Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[NH:18][C:19](=[O:21])[CH3:20])[NH:11][C:10]=2[CH3:22])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O.Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>O>[C:19]([NH:18][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[C:9]([S:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)=[C:10]([CH3:22])[N:11]2[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1cccc2[nH]c(C)c(Sc3ccc(Cl)cc3)c12
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)Cn1c(C)c(Sc2ccc(Cl)cc2)c2c(NC(C)=O)cccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-4-yl]acetamide (1.0 g, 3.0 mmol), anhydrous potassium carbonate (0.63 g, 4.6 mmol), acetone (10 mL) and ethyl bromoacetate (0.50 mL, 4.5 mmol) was heated under reflux for 1.5 h then cooled to r.t. and left stirring at this temperature overnight. After heating under reflux for an additional 1 h, the mixture was cooled to r.t. Water (2×10 mL) was added, the solid product was collected by filtration, washed with water (10 mL), then dried in a vacuum oven at 40° C. to afford the title compound as an off-white solid; 1.16 g (92%); purity 95.4 area % by HPLC; m/z: 417/419 (MH+); 1H-NMR: 9.52 (1H, s), 7.45 (1H, d, J=7.9 Hz), 7.33 (1H, d, J=8.2 Hz), 7.29 (2H, d, J=8.6 Hz), 7.11 (1H, t, J=8.0 Hz), 6.97 (1H, d, J=8.6 Hz), 5.24 (2H, s), 4.18 (2H, q, J=7.1 Hz), 2.39 (3H, s), 1.86 (3H, s), 1.22 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])[CH3:2].O.NN>C(O)COCCO.C(O)C.S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])[CH3:2]
Reactant: CCOC(=O)CCCCCC(=O)Cc1ccc(C)cc1C
Agent: NN
Agent: O=S(=O)(O)O
Solvent: OCCOCCO
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCCCc1ccc(C)cc1C
Yield: 61.6 %

Procedure:
12.8 g of 8-(2,4-dimethylphenyl)-7-oxo-octanoic acid ethyl ester [obtained according to (d)] are reduced, analogously to the method described by Huisgen [R. Huisgen et al., Liebigs Ann. 586 (1954), 52] with hydrazine hydrate in diethylene glycol. The isolated reduction product, in 200 ml of ethanol and 5 ml of concentrated sulphuric acid, is heated at the reflux temperature overnight and, after customary working up, gives 7.5 g of 8-(2,4-dimethylphenyl)-octanoic acid ethyl ester as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[N:9]1[C:16]2[N:12]([N:13]=[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH:11]=[CH:10]1.[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[N:35]=1)[C:30](O)=[O:31])([CH3:26])([CH3:25])[CH3:24].[OH-].[Na+]>>[C:23]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([Cl:36])[N:35]=1)[C:30]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([CH3:1])=[C:3]([N:9]2[C:16]3[N:12]([N:13]=[C:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH:11]=[CH:10]2)[CH:4]=1)=[O:31])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(Cl)n1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)cc12
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc(NC(=O)c2cc(Cl)nc(C(C)(C)C)c2)cc1-n1ccn2nc(-c3cccnc3)cc12

Procedure:
50 mg (0.17 mmol) of the compound of Example 6A and 37 mg (0.17 mmol) of the compound of Example 43A were reacted analogously to the procedure of Example 15, except that here only 6 ml of 0.1 M aqueous sodium hydroxide solution (instead of 15 ml) were used for work-up. The product obtained was re-purified by preparative HPLC (column: Reprosil-Pur C18, 10 μm, 250 mm×30 mm; mobile phase: methanol/water with 0.05% TFA, with gradient). The product-containing fractions were combined and concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed successively with saturated potassium carbonate solution and saturated sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. Drying of the residue gave 44 mg (97% pure, 51% of theory) of the title compound.
Reaction SMILES: [CH3:1][NH:2][O:3][CH3:4].[N:5]1([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][N:11]=2)[CH:9]=[CH:8][CH:7]=[N:6]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:4][O:3][N:2]([CH3:1])[C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:10]([N:5]2[CH:9]=[CH:8][CH:7]=[N:6]2)=[N:11][CH:12]=1
Reactant: O=C(O)c1ccc(-n2cccn2)nc1
Reactant: CNOC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(-n2cccn2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,O-Dimethylhydroxylamine (1.03 g, 10.6 mmol) was added to an ambient temperature solution of 6-(1H-pyrazol-1-yl)nicotinic acid (2 g, 10.6 mmol), EDC (2.4 g, 12.7 mmol), HOBt (1.94 g, 12.7 mmol) and NMM (5.2 mL, 47.6 mmol) in methylene chloride (100 mL). After stirring at ambient temperature overnight, the reaction mixture was diluted with methylene chloride and washed successively with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane afforded N-methoxy-N-methyl-6-(1H-pyrazol-1-yl)nicotinamide.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([Cl:18])=[O:17])[CH2:9]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)(=[O:34])=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O1CCOCC1>CN(C=O)C>[ClH:18].[CH2:36]([NH:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([NH:19][C:16]([C@@H:10]3[CH:11]4[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]4)[CH2:9]3)=[O:17])=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)(=[O:34])=[O:33])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2ccc(S(=O)(=O)NCc3ccccc3)cc2)cc1)[C@H]1CN2CCC1CC2
Reaction time: 18 h

Procedure:
73.5 mg (0.60 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 74.5 mg (0.35 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 60 mg (0.18 mmol) of 4′-amino-N-benzylbiphenyl-4-sulfonamide (Example 10A) in 2.2 ml of a 10:1 mixture of dioxane and DMF. After 18 h at 100° C., a further 74.5 mg (0.35 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride are added. After a further 24 h at 100° C., the reaction mixture is concentrated in vacuo. The residue is dissolved in water and acetonitrile and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of a 2:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 64 mg (70.5% of theory) of the title compound are obtained.
Reaction SMILES: Cl[CH:2]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[S:5][C:4]=1[CH3:18].[NH2:25][C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=1.[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.CN(C)C(=O)C>[CH:19]1([CH:2]([NH:25][C:26]2[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=2)[C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[S:5][C:4]=2[CH3:18])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Cl)C1CCCCC1
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCO
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)O)cc1)C1CCCCC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a mixture of 3-[chloro(cyclohexyl)methyl]-2-methyl-5-[4-(trifluoromethyl)phenyl]thiophene (1.27 g) synthesized above, methyl 4-aminobenzoate (1.03 g), sodium iodide (1.02 g) and N,N-dimethylacetamide (25 mL) was added sodium carbonate (721 mg), and the mixture was stirred overnight at 100° C. under an argon atmosphere. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20% ethyl acetate/hexane) to give a pale-yellow oil. To a mixture of the obtained oil, tetrahydrofuran (20 mL) and ethanol (20 mL) was added 1N aqueous sodium hydroxide solution (20 mL), and the mixture was stirred with heated under reflux for 4 hr, and concentrated under reduced pressure. The residue was dissolved in water (40 mL), 1N hydrochloric acid (20 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (1.15 g, 71%) as a white solid.
Reaction SMILES: Cl[C:2]([O:4]CC)=[O:3].[C:7]1([CH:13]2[NH:17][N:16]=[CH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[OH-].[Na+:26]>C(Cl)(Cl)Cl.C(O)C>[C:7]1([CH:13]2[N:17]([C:2]([O-:4])=[O:3])[N:16]=[CH:15][CH2:14]2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[Na+:26]
Reactant: CCOC(=O)Cl
Reactant: C1=NNC(c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C([O-])N1N=CCC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl chloroformate (12 g) was added dropwise under ice cooling to a solution of 14.6 g 5-phenyl-2-pyrazoline and 12 g triethylamine in 100 ml chloroform, and the mixture was stirred at room temperature for three hours. The reaction mixture was washed with 3% hydrochloric acid and 3% aqueous solution of sodium bicarbonate in that order and then dried over anhydrous sodium sulfate. The solvent was distilled off from the dried solution, and the oily residue thus obtained (20 g) was dissolved in 80 ml ethanol. To this ethanolic solution, was added 10 ml of 40% aqueous solution of caustic soda, the mixture was stirred at room temperature for one hour, and the crystals which precipitated out were collected by filtration and dried under reduced pressure, affording 12 g of pure product. M.p.: 210° C. (dec.); NMR (D2O): 2.6-3.4 (2H, m), 4.7 (1H, dd, J=12,5 Hz), 7.14 (1H, t, J=2 Hz), 7.40 (5H, s).
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([C:9]1[N:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)[CH3:8].[NH2:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][C:24]=2[Br:30].O>C(Cl)Cl>[Br:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[N:22]=[CH:21][C:20]([NH:19][S:15]([C:12]1[CH:13]=[N:14][C:9]([CH2:7][CH3:8])=[CH:10][CH:11]=1)(=[O:17])=[O:16])=[CH:29]2
Reactant: Nc1cnc2c(Br)cccc2c1
Reactant: CCc1ccc(S(=O)(=O)Cl)cn1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCc1ccc(S(=O)(=O)Nc2cnc3c(Br)cccc3c2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
Pyridine (0.5 ml) and a solution of 6-ethyl-3-pyridinesulfonyl chloride (30 mg) in methylene chloride (0.5 ml) were added to 3-amino-8-bromoquinoline (18 mg, Preparation Example 5) at 0° C. After stirring at room temperature for 30 minutes, water was added thereto and the mixture was extracted with ethyl acetate. The extract was purified by preparative TLC (hexane-ethyl acetate=1:1), to give the title compound (20 mg).
Reaction SMILES: [S:1]([N:11]1[C:23]2[CH:22]=[CH:21][C:20](I)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[N:25]1[C:30]2[NH:31][C:32]3[C:37]([C:29]=2[CH:28]=[CH:27][CH:26]=1)=[CH:36][CH:35]=[CH:34][CH:33]=3.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(N)CCCCC1N>[Cu]I.C1(C)C=CC=C(C)C=1>[S:1]([N:11]1[C:23]2[CH:22]=[CH:21][C:20]([N:31]3[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:29]4[CH:28]=[CH:27][CH:26]=[N:25][C:30]3=4)=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)n2c3ccccc3c3cc(I)ccc32)cc1
Reactant: c1ccc2c(c1)[nH]c1ncccc12
Agent: [Cu]I
Agent: NC1CCCCC1N
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1cccc(C)c1
Product: Cc1ccc(S(=O)(=O)n2c3ccccc3c3cc(-n4c5ccccc5c5cccnc54)ccc32)cc1

Procedure:
The synthesis of N-tosyl-3-iodocarbazole is described in WO2009/086028. Into a 250 mL flask was added 9H-pyrido[2,3-b]indole (5 g, 29.7 mmol), N-tosyl-3-iodocarbazole (14.63 g, 32.7 mmol), copper(I) iodide (0.283 g, 1.486 mmol) and potassium phosphate (13.25 g, 62.4 mmol). It was degassed before the addition of anhydrous m-xylene (150 mL) and cyclohexane-1,2-diamine (0.339 g, 2.97 mmol). The resultant green suspension was refluxed for three days. Column chromatography on silica gel (eluent hexane/DCM 1:4, v/v) provided the product 9-(9-tosyl-carbazol-3-yl)-pyrido[2,3-b]indole (9.9 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[C:4]([N:14]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15]2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][N:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.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].CCOC(C)=O>[F:19][C:16]1([F:20])[CH2:17][CH2:18][N:14]([C:4]2[N:3]=[C:2]([NH:21][C:22]3[CH:27]=[C:26]([C:28]([F:30])([F:29])[F:31])[CH:25]=[CH:24][N:23]=3)[CH:7]=[C:6]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=2)[CH2:15]1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: FC1(F)CCN(c2cc(-c3cccnc3)cc(Cl)n2)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: FC1(F)CCN(c2cc(-c3cccnc3)cc(Nc3cc(C(F)(F)F)ccn3)n2)C1
Temperature: 180 °C

Procedure:
To a mixture of 2-chloro-6-(3,3-difluoropyrrolidin-1-yl)-4-(3-pyridyl)pyridine (2-b, 63 mg, 0.2131 mmol), 2-amino-4-(trifluoromethyl)PYRIDINE (70 mg, 2.0 equiv., 0.4261 mmol), XantPhos (25 mg, 0.20 equiv., 0.04261 mmol), Pd2(dba)3 (20 mg, 0.10 equiv., 0.02131 mmol) in 1,4-dioxane (2.4 mL, 130 equiv., 27.70 mmol) was added cesium carbonate (208 mg, 3.0 equiv., 0.6392 mmol), and the reaction was maintained at 180° C. for 90 min. The crude was diluted with water, and extraction was done with EtOAc. After evaporation of the organic layers, the crude was purified via silica gel chromatography (0-100% EtOAc/Heptane) to 60 mg (67% after two steps) brown solid. 1H NMR (400 MHz, CDCl3) δ (delta) 8.86 (s, 1H), 8.66 (d, J=4.8 Hz, 1H), 8.58 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 7.89 (d, J=7.9 Hz, 1H), 7.46 (s, 1H), 7.43-7.35 (m, 1H), 7.05 (d, J=5.2 Hz, 1H), 6.55 (s, 1H), 6.10 (s, 1H), 3.93 (t, J=13.1 Hz, 2H), 3.79 (t, J=7.3 Hz, 2H), 2.62-2.47 (m, 2H). LCMS: m/z 422 (M+H).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([NH:9][C:10]3[C:11]4[CH2:27][CH2:26][CH2:25][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][CH:19]([OH:21])[CH2:18][CH:17]4[C:22](O)=[O:23])[N:15]=3)[NH:6][N:5]=2)[CH2:3][CH2:2]1.[F:28][C:29]1[N:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH:1]1([C:4]2[NH:5][N:6]=[C:7]([NH:9][C:10]3[C:11]4[CH2:27][CH2:26][CH2:25][C:12]=4[N:13]=[C:14]([N:16]4[CH2:20][C@H:19]([OH:21])[CH2:18][C@H:17]4[C:22]([NH:35][C:32]4[CH:33]=[N:34][C:29]([F:28])=[CH:30][CH:31]=4)=[O:23])[N:15]=3)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: Nc1ccc(F)nc1
Reactant: O=C(O)C1CC(O)CN1c1nc2c(c(Nc3cc(C4CC4)n[nH]3)n1)CCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(F)nc1)[C@@H]1C[C@@H](O)CN1c1nc2c(c(Nc3cc(C4CC4)[nH]n3)n1)CCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 4 %

Procedure:
To a solution of 1-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-4-hydroxypyrrolidine-2-carboxylic acid (200 mg, 0.54 mmol) in DMF (3 mL) was added 6-fluoropyridin-3-amine (121 mg, 1.08 mmol), HATU (246 mg, 0.648 mmol) and DIPEA (0.16 mL, 0.864 mmol). The reaction mixture was allowed to stir at RT for 16 h. The reaction mixture was diluted with EtOAc (50 mL), washed with water (4×25 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under reduced pressure gave a crude product that was purified by reverse phase HPLC to afford (2S,4R)-1-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-N-(6-fluoropyridin-3-yl)-4-hydroxypyrrolidine-2-carboxamide (10 mg). Compound No. 10a: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.68 (m, 2H), 0.80-0.92 (m, 2H), 1.71-1.81 (m, 1H), 1.90-2.01 (m, 1H), 2.03-2.17 (m, 2H), 2.30-2.41 (m, 2H), 2.65-2.83 (m, 4H), 3.75-3.91 (m, 2H), 4.51-4.60 (m, 1H), 6.07 (s, 1H), 6.97 (d, 1H), 7.99 (s, 1H), 8.19 (s, 1H). Compound No. 10b: 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 0.60-0.68 (m, 2H), 0.80-0.92 (m, 2H), 1.71-1.81 (m, 1H), 1.90-2.01 (m, 1H), 2.03-2.17 (m, 2H), 2.30-2.41 (m, 2H), 2.65-2.83 (m, 4H), 3.75-3.91 (m, 2H), 4.51-4.60 (m, 1H), 6.07 (s, 1H), 6.97 (d, 1H), 7.99 (s, 1H), 8.19 (s, 1H). Separation by chiral HPLC provided additional diastereomers 10c and 10d.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)#[N:2].C(=O)([O-])[O-:20].[K+].[K+].OO>CS(C)=O.CCOC(C)=O>[CH3:18][C:15]([S:13]([NH:12][C@H:9]([C:7]1[CH:6]=[CH:5][N:4]=[C:3]([C:1]([NH2:2])=[O:20])[CH:8]=1)[CH2:10][CH3:11])=[O:14])([CH3:17])[CH3:16]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(C#N)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a chilled (10° C.) rapidly stirred solution of 2-methyl-propane-2-sulfinic acid [(S)-1-(2-cyano-pyridin-4-yl)-propyl]-amide (4.4 g, 16.58 mmol) in DMSO (70 mL) was added potassium carbonate (3 g, 21.72 mmol) portionwise followed by a 30% aqueous solution of hydrogen peroxide (6.16 mL, 54.38 mmol) dropwise. The reaction was stirred at room temperature for 3.5 hours. The reaction was cooled to 5° C., diluted with EtOAc (100 mL), quenched with 10% aqueous sodium thiosulfate solution (25 mL), and stirred for 1 hour. The organic layer was separated, and the aqueous layer was extracted with EtOAc (4×100 mL). The combined organic layers were washed with water (3×50 mL), brine (20 mL), dried over sodium sulfate, filtered and concentrated to afford 4-[(S)-1-(2-methyl-propane-2-sulfinylamino)-propyl]pyridine-2-carboxylic acid amide as a thick colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[C:10](I)=[C:6]2[N:5]=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:10]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])=[N:8][N:7]3[C:2]([C:16]4[CH:15]=[CH:14][C:13]([Cl:18])=[CH:12][CH:17]=4)=[CH:3][CH:4]=[N:5][C:6]=23)=[CH:22][CH:21]=1
Reactant: Clc1ccccc1-c1nn2c(Cl)ccnc2c1I
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1ccc(-c2c(-c3ccccc3Cl)nn3c(-c4ccc(Cl)cc4)ccnc23)cc1
Temperature: 72 °C

Procedure:
A mixture of 7-chloro-2-(2-chlorophenyl)-3-iodopyrazolo[1,5-a]pyrimidine (I-1A-1d; 50 mg, 0.13 mmol), 4-chlorophenylboronic acid (30 mg, 0.19 mmol), Na2CO3 (108 mg, 0.67 mmol), and tetrakis(triphenylphosphine)palladium (15 mg, 0.013 mmol) in ethanol (1 ml) and water (0.23 ml) was degassed (3×) by pulling a vacuum followed by refilling with nitrogen gas. The reaction was heated at 72° C. for 2 hr, cooled to room temperature, and then extracted from water with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo. Purification on a Chromatotron using 20% ethyl acetate in hexanes as eluant afforded compound 14A-1 (17 mg, 30%) as a solid: +ESI MS (M+1) 450.3; 1H NMR (400 MHz, CD2Cl2) δ 8.62 (d, J=4.1 Hz, 1H), 8.01 (d, J=8.7 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 7.51–7.36 (m, 6H), 7.28 (d, J=8.7 Hz, 2H), 7.04 (d, J=4.1 Hz, 1H).
Reaction SMILES: S(Cl)(Cl)=O.ClC1C=CC=CC=1OC(C)C(O)=O.ClC1C=CC=CC=1OC(C)C(Cl)=O.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[N:39]=[CH:38][N:37]=[C:36]2[O:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1.[Cl:53][C:54]1[CH:67]=[CH:66][CH:65]=[CH:64][C:55]=1[O:56][CH:57]([CH3:63])[C:58]([N:60]=[C:61]=[S:62])=[O:59]>C1(C)C=CC=CC=1.C(O)C>[Cl:53][C:54]1[CH:67]=[CH:66][CH:65]=[CH:64][C:55]=1[O:56][CH:57]([CH3:63])[C:58]([NH:60][C:61]([NH:50][C:49]1[CH:51]=[CH:52][C:46]([O:45][C:36]2[C:35]3[C:40](=[CH:41][C:42]([O:43][CH3:44])=[C:33]([O:32][CH3:31])[CH:34]=3)[N:39]=[CH:38][N:37]=2)=[CH:47][CH:48]=1)=[S:62])=[O:59]
Reactant: CC(Oc1ccccc1Cl)C(=O)N=C=S
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: CC(Oc1ccccc1Cl)C(=O)Cl
Agent: CC(Oc1ccccc1Cl)C(=O)O
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)C(C)Oc4ccccc4Cl)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2-(2-chlorophenoxy)propanoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2-(2-chlorophenoxy)propanoyl isothiocyanate was prepared using the resultant 2-(2-chlorophenoxy)propanoyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-(2-chlorophenoxy)propanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (45 mg, yield 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:21][CH2:22][CH2:23][OH:24])[CH:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]1[O:32]C(C)(C)O[C:28](=[O:29])[CH:27]=1>>[C:28]([O:24][CH2:23][CH2:22][CH2:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[N:11]=1)(=[O:29])[CH2:27][C:26]([CH3:25])=[O:32]
Reactant: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Reactant: CC1=CC(=O)OC(C)(C)O1
Product: COc1ccc(-n2nc(CCCOC(=O)CC(C)=O)cc2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
5-(4-Chlorophenyl)-3-(3-hydroxypropyl)-1-(4-methoxyphenyl) pyrazole (1.71 g, 0.005 moles) and 2,2,6-trimethyl-1,3-dioxen-4-one (0.71 g, 0.005 moles) were dissolved in 100 ml of xylenes. The solution was stirred under reflux for 16 hours. At that time, the solution was cooled to room temperature, and concentrated in vacuo to a yellow oil. The oil was flash chromatographed on silica gel to afford 59 (1.7 g, 80%) as a pale yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([N+:14]([O-])=O)[C:9]([N+:11]([O-])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:17]>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([NH2:14])[C:9]([NH2:11])=[CH:10][C:5]=2[N:4]=[C:3]1[CH3:17]
Reactant: Cc1nc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2n1C
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1nc2cc(N)c(N)cc2n1C
Yield: 95.7 %

Procedure:
Pure 1,2-dimethyl 5,6-dinitro benzimidazole (0.7 grams) and 0.2 grams Pd/C in 20 ml ethanol and 20 ml glacial acetic acid were hydrogenated for 4 hours. Filtering and evaporating resulted in 0.5 grams, 95% yield of a white solid having a melting point of 212° C.