Hz, 1H), 10.35 (s, 1H), 10.80 (br s, 1H). (m/z)=478 (M+H)+.