Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[N:7]2.[F:18][C:19]1[CH:24]=[CH:23][C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][C:20]=1[C:34]1[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:3]3[C:8](=[N:7][C:6]([C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:21][C:20]=1[C:34]1[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: Clc1ccnc2nc(-c3cccnc3)ccc12
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: N#Cc1ccccc1-c1cc(-c2ccnc3nc(-c4cccnc4)ccc23)ccc1F
Yield: 88 %

Procedure:
This was prepared in 88% yield from 5-chloro-2-(pyridin-3-yl)-[1,8]naphthyridine (from step a) and 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (from Example 2, step e) using a similar procedure to that described in Example 55, step a. δH (400 MHz, CDCl3) 7.44-7.52 (3H, m), 7.55 (1H, td, J 7.4, 1.2), 7.61-7.65 (3H, m), 7.71 (1H, td, J 7.4, 1.2), 7.85 (1H, dd, J 7.8, 1.2), 8.06 (1H, d, J 9.0), 8.59 (1H, d, J 8.6), 8.71-8.75 (2H, m), 9.20 (1H, d, J 4.7), 9.46 (1H, d, J 1.6). m/z (ES+) 403 [MH]+.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:23]1[CH:24]=[C:25]([C:28]([F:29])([F:31])[F:30])[CH:26]=[CH:27][C:22]=1[O:21][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([CH3:20])[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: OB(O)c1ccccc1F
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-c2ccccc2F)c1

Procedure:
The tile compound is prepared by reacting 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-fluorobenzene boronic acid as in Example 38 to afford 0.216 g (88%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C30H25O4F4 525.1689, found 525.1675.
Reaction SMILES: [CH2:1]([N:4]([CH2:13][CH2:14][CH3:15])[C:5](/[CH:7]=[C:8](\[CH3:12])/[C:9]([OH:11])=O)=[O:6])[CH2:2][CH3:3].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:38]([O:42][C:43]([N:45]1[C@@H:50]([C@@H:51]([OH:63])[C@@H:52]([NH2:62])[CH2:53][C:54]2[CH:59]=[C:58]([F:60])[CH:57]=[C:56]([F:61])[CH:55]=2)[CH2:49][O:48][C@@H:47]([CH2:64][O:65][CH:66]2[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]2)[CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>ClCCl>[C:38]([O:42][C:43]([N:45]1[C@@H:50]([C@@H:51]([OH:63])[C@@H:52]([NH:62][C:9](=[O:11])/[C:8](/[CH3:12])=[CH:7]/[C:5](=[O:6])[N:4]([CH2:1][CH2:2][CH3:3])[CH2:13][CH2:14][CH3:15])[CH2:53][C:54]2[CH:59]=[C:58]([F:60])[CH:57]=[C:56]([F:61])[CH:55]=2)[CH2:49][O:48][C@@H:47]([CH2:64][O:65][CH:66]2[CH2:71][CH2:70][CH2:69][CH2:68][CH2:67]2)[CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1C[C@H](COC2CCCCC2)OC[C@@H]1[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Reactant: CCCN(CCC)C(=O)/C=C(\C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCN(CCC)C(=O)/C=C(\C)C(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](COC2CCCCC2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
Dissolve (E)-3-dipropylcarbamoyl-2-methylacrylic acid (0.029 g, 0.134 mmol) in dichloromethane (1.3 mL). Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (0.028 g, 0.148 mmol) then 1-hydroxybenzotriazole (HOBT) (0.023 g, 0.148 mmol). Stir at room temperature for 30 minutes. To this stirring solution add (2R,5R)-5-[(1S,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-cyclohexyloxymethylmorpholine-4-carboxylic acid tert-butyl ester (0.065 g, 0.134 mmol) in dichloromethane (1.5 mL). Stir for 2.5 hours, quench with 10% aqueous potassium carbonate (20 mL), and dilute with dichloromethane (75 mL). Extract the organic layer, wash with 5% aqueous citric acid (25 mL), saturated aqueous sodium chloride (30 mL), dry (magnesium sulfate) and purify (silica gel chromatography, eluting with 30:70 to 70:30 ethyl acetate:hexanes) to give the title compound as a white foam (0.041 g, 45.2%).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6](=[O:22])/[C:7](=[CH:9]/[C:10]3[C:18]4[C:13](=[CH:14][C:15]([N+:19]([O-])=O)=[CH:16][CH:17]=4)[NH:12][CH:11]=3)/[O:8][C:4]=2[C:3]=1[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.[H][H]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[NH2:19][C:15]1[CH:14]=[C:13]2[C:18]([C:10](/[CH:9]=[C:7]3\[O:8][C:4]4[C:3]([CH2:25][N:26]5[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:37])([CH3:36])[CH3:38])=[O:33])[CH2:30][CH2:31]5)=[C:2]([OH:1])[CH:24]=[CH:23][C:5]=4[C:6]\3=[O:22])=[CH:11][NH:12]2)=[CH:17][CH:16]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cc([N+](=O)[O-])ccc24)C3=O)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4cc(N)ccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.7 %

Procedure:
A solution of tert-butyl (Z)-4-({6-hydroxy-2-[(6-nitro-1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.025 g, 0.048 mmol) obtained in Example A24, Step 2 in ethanol (2.0 mL) was added with Lindlar's catalyst (0.010 mg) under an argon atmosphere, and then the inside of the reaction vessel was replaced with hydrogen. The reaction mixture was stirred at room temperature for 5 hours, and then filtered through Celite, and the solvent was evaporated under reduced pressure to obtain tert-butyl (Z)-4-({2-[(6-amino-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.023 g, 97%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:27])[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH2:28](O)[CH2:29][OH:30].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:30][CH2:29][CH2:28][O:27]2)[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[CH2:13][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(CCC1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(F)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CCC(CCC2(c3ccc(F)cc3)OCCO2)CC1
Reaction time: 1 h
Yield: 84 %

Procedure:
A solution of 71 mg (0.19 mmol) of 4-(3-(4-fluorophenyl)-3-oxo-propyl)-1-(benzyloxycarbonyl) piperidine (from EXAMPLE 189, Step B), 0.05 mL (0.9 mmol) of ethylene glycol and 5 mg (0.26 mmol) of p-toluene sulfonic acid x H2O in 3 mL of toluene was heated at 80° C. After 1 h, and additional 5 mg of p-toluene sulfonic acid×H2O was added and the resulting mixture was heated at reflux. After 2 h, the mixture was cooled and partitioned between 30 mL of ether and 10 mL of 1.0 N NaOH. The organic layer was separated, dried and concentrated. Flash chromatography on 4 g of silica gel using 3:1 v/v hexanes/ether afforded 66 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 1.00-1.10 (m, 2H), 1.261.36 (3H), 1.50-1.60 (m, 2H), 1.86-1.89 (m, 2H), 2.65-2.75 (m, 2H), 3.71-3.78 (m, 2H), 3.96-4.03 (m, 2H), 4.064.16 (m, 2H), 5.10 (s, 2H), 6.99-7.04 (m, 2H), 7.26-7.40 (7H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:14]([C:4]1[CH:5]=[N:6][C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([CH3:1])[CH:3]=1)[CH3:15])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(OCC(F)(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1OCC(F)(F)F
Yield: 79 %

Procedure:
The title compound is prepared in 79% yield (1.70 g, colorless oil) from 1-(5-methyl-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethanone (1.47 g, 6.32 mmol, Step-3) and (R)-2-methylpropane-2-sulfinamide in a similar manner to Step-4 of Amine-1.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:18]([F:21])([F:20])[F:19])[CH2:14][CH2:15][CH2:16][CH3:17])(=O)=O)=CC=1.[OH:23][C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.[H-].[Na+]>CN(C)C=O>[F:19][C:18]([F:20])([F:21])[CH:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH2:11][O:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:33][CH:34]=1
Reactant: CCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Reaction time: 8 h
Yield: 87.5 %

Procedure:
In a round-bottomed flask, 0.88 g of the 3-trifluoromethylheptyl p-toluenesulfonate 2, 0.4 g of ethyl p-hydroxybenzoate and 1 ml of dimethylformamide were placed, and 50 mg of sodium hydride was added thereto, followed by 8 hours of heat-refluxing and 15 hours of standing at room temperature. After the reaction, dimethylformamide was distilled off, and dilute hydrochloric acid was added to the product, which was then extracted with methylene chloride. The resultant organic layer was washed with water and dried with magnesium sulfate, followed by distilling-off of the solvent and purification by thin layer chromatography (developer: methylene chloride/ hexane=1/1) to obtain 0.7 g of ethyl p-(3-trifluoromethylheptyloxy)benzoate 3. (Yield: 80%)
Reaction SMILES: Br[CH2:2][C@@H:3]([OH:9])[CH2:4][C:5]([O:7][CH3:8])=[O:6].[I-:10].[Na+]>C(C(C)=O)C>[OH:9][C@H:3]([CH2:2][I:10])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C[C@H](O)CBr
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Product: COC(=O)C[C@H](O)CI
Temperature: 92 °C
Reaction time: 23 h

Procedure:
A solution of (S)-4-Bromo-3-hydroxybutanoic acid, methyl ester (14.822 g, 75.2 mmol) in methyl ethyl ketone (255 mL) was treated with anhydrous sodium iodide (56.6 g, 376 mmol). The resulting red mixture was stirred for 23 hours under argon at a bath temperature of 92° C. The solution was allowed to cool to room temperature and the solids were filtered through celite. The receiver flask was switched and the celite bed was washed with ethyl acetate (3×50 mL). The original MEK product-rich filtrate was concentrated to approximately 60 mL. The residue was treated with the ethyl acetate wash from above followed by 250 mL of fresh ethyl acetate. The solution was washed with sodium sulfite solution (2×100 mL), brine (1×75 mL) and dried (sodium sulfate). Filtration followed by concentration in vacuo produced a yellow liquid which was evaporated several times from hexane and dried under high vacuum (5 mm) to 15.48 g (84%).
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH:12]N)=[CH:8][CH:7]=1)(=[O:5])=[O:4].[C:14]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)(=O)[CH3:15].C(=O)([O-])O.[Na+]>>[CH3:2][S:3]([C:6]1[CH:11]=[C:10]2[C:9](=[CH:8][CH:7]=1)[NH:12][C:14]([C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)=[CH:15]2)(=[O:5])=[O:4]
Reactant: CC(=O)c1ccncc1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(4-methanesulfonyl-phenyl)-hydrazine hydrochloride (1.0 g) and polyphosphoric acid (15 g), 4-acetylpyridine (0.47 ml) was added and the mixture was stirred at 150° C. for 1 hour. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with chloroform. The organic layer was concentrated under reduced pressure. The resulting residue was washed with n-hexane to obtain 0.9591 g of the desired product as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([CH:38]=[O:39])[S:36][CH:37]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH2:23]([S:20]([N:17]1[CH2:18][CH2:19][CH:14]([C:5]2[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=[C:2]([C:33]4[CH:34]=[C:35]([CH:38]=[O:39])[S:36][CH:37]=4)[CH:3]=3)[NH:7][CH:6]=2)[CH2:15][CH2:16]1)(=[O:22])=[O:21])[CH3:24]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC1(C)OB(c2csc(C=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Temperature: 150 °C
Yield: 89.2 %

Procedure:
To a solution of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (909 mg, 2.2 mmol) in dioxane (7.5 mL) and H2O (2.5 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarbaldehyde (1.57 g, 6.6 mmol), potassium carbonate (1.82 g, 13.2 mmol), and tetrakis(triphenylphospine)palladium (0) (30 mg, 0.22 mmol). The reaction was heated in the microwave at 150° C. for 20 min. The mixture was then concentrated to dryness. EtOAc (50 mL) was added to the residue and washed with brine. The precipitate which formed between the water and organic layer was filtered and collected as a brown solid to give 874 mg of the title compound (89%).
Reaction SMILES: [C:1]([CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][NH:10][C:11]1[N:15]([C@@H:16]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=2[N:12]=1)([OH:3])=O.[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O1CCCC1.C(N(CC)CC)C>[OH:35][CH2:34][CH:33]([NH:32][C:1]([CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([CH:29]=[CH:30][CH:31]=1)[CH2:9][NH:10][C:11]1[N:15]([C@@H:16]2[O:22][C@H:21]([CH2:23][OH:24])[C@@H:19]([OH:20])[C@H:17]2[OH:18])[C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]=2[N:12]=1)=[O:3])[CH2:36][OH:37]
Reactant: O=C(O)C=Cc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Reactant: NC(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(C=Cc1cccc(CNc2nc3ccccc3n2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c1)NC(CO)CO
Reaction time: 17 h
Yield: 88.8 %

Procedure:
2-[3-(2-Carboxyvinyl)benzylamino]-1-(β-D-ribofuranosyl)-1H-benzimidazole (50 mg), 2-amino-1,3-propanediol (21 mg), 1-hydroxybenzotriazole (36 mg) and triethylamine (41 μL) were suspended in tetrahydrofuran (2 mL). To the mixture was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (45 mg), and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure, and the obtained residue was purified by preparative reverse phase column chromatography (Shiseido CAPSELL PAC C18UG80, 5 μm, 20×50 mm, flow rate 30 mL/minutes linear gradient, water/methanol=70/30-10/90) to give the title compound (52 mg)
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13]#[C:14][C:15](=[O:18])[CH2:16][CH3:17])[O:4]1.[NH2:19][OH:20]>C(O)C>[CH3:1][O:2][C@H:3]1[C@@H:7]2[O:8][C:9]([CH3:12])([CH3:11])[O:10][C@@H:6]2[C@@H:5]([C:13](=[N:19][OH:20])[CH2:14][C:15](=[O:18])[CH2:16][CH3:17])[O:4]1
Reactant: NO
Reactant: CCC(=O)C#C[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: CCO
Product: CCC(=O)CC(=NO)[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 22 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]pent-1-yn-3-one (550 mg) and hydroxylamine (50% solution in water) (0.2 ml) in ethanol (10 ml) was stirred overnight at 22° C. The mixture was concentrated in vacuo to afford the title compound as a yellow oil (554 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=[O:9])=[N:6][C:5]([Cl:10])=[C:4]([Cl:11])[N:3]=1.[S:12]1[CH:16]=[CH:15][N:14]=[C:13]1[Li].[Cl-].[NH4+]>CCOCC>[NH2:1][C:2]1[C:7]([CH:8]([OH:9])[C:13]2[S:12][CH:16]=[CH:15][N:14]=2)=[N:6][C:5]([Cl:10])=[C:4]([Cl:11])[N:3]=1
Reactant: [Li]c1nccs1
Reactant: Nc1nc(Cl)c(Cl)nc1C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Nc1nc(Cl)c(Cl)nc1C(O)c1nccs1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
In 5 ml of ether there was dissolved 2-amino-5,6-dichloro-3-formylpyrazine (144 mg; 0.75 mMol) prepared as in Example 1, Step B above. The (thiazol-2-yl)lithium (1 mMol) prepared in Step A above was cooled to -78° C., after which the solution of 2-amino-5,6-dichloro-3-formylpyrazine was added dropwise under nitrogen. The reaction mixture was then allowed to warm up gradually to -15° C. and kept at that temperature for 30 minutes. When thin layer chromatography indicated substantial amounts of starting material remaining, additional (thiazol-2-yl)lithium was added. Ammonium chloride solution was then added and the reaction mixture was stirred for 15 minutes at -15° C. The mixture was extracted with ether, passed through a silica gel column, and eluted with dichloromethane to give the product (44 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[CH2:13]([O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=2)=[CH:27][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: CCOC(=O)c1ccc(N)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCc2ccc(OCc3ccccc3)cc2)cc1

Procedure:
A mixture of 16.5 g. of ethyl p-aminobenzoate, 11.64 g. of p-benzyloxybenzyl chloride and 50 ml. of hexamethylphosphoramide are heated in an oil bath at 110° C. for 20 hours. The mixture is chilled, diluted with 25 ml. of water, chilled and the solid mass diluted with additional water in order to filter. The solid is washed with water and recrystallized from ethanol to give off-white crystals, m.p. 144°-146° C. A sample is recrystallized from ethanol to give off-white crystals, m.p. 146°-147° C.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>O1CCCC1>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[N:17]=[C:18]4[NH:23][C:25](=[O:26])[NH:22][C:19]4=[CH:20][CH:21]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: CN(c1ccc(N)c(N)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(c1ccc2[nH]c(=O)[nH]c2n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1

Procedure:
A solution of (R)—N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine-2,5,6-triamine (35 mg, 0.11 mmol,) and 1,1′-carbonyldiimidazole (21 mg, 0.13 mmol) in tetrahydrofuran (3.0 mL) was stirred at reflux for 1 h. The volatiles were removed and the residue was purified by chromatography to give the title compound. MS (m/z): 351 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:14]=[C:13]([C:15]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][C:23]=2[C@H:24]2[CH2:29][C@@H:28]([NH:30]C(=O)OC(C)(C)C)[C:27](=[O:38])[C@@H:26]([CH3:39])[CH2:25]2)=[O:16])[CH:12]=[CH:11][C:10]=1[F:40].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:30][C@H:28]1[C:27](=[O:38])[C@@H:26]([CH3:39])[CH2:25][C@@H:24]([C:23]2[CH:22]=[CH:21][N:20]=[CH:19][C:18]=2[NH:17][C:15](=[O:16])[C:13]2[CH:12]=[CH:11][C:10]([F:40])=[C:9]([C:3]3[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[N:14]=2)[CH2:29]1
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](N)C1=O
Yield: 98 %

Procedure:
Tert-butyl (1R,3S,5R)-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methyl-2-oxocyclohexylcarbamate was treated with 25% TFA/CH2Cl2 for 30 minutes. The volatiles were removed in vacuo, the residue was dissolved in DMSO and purified by reverse phase HPLC to yield N-(4-((1R,3R,5S)-3-amino-5-methyl-4-oxocyclohexyl)pyridin-3-yl)-6-(2,6-difluorophenyl)-5-fluoropicolinamide in 98% yield. LC/MS (m/z)=455.1 (MH+), Rt=0.57 min. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.55 (s, 1H), 8.55 (s, 1H), 8.47 (d, J=4.0, 1H), 8.37 (dd, J=8.0, 4.0, 1H), 8.21 (t, J=8.0, 1H), 8.16 (broad doublet, J=4.0, 2H), 7.67-7.74 (m, 1H), 7.40 (d, J=8.0, 1H), 7.36 (t, J=8.0, 2H), 4.20-4.26 (m, 1H), 3.50-3.70 (m, 2H), 2.76-2.82 (m, 1H), 2.49-2.54 (m, 1H), 2.32-2.36 (m, 1H), 2.16-2.18 (m, 1H), 1.91 (q, J=12, 1H), 1.65 (q, J=12, 1H), 0.97 (d, J=8.0, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:17]([CH2:18][S:19][CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:16]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][C:37]([C:40]4([C:43]([OH:45])=[O:44])[CH2:42][CH2:41]4)=[CH:36][CH:35]=3)=[CH:30][CH:29]=2)[O:15][N:14]=1>C(Cl)Cl>[CH3:12][C:13]1[C:17]([CH2:18][S:19]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:9])=[C:16]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:35]=[CH:36][C:37]([C:40]4([C:43]([OH:45])=[O:44])[CH2:41][CH2:42]4)=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)[O:15][N:14]=1
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CSCCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1CS(=O)CCc1ccccc1
Reaction time: 0.25 h

Procedure:
m-Chloroperbenzoic acid (0.023 g, 0.11 mmol) was added to a solution of 1-[4′-(3-methyl-4-phenethylsulfanylmethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid (0.050 g, 0.11 mmol) in CH2Cl2. After stirring for 15 minutes the mixture was concentrated and the residue was purified by preparative HPLC to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12].[OH-].[Na+]>C1(O)C=CC=CC=1>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=2[O:9][CH3:10])=[CH:20][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: COc1c(Cl)ccnc1C
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: COc1c(Nc2ccc(C(C)(C)C)cc2)ccnc1C

Procedure:
7.9 g of 4-chloro-3-methoxy-2-methylpyridine and 22.4 g of 4-tert-butylaniline are heated at 120° C. for 8 hours in 20 g of phenol. After cooling, the mixture is poured into NaOH and the product is extracted using methylene chloride. After concentrating, the excess of amine is distilled off in vacuo and the residue is crystallized using hexane. 9.5 g=55%
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:28]=[C:27]5[C:22]([C:23]([CH3:33])([CH3:32])[CH2:24][CH2:25][N:26]5C(=O)C)=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:1][C:2]1[C:3]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([NH:18][C:19]4[CH:28]=[C:27]5[C:22]([C:23]([CH3:33])([CH3:32])[CH2:24][CH2:25][NH:26]5)=[CH:21][CH:20]=4)=[N:13][CH:12]=[N:11][C:10]=3[CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCC(C)(C)c2ccc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)cc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC1(C)CCNc2cc(Nc3ncnc4c3CCN(c3ncccc3Cl)C4)ccc21
Temperature: 90 °C
Yield: 77 %

Procedure:
A mixture of 1-(7-(7-(3-chloropyridin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-ylamino)-3,4-dihydro-4,4-dimethylquinolin-1(2H)-yl)ethanone (10 mg), acetonitrile (2 mL), and 5 N HCl (0.5 mL) was heated at 90° C. for 3 h. The cooled solution was treated with saturated aqueous sodium bicarbonate and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried, and evaporated. The residue was purified by peparative TLC to give an off-white solid (7 mg).