Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[OH:11][C:12]1[CH:25]=[CH:24][C:15]2[C:16]([C:20]([O:22][CH3:23])=[O:21])=[C:17]([CH3:19])[O:18][C:14]=2[CH:13]=1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:19][C:17]1[O:18][C:14]2[CH:13]=[C:12]([O:11][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[CH:9][S:10][C:3]=34)[CH:25]=[CH:24][C:15]=2[C:16]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: Clc1ccnc2ccsc12
Reactant: COC(=O)c1c(C)oc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1c(C)oc2cc(Oc3ccnc4ccsc34)ccc12

Procedure:
This material was prepared by the reaction of 7-chloro-thieno[3,2-b]pyridine with methyl 6-hydroxy-2-methylbenzofuran-3-carboxylate 89c and Cs2CO3 in a manner as previously described. 1H NMR (CDCl3) δ 8.48 (1H,d, J=5.3 Hz), 7.99 (1H, d, J=8.3 Hz), 7.74 (1H, d, J=5.6 Hz), 7.56 (1H, d, J=5.3 Hz), 7.29 (1H, d, J=2.0 Hz), 7.16 (1H, dd, J=8.6, 2.3 Hz), 6.53 (1H, d, J=5.3 Hz), 3.96 (3H, s), 2.79 (3H, s).
Reaction SMILES: N[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1.C(O)(=O)C.[BrH:27].N([O-])=O.[Na+]>O>[Br:27][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)[CH:3]=1
Reactant: CCOC(=O)c1ccc(N)cc1-c1ccc(OC)c(OC)c1
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1ccc(Br)cc1-c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
Ethyl 4-amino-2-(3,4-dimethoxyphenyl)benzoate (20.0 g; 0.066 mole; compound 252) and acetic acid (200 ml) are introduced into a 1000 ml three-necked flask. After dissolution, 47% strength hydrobromic acid (60 ml) is added, the mixture is cooled to 0° C. and then distilled water (150 ml) is added. Sodium nitrite (4.6 g; 0.066 mole) dissolved in water (30 ml) is poured in. Stirring is continued at between 0° and 5° C. for one hour, then the mixture is poured onto a solution of cuprous bromide (9.5 g; 0.066 mole) in 47% strength hydrobromic acid (100 ml). The reaction mixture is heated to 65% for one hour, the poured into water. The precipitate formed is filtered, rinsed with water and then dried in the air. Ethyl 4-bromo-2-(3,4-dimethoxyphenyl)benzoate (18.4 g; yield: 76.3%) is thus obtained, m.p. 53° C. (compound 250).
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3](=[O:8])[C:4](Cl)=[N:5][OH:6].[CH2:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])O.[K+]>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:9])[C:3]([C:4]1[CH2:10][CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:6][N:5]=1)=[O:8]
Reactant: CN(C)C(=O)C(Cl)=NO
Reactant: C=Cc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)C1=NOC(c2ccccc2)C1
Reaction time: 0.17 h

Procedure:
To a solution of 2-(dimethylamino)-N-hydroxy-2-oxoethanimidoyl chloride (prepared according to the procedure of E. Raleigh, U.S. Pat. No. 3,557,089) (6.0 g, 40 mmol) and styrene (6.0 g, 60 mmol) in toluene (15 mL) was added a solution of potassium hydrogen carbonate (5.0 g, 50 mmol) in water (25 mL) over 1 h, while keeping the reaction temperature between 7 and 10° C. The reaction mixture was diluted with 10 mL of toluene and stirred for an additional 10 minutes. The organic layer was separated and washed with water. The organic layer was concentrated under reduced pressure until no styrene remained to give 8.7 g of the title compound as a light yellow oil. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[Br:6][C:7]([Br:12])([Br:11])[C:8](O)=[O:9].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:5][C:8](=[O:9])[C:7]([Br:12])([Br:11])[Br:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO
Reactant: O=C(O)C(Br)(Br)Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCCOC(=O)C(Br)(Br)Br

Procedure:
n-Butanol (7.4 g) and tribromoacetic acid (29.6 g) were dissolved in toluene (100 ml). p-Toluenesulfonic acid (0.7 g) was added, and the solution was heated under reflux in a Dean and Stark apparatus. After 90 minutes water (2 ml) had been collected. The solvent was spun off on a rotary evaporator and the residue was distilled under water pump vacuum, collecting the fraction boiling between 120°-130° C. The fraction was redistilled yielding a colorless oil b.p. 128° C./15-18 mm (31 g).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[O:10]=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[N:12]1[CH:21]([CH3:34])[CH2:22]OS(C1C=CC(C)=CC=1)(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:34][CH:21]([N:12]2[C:13](=[O:20])[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]2=[O:10])[CH3:22])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1cnc(F)cc1I
Reactant: Cc1ccc(S(=O)(=O)OCC(C)N2C(=O)c3ccccc3C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(COc1cnc(F)cc1I)N1C(=O)c2ccccc2C1=O
Yield: 42.8 %

Procedure:
Heat a mixture of 6-fluoro-4-iodo-pyridin-3-ol (150 mg, 0.63 mmol), toluene-4-sulfonic acid 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl ester (226 mg, 0.63 mmol), cesium carbonate (206 mg, 0.63 mmol) in DMF (2 mL) at 100° C. for 5 h. Cool the mixture and add water. Extract with ethyl acetate. Wash the organic layer with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo to a light yellow solid. Purify by column chromatography (hexane to 10% ethyl acetate in hexane) to afford the title compound as a white solid (115 mg, 43%). MS (ES) m/z 427 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:24](O)=[O:25])=[N:22][CH:23]=1)#[N:17]>>[C:16]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8]([CH2:12][OH:13])=[C:7]([CH3:14])[C:6]=3[CH:15]=2)=[O:25])=[N:22][CH:23]=1)#[N:17]
Reactant: CC1=C(CO)CCCc2ccc(N)cc21
Reactant: N#Cc1ccc(C(=O)O)nc1
Product: CC1=C(CO)CCCc2ccc(NC(=O)c3ccc(C#N)cn3)cc21

Procedure:
In a manner similar to the procedure of step 3A, (E)-(2-amino-9-methyl-6,7-dihydro-5H-benzo[7]annulen-8-yl)methanol from preparation J was coupled with 5-cyanopicolinic acid to afford the titled compound of Step 44A. 1H NMR (500 HMz, chloroform-d) δ 9.84 (s, 1H), 8.90 (dd, J=2.0, 0.8 Hz, 1H), 8.45 (dd, J=8.1, 0.8 Hz, 1H), 8.21 (dd, J=8.1, 2.0 Hz, 1H), 7.68 (d, J=2.3 Hz, 1H), 7.56 (dd, J=8.1, 2.3 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 4.41 (s, 2H), 2.56 (t, J=7.0 Hz, 2H), 2.16 (s, 3H), 2.12 (quin, J=7.1 Hz, 2H), 2.02-1.96 (m, 2H), 1.57 (br. s., 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH2:15][C@H:14]3[C@H:11]([NH:12][CH2:13]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[C:19]([C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([N:9]2[CH2:16][CH2:15][C@H:14]3[C@H:11]([N:12]([C:21]([C:20]4[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[C:19]=4[C:27]4[N:28]=[CH:29][CH:30]=[CH:31][N:32]=4)=[O:22])[CH2:13]3)[CH2:10]2)[N:5]=1
Reactant: O=C(O)c1cccc(F)c1-c1ncccn1
Reactant: Cc1cc(C)nc(N2CC[C@@H]3CN[C@@H]3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(C)nc(N2CC[C@@H]3CN(C(=O)c4cccc(F)c4-c4ncccn4)[C@@H]3C2)n1
Yield: 38.2 %

Procedure:
To a mixture of (1S,6R)-3-(4,6-dimethylpyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 34, 30 mg, 0.14 mmol), 3-fluoro-2-(pyrimidin-2-yl)benzoic acid (Intermediate 35, 30 mg, 0.14 mmol), and TEA (29 μL, 0.21 mmol) in DMF (1.3 mL) was added HATU (58 mg, 0.15 mmol) After 15 h, the reaction mixture was purified using prep HPLC (agilent, basic) to give 22.4 mg (39%) of the title compound as a clear oil. MS (ESI) mass calcd. For C23H23FN6O, 418.48; m/z found 419.2 [M+H]+. 1H NMR (CDCl3): 8.89-8.57 (m, 2H), 7.50-7.32 (m, 1H), 7.28-7.04 (m, 3H), 6.37-6.23 (m, 1H), 4.76-4.50 (m, 2H), 4.15-3.45 (m, 4H), 3.25-2.73 (m, 2H), 2.43-2.24 (m, 6H), 2.20-1.69 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH:8]=[CH:9][S:10][C:5]2=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[Li]CCCC.[Cl:23]N1C(=O)CCC1=O.[NH4+].[Cl-]>C1COCC1>[Cl:23][C:9]1[S:10][C:5]2[C:6](=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2sccc2n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1ccc2sc(Cl)cc2n1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
To a solution 5-methylthieno[3,2-b]pyridine (3.60 g, 24 mmol) and N,N-diisopropylamine (100 uL) in THF (80 mL) at -78° C. was added dropwise 16 mL of n-BuLi (1.6M, 25.6 mmol). The mixture was stirred at -78° C. for 20 min and then transfered via a cannula to a solution of N-chlorosuccinimide (4.5 g, 34 mmol) in THF (300 mL) at -10° C. The mixture was stirred at -10° C. for 30 min. Saturated NH4Cl solution was then added and the product was extracted with EtOAc, dried over MgSO4, and concentrated to an oil. Chromatography of the crude oil on silica gel (eluted with 15% EtOAc in hexane) yielded 3.60 g (81%) of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([Cl:10])[C:7]([N+:11]([O-:13])=[O:12])=[C:6](Cl)[CH:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([NH:29][C:6]1[CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=[C:8]([Cl:10])[C:7]=1[N+:11]([O-:13])=[O:12])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)cc(C2CC2)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(NCc2ccccc2)cc(C2CC2)nc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.1 %

Procedure:
6-Cyclopropyl-2,4-dichloro-3-nitro-pyridine (160 mg, 0.8 mmol) was dissolved in THF (2 mL) and triethylamine (104□l, 0.8 mmol) and benzylamine (81□l, 0.8 mmol) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 48 hours by which time a yellow precipitate had formed. The volatiles were removed in vacuo and the residue was stored in a stoppered flask at room temperature for 10 days. The residue was purified by column chromatography on silica gel eluting with 99:1 DCM:MeOH then 98:2 DCM:MeOH to give the title compound (185 mg) as a yellow crystalline solid.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].Cl.[CH:8]1([C:11]2[C:12]([N:31]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][CH2:43][B:44]4[O:48]C(C)(C)C(C)(C)[O:45]4)[CH:37]=3)[S:32]([CH3:35])(=[O:34])=[O:33])=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:16]([C:26]([NH:28][CH3:29])=[O:27])[C:15]=3[CH:30]=2)[CH2:10][CH2:9]1>C1COCC1.CCOC(C)=O>[CH:8]1([C:11]2[C:12]([N:31]([C:36]3[CH:37]=[C:38]([CH:39]=[CH:40][CH:41]=3)[CH2:42][CH2:43][B:44]([OH:48])[OH:45])[S:32]([CH3:35])(=[O:33])=[O:34])=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[C:16]([C:26](=[O:27])[NH:28][CH3:29])[C:15]=3[CH:30]=2)[CH2:10][CH2:9]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(CCB4OC(C)(C)C(C)(C)O4)c3)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cccc(CCB(O)O)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 33.6 %

Procedure:
Sodium periodate (380 mg, 1.78 mmol) and 1N aqueous HCl (1.5 mL, 1.5 mmol) were added to a cold (0° C.) solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)ethyl)phenyl)methylsulfonamido)benzofuran-3-carboxamide (75 mg, 0.119 mmol) in THF (3 mL). The mixture was stirred at 0° C. for 10 min then warmed to room temperature. After one hour, the reaction mixture was diluted with EtOAc and the organic layer was separated and washed with 5% aqueous sodium thiosulfate and brine and dried over sodium sulfate. The solvent was evaporated and the residue was subjected to reverse phase HPLC (C18, acetonitrile:water with 0.1% formic acid) to give the title compound (22 mg, 34%) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 8.42-8.53 (m, 1H) 8.06-8.13 (m, 1H) 7.92-8.02 (m, 2H) 7.55 (s, 2H) 7.34-7.46 (m, 3H) 7.24-7.30 (m, 2H) 7.14-7.18 (m, 1H) 7.04-7.11 (m, 1H) 2.83 (d, J=4.68 Hz, 3H) 2.58-2.67 (m, 2H) 2.48-2.55 (m, 3H) 2.15-2.31 (m, 1H) 0.94-1.11 (m, 1H) 0.75-0.94 (m, 4H) 0.47 (m, 1H). LCMS (m/z, ES+)=551 (M+H+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:33][CH2:32][N:7]2[C:8]3[C:13]([C:14]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH3:29])[CH:21]=4)=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl.C(=O)([O-])O.[Na+]>[C:34]([NH:2][CH2:3][CH:4]1[CH2:33][CH2:32][N:7]2[C:8]3[C:13]([C:14]([C:15]4[C:16](=[O:31])[NH:17][C:18](=[O:30])[C:19]=4[C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[N:22]([CH3:29])[CH:21]=4)=[C:6]2[CH2:5]1)=[CH:12][CH:11]=[CH:10][CH:9]=3)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CN)C4)C(=O)NC2=O)c2ccccc21
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1cc(C2=C(c3c4n(c5ccccc35)CCC(CNC(=O)c3ccccc3)C4)C(=O)NC2=O)c2ccccc21
Reaction time: 17 h

Procedure:
250 mg of the pyrroledione product of Example 2 were stirred in a mixture of 25 ml of dichloromethane and 15 ml of 5% aqueous sodium hydrogen carbonate. The mixture was treated with 1 ml of benzoyl chloride and stirred for 17 hours. The phases were separated and the organic phase was dried and evaporated. Chromatography of the residue on silica gel with methanol/dichloromethane (7:93) followed by trituration with n-hexane gave 220 mg of 3-[8-(benzamidomethyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione of melting point 297°-303° C.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][OH:30])[N:23]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:20])[C:8]([NH:21][C:22]2[CH:26]=[CH:25][N:24]([CH2:27][CH2:28][CH2:29][OH:30])[N:23]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Reactant: Nc1ccn(CCCO)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccn(CCCO)n1)[C@H](CC1CCCC1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.4 %

Procedure:
To a solution of (S)-3-cyclopentyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared as in Example 9, 80 mg, 0.29 mmol) and 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared as in US 20080021032, Example 23, 49 mg, 0.35 mmol) and benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Chemimpex, 0.15 g, 0.35 mmol) in methylene chloride (8 mL) was added N,N-diisopropylethylamine (0.15 mL, 0.88 mmol) dropwise and the resulting solution stirred at room temperature for 4 h. The solution was diluted with methylene chloride, washed with a 1 N hydrochloric acid solution (25 mL), a saturated sodium bicarbonate solution (25 mL) dried over magnesium sulfate. The mixture was filtered and evaporated and the resulting material purified via automated flash chromatography (Analogix, SF4-12 g column, 50-70% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide (28 mg, 24%) as an off white solid: HR-ES(+) m/e calcd for C22H28N4O3 [M+H]+ 397.2234, observed 397.2233; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.94-2.34 (m, 7H), 4.04 (t, J=6.79 Hz, 3H), 4.37-5.28 (m, 6H), 6.39 (s, 2H), 7.31-7.90 (m, 8H), 10.86 (s, 2H).
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][C:9]2[C:13](=[O:20])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:7]3[C:8]=2[C:3]=1[CH2:4][CH2:5][N:6]3[CH3:21].[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C1CCN2C(=NCCC2)CC1>CN(C)C=O>[N:22]1([C:2]2[C:11]([F:12])=[CH:10][C:9]3[C:13](=[O:20])[C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:15][N:7]4[C:8]=3[C:3]=2[CH2:4][CH2:5][N:6]4[CH3:21])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCNC1
Reactant: COC(=O)c1cn2c3c(c(F)c(F)cc3c1=O)CCN2C
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cn2c3c(c(N4CCCC4)c(F)cc3c1=O)CCN2C
Temperature: 80 °C
Yield: 75.9 %

Procedure:
2.92 g of the compound (6) obtained in Example 2 (1), 1.07 g of pyrrolidine and 2.25 g of 1,8-diazabicyclo[5.4.0]-7-undecene were added to 20 ml of N,N-dimethylformamide, and the solution was heated at 80° C. for 12 hours. The solvent was removed by distillation, and 100 ml of chloroform was added to the residue. After washing with water, the organic layer was separated from the solution. After drying over magnesium sulfate, the solvent was removed by distillation. To the residue, 50 ml of isopropyl ether was added, and the solid was filtered to obtain 2.60 g of the subject compound (122).
Reaction SMILES: C(O[C:6](=[O:15])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH3:14])[CH:8]=1)CCC.Cl.[CH3:17][NH:18][O:19][CH3:20].C([Mg]Cl)(C)C>C1COCC1>[CH3:20][O:19][N:18]([CH3:17])[C:6](=[O:15])[C:7]1[CH:8]=[C:9]([CH3:14])[N:10]=[C:11]([CH3:13])[CH:12]=1
Reactant: CNOC
Reactant: CCCCOC(=O)c1cc(C)nc(C)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(C)nc(C)c1
Temperature: -20 °C
Reaction time: 2.5 h
Yield: 90.3 %

Procedure:
Under argon a suspension of 2,6-dimethyl-isonicotinic acid butyl ester (16.67 g) and N,O-dimethylhydroxylamine hydrochloride (12.2 g) in THF (150 mL) was cooled down to −20° C. A solution of isopropylmagnesium chloride (2M in THF, 120.6 mL) was added over 20 min maintaining the temperature below −5° C. The mixture was stirred for 2.5 hours at −10° C. and quenched with a saturated aqueous solution of NH4Cl (200 mL). The phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Column chromatography on silica gel (EtOAc/n-heptane 2:1 to EtOAc) yielded the title compound (14.1 g, 90%) as a yellow liquid, MS (ESI+): m/z=195.0 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3](=[O:12])[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[SH:13][CH2:14][CH2:15][OH:16].C(N(CC)CC)C>C(Cl)(Cl)Cl>[OH:16][CH2:15][CH2:14][S:13][CH2:2][C:3](=[O:12])[C:4](=[N:10][OH:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: OCCS
Reactant: CCOC(=O)C(=NO)C(=O)CCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=NO)C(=O)CSCCO
Temperature: 20 °C
Reaction time: 15 h

Procedure:
Ethyl 4-chloro-2-hydroxyimino-3-oxo-butyrate (340 g.) is dissolved in chloroform (1.5 liters) and 2-mercapto-ethanol (126 cc.) is then added. Triethylamine (248 cc.) dissolved in chloroform (1 liter) is added to the resulting solution at about 20° C., over the course of 30 minutes. The reagents are left in contact for 15 hours whilst stirring at about 20° C. Then the reaction mixture is washed with water (200 cc.) followed by 2 N hydrochloric acid (200 cc.) and finally four times with water (a total of 1 liter). The organic phase is dried over sodium sulphate treated with decolourising charcoal, filtered and concentrated to dryness under reduced pressure (20 mm.Hg). Ethyl 4-(2-hydroxy-ethylthio)-2-hydroxyimino-3-oxo-butyrate (321 g.) is thus obtained in the form of an oil which gradually solidifies.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:15]3=[N:16][C:17]([Sn](C)(C)C)=[CH:18][N:19]=[C:14]3[NH:13][CH2:12][C:11]2=[O:24])[CH2:5][CH2:4]1.Br[C:26]1[C:27]([CH3:34])=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=1.C(N(CC)CC)C.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[CH3:1][O:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][N:10]2[C:11](=[O:24])[CH2:12][NH:13][C:14]3[N:19]=[CH:18][C:17]([C:26]4[C:27]([CH3:34])=[CH:28][C:29]([C:32]#[N:33])=[N:30][CH:31]=4)=[N:16][C:15]2=3)[CH2:5][CH2:4]1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc([Sn](C)(C)C)nc32)CC1
Reactant: Cc1cc(C#N)ncc1Br
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C#N)cc4C)nc32)CC1
Temperature: 100 °C

Procedure:
1-(((trans)-4-Methoxycyclohexyl)methyl)-7-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.721 g, 1.64 mmol), 5-bromo-4-methylpicolinonitrile (0.323 g, 1.64 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.150 g, 0.164 mmol), triethylamine (0.687 mL, 4.93 mmol), tri-ortho-toylphosphine (0.100 g, 0.328 mmol) and dimethylformamide (8 mL) were combined in a sealed reaction vessel. Nitrogen was bubbled through the reaction for 5 min and reaction was heated at 100° C. for 3 h. Reaction is filtered, concentrated and purified by silica gel column chromatography (0-80% ethyl acetate in hexanes). Fractions were combined and concentrated to afford the crude title compound used directly for next step (0.607 g, 1.55 mmol, 94% yield). MS (ESI) m/z 393.5 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[CH2:23]([NH2:26])[C:24]#[CH:25]>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:26][CH2:23][C:24]#[CH:25])=[O:11])[CH2:7]1
Reactant: O=C(Cl)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reactant: C#CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C#CCNC(=O)N1CC(Oc2ccc(Cl)c(Cl)c2)C1
Reaction time: 18 h
Yield: 83.2 %

Procedure:
A stirred mixture of 5.6 g (0.02 mole) of 3-(3,4-dichlorophenoxy)-1-azetidinecarbonyl chloride and 3 g (0.02 mole) of potassium carbonate in 20 ml of tetrahydrofuran was treated with 1.1 g (0.02 mole) of 2-propynylamine added dropwise from a needle syringe then stirred for an additional 18 hr. The reaction mixture was diluted with 200 ml of water and the resulting solid collected by filtration to yield 7.1 g of crude product. Recrystallization from isopropyl ether yielded 4.98 g (83.2%) of pale beige crystals, m.p. 119°-121° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].O>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])[N:17]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)CCCCl
Reactant: CC(C)(C)c1cc(-c2n[nH]c3ncccc23)cc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1cc(-c2nn(CCCC(=O)O)c3ncccc23)cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 21 h
Yield: 67.6 %

Procedure:
To a solution of 9.7 g of the compound of Example 1 in 70 ml of dimethylformamide are added 5.5 g of potassium carbonate and 6 g of ethyl 4-chlorobutyrate, and the mixture is stirred at 60° C. for 21 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated. To a solution of the residue in 100 ml of 80 % methanol is added 3 g of potassium hydroxide, and the mixture is stirred at room temperature for two hours. After completion of the reaction, the methanol is distilled off under reduced pressure and the residue is dissolved into water and the aqueous solution is acidified with dilute hydrochloric acid. The precipitated crystals are collected by filtration and then recrystallizing from ethanol to give 8.3 g of 4-[3-(3,5-di-tertiary butyl-4-hydroxyphenyl)-1H-pyrazolo[3,4-b]pyridin-1-yl]butyric acid as pale yellow crystals, melting at 192°-194° C.