Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](C)=[CH:4][CH:3]=1.O(Cl)Cl.[C:12]([Cl:16])(Cl)([Cl:14])[Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]([Cl:16])([Cl:14])[Cl:13])=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc(Cl)cc1
Agent: ClOCl
Product: Clc1ccc(C(Cl)(Cl)Cl)cc1
Reaction time: 120 h
Yield: 83.9 %

Procedure:
p-Chlorotoluene (1.17 g, 0.0092 mole) and dichlorine monoxide (2.40 g, 0.028 mole) in carbon tetrachloride (35 ml) were mixed and stored in a stoppered bottle at room temperature for 5 days. The initial reaction ws exothermic. The product was dried (MgSO4) and the solvent removed on a rotary evaporator to give 4-chlorotrichloromethylbenzene as a pale yellow oil (2.00 g, purity by HPLC 88.78%; yield 83.9%), containing a small amount of dichlorotrichloromethylbenzene.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11](Cl)=[O:12].[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:44])[CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]2)=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]2[C:21]([C:24]3[CH:29]=[CH:28][C:27]([NH:30][C:11]([C:3]4[N:2]([CH3:1])[C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[O:12])=[C:26]([O:31][CH3:32])[CH:25]=3)=[CH:22][S:23][C:19]=2[C:18]([NH:33][C:34](=[O:44])[CH2:35][CH2:36][N:37]2[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]2)=[CH:17][N:16]=1
Reactant: COc1cc(-c2csc3c(NC(=O)CCN4CCN(C)CC4)cnc(N)c23)ccc1N
Reactant: Cn1c(C(=O)Cl)cc2ccccc21
Product: COc1cc(-c2csc3c(NC(=O)CCN4CCN(C)CC4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C

Procedure:
The title compound was prepared using 1-methyl-1H-indole-2-carbonyl chloride, N-[4-amino-3-(4-amino-3-methoxyphenyl)thieno[3,2-c]pyridin-7-yl]-3-(4-methylpiperazin-1-yl)propanamide, and the procedure described in General Procedure F. m/z (M+H)+598.4.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1.[CH3:11][O-:12].[Na+]>CN(C=O)C>[CH3:11][O:12][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1
Reactant: COc1ccc(I)nc1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1OC
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-bromo-3-methoxy-6-iodopyridine (11-3, 34 g, 162 mmol) in DMF (65 mL) was added sodium methoxide (37 mL, 162 mmol) and heated to 100° C. The mixture was stirred for 10 minutes and partitioned between saturated NaHCO3 and DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica (0 to 20% EtOAc in hexanes) to afford the title compound (11-4) as a white powder. ESI+MS [M+H]+ C7H8INO2: 265.8 found, 266.0 required
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[SH:26][CH:27](O)[CH3:28].B(F)(F)F>O1CCCC1>[S:26]1[C:2]2([CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([N:14]4[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]4=[O:24])=[CH:10][C:9]=3[F:25])[CH2:6][CH2:7]2)[O:1][CH2:28][CH2:27]1
Reactant: CC(O)S
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: FB(F)F
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCCS4)c(F)c2)C(=O)O1
Yield: 85 %

Procedure:
The mixture of (S)—N-{3-[4-(4-oxo-piperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (2.86 mmol), mercaptoethanol (3.15 mmol) and BF3 etherate (5.14 mmol) in 10 ml tetrahydrofuran was heated under reflux for 6 hours. The solvent was evaporated and the residue was extracted with ethyl acetate water mixture the organic layer was concentrated and the crude residue was purified on a silica gel column to afford the titled compound in 85% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][O:10][C:9]2=[O:13])=[C:4]([Cl:14])[CH:3]=1.[CH3:15][O:16][N:17]([CH3:21])[C:18](Cl)=[O:19]>C(N(CC)CC)C>[Cl:14][C:4]1[CH:3]=[C:2]([NH:1][C:18](=[O:19])[N:17]([O:16][CH3:15])[CH3:21])[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:12][CH2:11][O:10][C:9]1=[O:13]
Reactant: Nc1ccc(N2CCOC2=O)c(Cl)c1
Reactant: CON(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Nc1ccc(N2CCOC2=O)c(Cl)c1
Reaction time: 12 h

Procedure:
10.1 g of triethyamine was added to the solution of 1C, then 13.6 g of N-methoxy-N-methylcarbamoyl chloride was added drop-by-drop. After 12 hours at room temperature, the mixture was washed with water and extracted with ether. The extract was dried and the ether was evaporated under reduced pressure. The residue was chromatographed over silica gel to give 1, as a white solid, mp: 151°-153° C.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9](=[N:16][CH2:17][C:18]#[N:19])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[F:30]>CN(C)C=O>[C:18]([CH:17]([N:16]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[CH2:21][C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=1[F:30])#[N:19]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC(C#N)N=C(c2ccccc2)c2ccccc2)c(F)c1
Temperature: 0 °C

Procedure:
To a suspension of sodium hydride (2.62 g) in dimethylformamide (100 ml) at 0° C. was slowly added a solution of [(diphenylmethylidene)amino]acetonitrile (13.20 g) in 40 ml of dimethylformamide. The reaction temperature varied between 2 and 8° C. during the addition. The color went from yellow to brown with gas evolution. The reaction mixture was stirred at 0° C. for 10 more minutes then 4-(bromomethyl)-3-fluorobenzonitrile from step 1 (12.72 g) was added very quickly in 60 ml of dimethylformamide. The temperature rose to 27° C. and the cold bath was removed. The reaction was stirred for 4 h. The flask content was poured into sodium dihydrogen phosphate solution (300 ml) and icy water (1.4 L). The mixture turned yellow and a big lump formed along with very small amounts of fine powder. The fine solid was filtered and the lump kept in the Erlenmeyer. The lump was dissolved in ether (500 ml) and put in a separating funnel along with water (200 ml). The phases were separated and the organic layer was washed with brine (100 ml) and dried over magnesium sulfate. The organic phase is concentrated under reduced pressure to give 4-{2-cyano-2-[(diphenylmethylene)amino]ethyl}-3-fluorobenzonitrile an orange solid that was used as such in the next step.
Reaction SMILES: [F:1][C:2]1[C:3](=O)[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11]>O1CCOCC1>[F:1][C:2]1[C:3](=[S:11])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: C1COCCO1
Product: O=c1[nH]cc(F)c(=S)[nH]1
Yield: 144.8 %

Procedure:
A mixture of 5-fluorouracil (26 g, 0.12 mole) and phosphorus pentasulfide (45 g, 0.2 mole) in 500 mL dioxane was heated under reflux for 3 hr. The hot reaction mixture was filtered and concentrated in vacuo. The residue was dissolved in 650 mL water, heated with 5 g charcoal and filtered. The solid which crystallized on cooling was collected by filtration to yield 25.4 g (88%) of 5-fluoro-4-thiouracil, m.p. 269°-272° C.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][CH:11]([OH:18])[CH2:12][C:13]([CH3:17])([O:15][OH:16])[CH3:14]>C(N(CC)CC)C.CCOCC>[CH:1]1([NH:7][C:8](=[O:9])[O:18][CH:11]([CH3:10])[CH2:12][C:13]([CH3:17])([O:15][O:16][C:8](=[O:9])[NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(O)CC(C)(C)OO
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(CC(C)(C)OOC(=O)NC1CCCCC1)OC(=O)NC1CCCCC1
Reaction time: 48 h
Yield: 39 %

Procedure:
A mixture of 18.7 g. (0.15 mole) of cyclohexyl isocyanate, 6.7 g. (0.05 mole) of 1,3-dimethyl-3-hydroperoxybutyl alcohol and 3 drops of triethylamine was stirred for 5 days at ambient temperature. The reaction vessel was protected with a calcium chloride tube to keep out moisture. Within 2 days, a solid began to appear, and after the 5 day stirring period the reaction mixture was stripped in vacuo. The residue was slurried in 100 ml of ether and filtered. The filter cake was washed with an additional 30 ml of ether and air dried. A total of 7.5 grams of a colorless solid was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:17](F)=[CH:18][N:19]=1)[C:5]([C:7](=[CH:13][N:14]([CH3:16])C)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].Cl.[CH3:22][N:23]1[CH2:26]C(N)[CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][N:19]=1)[N:14]([CH:16]1[CH2:24][N:23]([CH3:26])[CH2:22]1)[CH:13]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]2=[O:6]
Reactant: CN1CC(N)C1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)ncc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2CN(C)C2)c2cnc(Br)cc2c1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 163.8 %

Procedure:
To a solution of ethyl 2-(2-bromo-5-fluoroisonicotinoyl)-3-(dimethylamino)acrylate (Intermediate 66, 0.690 g, 2 mmol, 1 equiv.) in THF (7 mL) was added 1-methylazetidin-3-amine HCl (245 mg, 2 mmol, 1 equiv.) and potassium carbonate (276 mg, 2 mmol, 1 equiv.). This reaction mixture was stirred at 60° C. for 1 h. The reaction mixture was concentrated under reduced pressure and re-suspended in DMF (7 mL). Potassium carbonate (553 mg, 4 mmol, 2 equiv.) was added, and the reaction mixture was stirred at 70° C. for 3 h. The reaction mixture was cooled to room temperature and quenched with water. 1 N HCl was added until pH 4-5 was reached. The precipitate was washed with water and hexanes and dried to provide ethyl 6-bromo-1-(1-methylazetidin-3-yl)-4-oxo-1,4-dihydro-1,7-naphthyridine-3-carboxylate (1.2 g, ≧99%). Calcd for C15H16BrN3O3 [M+H]+: 367.91.
Reaction SMILES: [Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]=[O:25].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1>C1COCC1.O>[Br:1][C:2]1[S:23][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)[C:9](=[O:10])[C:4]=2[C:3]=1[CH:24]([C:30]1[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=1)[OH:25]
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C=O)c(Br)sc21
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Br)sc21
Reaction time: 0.08 h
Yield: 51.6 %

Procedure:
To a solution of 6-bromo-1-methyl-2,4-dioxo-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidine-5-carbaldehyde (See Compound 2, Step 4, 185 mg, 0.428 mmol) in THF (5 mL) was added (4-chlorophenyl)magnesium bromide (0.77 mL, 0.772 mmol). The reaction was stirred for 5 min, diluted with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (5:1 to 1:1) to give 6-bromo-5-((4-chlorophenyl) (hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (120 mg, 51.4% yield) as a solid. LCMS: [M+-THP-OH] 441 and TR=2.021 min.
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9](=[O:17])[NH:8]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH2:2][C:3]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:17])[NH:8][CH:7]2[CH3:6])=[O:4]
Reactant: O=C(Cl)CBr
Reactant: CC1NC(=O)Nc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC1NC(=O)Nc2ccc(C(=O)CBr)cc21

Procedure:
2-Bromoacetyl chloride (9.7 g) is added dropwise to a stirred mixture of 3,4-dihydro-4-methyl-2(1H)-quinazolinone (5 g), anhydrous aluminum chloride (10.3 g) and carbon disulfide (100 ml) under nitrogen. The reaction mixture is refluxed for about 18 hours, the carbon disulfide decanted, and the residue treated with hydrochloric acid (6N) and ethyl acetate. The layers are separated, and the aqueous layer extracted with ethyl acetate and the combined ethyl acetate extracts washed with sat'd. aqueous sodium bicarbonate and water and dried. The dried organic extract is filtered and the filtrate evaporated, affording the desired product as a solid, which is used without further purification, M.P. 188°-190° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=S)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N=C=NC(C)C)(C)C.[NH2:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([N:29]([CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])=[O:28])=[CH:25][C:24]=1[NH:42][CH2:43][CH2:44][CH:45]1[O:49][CH2:48][CH2:47][O:46]1>O1CCCC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:42]([CH2:43][CH2:44][CH:45]3[O:46][CH2:47][CH2:48][O:49]3)[C:24]3[CH:25]=[C:26]([C:27]([N:29]([CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:35][CH2:36][CH:37]([CH3:38])[CH3:39])=[O:28])[CH:40]=[CH:41][C:23]=3[N:22]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(N=C=S)cc1
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc(N)c(NCCC2OCCO2)c1
Agent: CC(C)N=C=NC(C)C
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCC2OCCO2)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
4-acetylphenyl isothiocyanate (1.1 g, 1.2 eq) and diisopropylcarbodiimide (1.95 g, 3 eq) are successively added to a solution of 4-amino-3-{[2-(1,3-dioxolan-2-yl)ethyl]amino}-N,N-bis(3-methylbutyl)benzamide (2 g, 1 eq) in tetrahydrofuran (50 ml). The mixture is heated under reflux for 18 hours then cooled down to ambient temperature and concentrated under reduced pressure at 40° C. Water (100 ml) and dichloromethane (200 ml) are added to the residue obtained. After decantation and extractions, the combined organic phases are washed with salt water, dried over Na2SO4 then concentrated under reduced pressure at 40° C. Purification of the residue by flash chromatography on silica gel (eluent:heptane/ethyl acetate 4:6) produces the expected compound in the form of a white foam (1.8 g; 66% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>OS(O)(=O)=O>[NH2:1][C:2]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 25.1 %

Procedure:
2-Amino-5-methylpyridine (2.16 g, 20.0 mmol) was added into 10 mL of conc H2SO4 in portions at room temperature with stirring. To the resulting solution was added 70% (HNO3 2.0 mL, 31.5 mmol) at room temperature dropwise with stirring. The mixture was then stirred at 55° C. (bath) for 2 h, cooled to room temperature and poured into crushed ice (about 100 g). The mixture was basified to pH 9 in ice-water bath by the addition of 40% aq. NaOH dropwise and the mixture was extracted with CHCl3 (5×25 mL). The CHCl3 extracts were combined, washed with brine (20 mL), dried (MgSO4), and rota-evaporated to dryness to give 770 mg (25%) of 38 as a bright yellow powder, mp 175°-6° C. 1H NMR (CDCl3) δ 2.291 (s, 3H), 6.556 (bs, 2H), 8.219 (s, 1H), 8.237 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[Cl:24])=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:7][CH:8]=1
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Product: COc1ccc(-c2cc(Oc3ccc(Cl)cc3Cl)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (150 mg, 0.495 mmol) and 2,4-dichlorophenol were reacted as starting materials at 150° C. for 15 hours and post-treatment was then conducted, whereby the title compound was obtained as a colorless crystalline powder (195.5 mg, 93.9%). Melting point: 152.2-152.8° C. (ethyl acetate-hexane).
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@@H:16]([N:19]=[N+]=[N-])[CH2:15][C@H:14]2[CH2:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:9]1=[O:34])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[C:1]([O:5][C:6](=[O:35])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C@H:13]2[CH2:18][CH2:17][C@@H:16]([NH2:19])[CH2:15][C@H:14]2[CH2:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:9]1=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N=[N+]=[N-])CC[C@@H]2N2CC[C@H](NC(=O)OC(C)(C)C)C2=O)cc1
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: CO
Product: CSc1ccc(S(=O)(=O)C[C@@H]2C[C@H](N)CC[C@@H]2N2CC[C@H](NC(=O)OC(C)(C)C)C2=O)cc1
Yield: 149.4 %

Procedure:
{(3S)-1-[(1S,2R,4R)-4-Azido-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (350 mg), from the synthesis of Example 17 (analogous to 10f), was dissolved in MeOH (5 mL) prior to the addition of 5% Pd/BaSO4 (300 mg). A hydrogen balloon was added and the mixture was stirred. After stirring 1 h, the Pd/BaSO4 was filtered off and the solvent was concentrated to give {(3S)-1-[(1S,2R,4R)-4-amino-2-(4-methylsulfanyl-benzenesulfonylmethyl)-cyclohexyl]-2-oxo-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (497 mg). MS found: (M−H)−=496.5. (18b) A portion of the above material (341 mg) was dissolved in dichloroethane (5 mL) prior to the adddition of acetone (0.25 mL) and NaBH(OAc)3 (436 mg). After 2 h, the solution was concentrated. The resulting residue was dissolved in EtOAc and washed with saturated NaHCO3. The organic layer was dried, filtered, and concentrated. The resulting residue was dissolved in MeOH (2 mL) prior to the addition of 37% formaldehyde in water (0.1 mL). After 15 min, NaBH3CN (111 mg) was added. After 2 h, saturated NaHCO3 was added and some of the MeOH was removed. EtOAc was added and the organic layer was dried, filtered, and concentrated. This material was passed through a plug of silica and concentrated. This material (300 mg) was dissolved in CH2Cl2 (5 mL) prior to the addition of TFA (2.5 mL). After 30 min, it was concentrated and dried. A portion of the resulting residue (35 mg) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.02 mL) and 3-trifluoromethylphenyl isocyanate (0.013 mL). After 2 h, the solution was concentrated. Reverse phase HPLC purification (gradient elution, water/acetonitrile/TFA) of the resulting residue provided the title compound (7 mg). MS found: (M+H)+=641.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][NH2:15])[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:27]=[C:28]2[CH:34]=[C:33]([C:35](O)=[O:36])[NH:32][C:29]2=[CH:30][N:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][NH:15][C:35]([C:33]3[NH:32][C:29]4=[CH:30][N:31]=[C:26]([Cl:25])[CH:27]=[C:28]4[CH:34]=3)=[O:36])[O:10][CH2:11][CH2:12][O:13]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(CN)OCCO2)cc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2(CNC(=O)c3cc4cc(Cl)ncc4[nH]3)OCCO2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of [2-(4-methoxyphenyl)-[1,3]-dioxolan-2-yl]methylamine (Preparation 45, 0.117 g, 0.56 mmol) in dichloromethane (5 mL) was added DIPEA (213 μL, 1.22 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 0.100 g, 0.51 mmol) and HOBT (0.076 g, 0.56 mmol). The resulting solution was stirred for 2 min then EDCI (0.117 g, 0.61 mmol) was added and stirring was continued for 18 h at rt. The reaction mixture was partitioned between dichloromethane (30 mL) and water (20 mL) and the layers separated. The aqueous phase was extracted with dichloromethane (3×20 mL) then the combined organics were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Recrystallisation from methanol/dichloromethane gave the title compound as an orange solid. δH (CDCl3): 3.81 (3H, s), 3.84-3.91 (4H, m), 4.05 (2H, m), 6.56 (1H, t), 6.76 (1H, s), 6.89 (2H, d), 7.44 (2H, d), 7.57 (1H, s), 8.68 (1H, s), 9.94 (1H, br s).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]2[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1.[H-].[Na+]>CN(C)C=O>[CH2:21]([N:11]([C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][N:13]=1)[S:8]([C:5]1[CH:6]=[CH:7][C:2]([O:32][CH2:31][CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(F)cc1
Reactant: OCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)CN(c1ccc(C(C)C)cn1)S(=O)(=O)c1ccc(OCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.3 %

Procedure:
4-fluoro-N-isobutyl-N-(5-isopropylpyridin-2-yl)benzenesulfonamide (30 mg, 0.086 mmol) was dissolved in N,N-dimethylformamide (DMF) (3 mL) and to this solution was added (tetrahydro-2H-pyran-4-yl)methanol (12 mg, 0.10 mmol) and sodium hydride (2 mg, 0.10 mmol, 60% wt in mineral oil). The reaction was stirred under nitrogen for 2 hours at room temperature. The reaction was quenched then concentrated in vacuo and the crude product extracted to the organic phase of an aqueous work up between ethyl acetate and water. The organic phase was passed through a hydrophobic frit, concentrated in vacuo and purified by mass directed autoprep (formic acid modifier) to give the title compound (17 mg). LCMS (2 min, formic) Rt 1.41 min, m/z (ES+) 447 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].O=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.N1CCCC1>O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: O
Solvent: C1CCNC1
Product: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
A solution of 5-nitro-1H-indole (1 g, 6.17 mmol), tert-butyl 4-oxopiperidine-1-carboxylate (2.458 g, 12.33 mmol) and pyrrolidine (1.530 mL, 18.50 mmol) were refluxed for 48 hours. The reaction was brought to room temperature, diluted with water (50 mL) and product was extracted into ethyl acetate (2×50 mL). The combined ethyl acetate layer was washed with brine (15 mL) and dried (Na2SO4). Solvent was evaporated and crude was diluted with isopropanol: hexanes, 1:6 (20 mL). After stirring for 15 minutes, the solid was filtered off, washed with hexanes (2×10 mL), and dried to obtain tert-butyl 4-(5-nitro-1H-indol-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.515 g, 71.5%). 1H NMR (CDCl3) δ 8.83 (d, 1H, J=1.5 Hz), 8.60 (brs, 1H), 8.14 (dd, 1H, J=2.1, 9.0 Hz), 7.42 (d, 1H, J=9.0 Hz), 7.31 (d, 1H, J=2.1 Hz), 6.21 (s, 1H), 4.20-4.16 (m, 2H), 3.70 (t, 2H, J=5.7 Hz), 2.60-2.50 (m, 2H), 1.51 (s, 9H).