Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH3:10])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH:12]1CC(O)=O.NC1C=C[C:32]([O:35]CC)=[CH:31]C=1N1CCN(CC2C=CC=CC=2)CC1CC(O)=O.FC1C=C(OCC)C=CC=1[N+]([O-])=O>>[CH2:17]([N:14]1[CH2:15][CH2:16][N:11]2[C:3]3[CH:4]=[C:5]([O:8][CH2:9][CH3:10])[CH:6]=[CH:7][C:2]=3[NH:1][C:32](=[O:35])[CH2:31][C@H:12]2[CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOc1ccc(N)c(N2CCN(Cc3ccccc3)CC2CC(=O)O)c1
Agent: CCOc1ccc([N+](=O)[O-])c(F)c1
Product: CCOc1ccc2c(c1)N1CCN(Cc3ccccc3)C[C@@H]1CC(=O)N2

Procedure:
The title compound was prepared according to the procedure outlined in Example 43A substituting 2-(1-(2-amino-5-methoxyphenyl)-4-benzylpiperazin-2-yl)acetic acid for 2-(1-(2-amino-5-ethoxyphenyl)-4-benzylpiperazin-2-yl)acetic acid 2-(1-(2-Amino-5-ethoxyphenyl)-4-benzylpiperazin-2-yl)acetic acid was prepared according the procedure outlined in Examples 12D, 12E, and 12F by substituting 2-fluoro-4-methoxy-1-nitrobenzene with 2-fluoro-4-ethoxy-1-nitrobenzene.
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:45][CH3:46])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[CH:25]=[CH:24][CH:23]=5)[C:19]4[CH:32]=[CH:33][N:34]([S:35]([C:38]5[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=5)(=[O:37])=[O:36])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:48][CH:49]([CH3:52])[CH2:50][NH2:51]>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:47])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:45][CH3:46])=[C:12]([NH:15][C:16]3[N:29]=[C:20]([NH:21][C:22]4[CH:23]=[CH:24][CH:25]=[C:26]([F:31])[C:27]=4[C:28]([NH:51][CH2:50][CH:49]([CH3:52])[CH3:48])=[O:30])[C:19]4[CH:32]=[CH:33][N:34]([S:35]([C:38]5[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=5)(=[O:37])=[O:36])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(C)CN
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cccc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(=O)NCC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8-fluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (200 mg, 0.305 mmol) in THF (5 mL) was added (2-methylpropyl)amine (0.153 mL, 1.52 mmol). The resulting mixture was let stir at rt for 16 h at which time it was diluted with ethyl acetate and washed with a saturated ammonium chloride solution,a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-(2-methylpropyl)benzamide. This crude material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a brown solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-(2-methylpropyl)benzamide (106 mg, 0.184 mmol) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.68 Hz, 6 H), 1.73-1.89 (m, 1 H), 2.26 (s, 6 H), 3.05-3.23 (m, 6 H), 3.77 (s, 3 H), 4.18 (t, J=8.33 Hz, 2 H), 6.24 (br. s., 1 H), 6.83-7.00 (m, 3 H), 7.24-7.38 (m, 1 H), 7.56 (s, 1 H), 8.32 (d, J=8.42 Hz, 1 H), 8.57-8.68 (m, 2 H), 9.77 (s, 1 H), 11.26 (br. s., 1 H). (ESIMS (M+H)+=575)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][C:17](O)=[O:18])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.O/[N:21]=[C:22](/[C:24]1[CH:29]=[CH:28][NH:27][C:26](=[O:30])[CH:25]=1)\[NH2:23].C(N=C=NC(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C(#N)C.CCOC(C)=O>[F:8][C:6]1[CH:5]=[C:4]([C:9]2([CH2:15][CH2:16][C:17]3[O:18][N:23]=[C:22]([C:24]4[CH:29]=[CH:28][NH:27][C:26](=[O:30])[CH:25]=4)[N:21]=3)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)CCC1(c2cc(F)cc(F)c2)CCCCC1
Reactant: N/C(=N\O)c1cc[nH]c(=O)c1
Agent: CC(C)N=C=NC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=c1cc(-c2noc(CCC3(c4cc(F)cc(F)c4)CCCCC3)n2)cc[nH]1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.6 %

Procedure:
To a solution of 3-(1-(3,5-difluorophenyl)cyclohexyl)propanoic acid (20 mg, 0.075 mmol) and (Z)—N′-hydroxy-2-oxo-1,2-dihydropyridine-4-carboximidamide (11.42 mg, 0.075 mmol) in acetonitrile (1 mL) was added N,N′-diisopropylcarbodiimide (0.013 mL, 0.082 mmol), and the mixture was stirred for 2.5 hrs at room temp. TBAF (0.112 mL, 0.112 mmol) was added and the mixture was stirred for 40 hrs at room temp. After addition of EtOAc the mixture was washed with water and brine, dried over Na2SO4 and evaporated to give an oily residue which was purified by Combiflash (12 g silica gel). Elution with 7:93 MeOH—CH2Cl2 gave a white solid residue which was repurified by prep HPLC to give 4-(5-(2-(1-(3,5-difluorophenyl)cyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)pyridin-2(1H)-one (4.8 mg, 16.64% yield) as a white solid. HPLC: tR=3.95 min, Waters Sunfire C18 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH-0.1% TFA; Final solvent: 90% aq. MeOH-0.1% TFA. LC/MS: m/e 386.13 (M+H)+. 1H NMR (400 MHz, CDCl3): δ ppm 7.45 (1 H, d), 7.24 (1H, s), 6.84-6.88 (3 H, m), 6.65 (1H, m), 2.56-2.6 (2 H, m), 2.05-2.07 (4 H, m), 1.23-1.63 (8 H, m).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:38])[C@@H:6]([CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)[NH:7][C:8](=[O:27])[C@H:9]([CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].O>CO>[CH2:14]([O:13][C:11]([NH:10][C@H:9]([C:8]([NH:7][C@@H:6]([C:5]([OH:38])=[O:4])[CH2:28][C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[NH:31][CH:30]=1)=[O:27])[CH2:21][C:22]1[N:26]=[CH:25][NH:24][CH:23]=1)=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Temperature: 25 °C

Procedure:
Aqueous sodium hydroxide (15.4 g, 192 mL, 0.08 g/mL solution, 0.38 mol) was added to a solution of dipeptide 25 (187.1 g, ca. 0.38 mol), water (360 mL) and MeOH (ca. 6 L). The solution was stirred at room temperature until hydrolysis was complete (ca. 24 hours). The disappearance of the starting peptide was established by HPLC analysis. The solution was concentrated in vacuo to a residue which was dissolved in water (ca. 1 L). The aqueous layer (pH ca. 10) was then extracted with EtOAc (2×500 mL) in a separatory funnel. The resulting aqueous phase was adjusted to a pH of 5 with concentrated HCl at which point a crystalline precipitate formed. The solid was collected by vacuum filtration and dried in vacuo (148.4 g, 0.31 mol, 82%). The pH of the filtrate was adjusted to 4.5. A second crop of solid was again collected by vacuum filtration and dried in vacuo (20.2 g, 0.043 mol, 11%). 1H NMR showed both samples to contain dipeptide 26 in high purity. In two repetitions of this reaction, yields of 83% (ca. 0.06 mole scale) and 58% (ca. 0.3 mole scale) were obtained.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[CH2:9][C:8]2=1)#[N:4].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br>CN(C)C=O>[C:3]([C:5]1[CH:6]=[C:7]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=1[C:25]([F:24])([F:34])[F:35])[C:13]1[CH2:12][CH2:11][CH:10]([NH:18][C:19](=[O:23])[CH:20]([CH3:21])[CH3:22])[CH2:9][C:8]2=1)#[N:4]
Reactant: CC(C)C(=O)NC1CCc2[nH]c3ccc(C#N)cc3c2C1
Reactant: FC(F)(F)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2ccccc2C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
Suspend sodium hydride (60% in oil, 48 mg, 1.20 mmol) in N,N-dimethylformamide (2.5 mL) and chill to 0° C. Add slowly a solution of N-(6-cyano-2,3,4,9-tetrahydro-1H-carbazol-3-yl)-isobutyramide (281 mg, 1.00 mmol) in N,N-dimethylformamide (2.5 mL) via syringe, and stir 10 min before warming to ambient temperature for 30 min. Add 2-(trifluoromethyl)benzyl bromide (263 mg, 1.10 mmol) and stir approximately 16 h. Add ethyl acetate (75 mL), wash with water (50 mL) and brine (2×50 mL). Dry the organic phase over magnesium sulfate, filter, and evaporate under reduced pressure. Triturate the residue with 2:1 bexanes:methylene chloride to afford the title compound (333 mg, 76%). MS (ES): m/z 440 (M+1); 1H NMR (300 MHz, CDCl3): δ 7.83 (s, 1H), 7.73 (d, J=7.2 Hz, 1H), 7.39-7.29 (m, 3H), 7.16 (d, J=8.4 Hz, 1H), 6.27 (d, J=7.4 Hz, 1H), 5.53-5.51 (m, 1H), 5.46 (s, 2H), 4.47-4.30 (m, 1H), 3.21-3.15 (m, 1H), 2.67-2.59 (m, 3H), 2.33 (septet, J=6.8 Hz, 1H), 2.16-2.11 (m, 1H), 2.03-1.93 (m, 1H), 1.16 (d, J=6.8 Hz, 3H), 1.15 (d, J=6.8 Hz, 3H); m.p.=222-225° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:32])=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH:22]([OH:29])[C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])=[CH:15][C:14]=2[O:30][CH3:31])[N:10]=1.[C:33](OC=C)(=[O:35])[CH3:34]>C1(C)C=CC=CC=1>[C:33]([O:29][C@H:22]([CH2:21][CH2:20][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:9]2[N:10]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[O:7][C:8]=2[CH3:32])=[C:14]([O:30][CH3:31])[CH:15]=1)[C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])(=[O:35])[CH3:34]
Reactant: C=COC(C)=O
Reactant: COc1cc(CCCC(O)C(=O)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Solvent: Cc1ccccc1
Product: COc1cc(CCC[C@@H](OC(C)=O)C(=O)OC(C)C)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A 3-L flask was successively charged with isopropyl (±)-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]-2-hydroxypentanoate (33.0 g), LIP-301 [immobilized lipase derived from Pseudomonas sp, TOYOBO CO., LTD] (16.5 g), molecular sieve 4A (33 g), toluene (1650 ml) and vinyl acetate (158 ml). The mixture was stirred for 4 hours at 23° C. The reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was subjected to column chromatography on silica gel. From the fraction eluted with isopropyl ether, was obtained isopropyl (R)-(+)-2-acetoxy-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]pentanoate (15.9 g). Chiral analysis of this compound by HPLC showed 96% ee.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][C:31]([NH:33][O:34]C(C)(C)C)=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:18][CH2:17]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1.FC(F)(F)C(O)=O>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][C:24]3([CH2:30][C:31]([NH:33][OH:34])=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[CH2:20][CH2:21]2)[C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[N:6][CH:7]=1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)NOC(C)(C)C)CCCCC3)CC2)nc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CC(=O)NO)CCCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 31.6 %

Procedure:
To tert-butyl [1-[2-[4-[N-(5-methylpyridin-2-yl)-2-furancarboxamido]piperidin-1-yl]ethyl]cyclohexyl]acetohydroxamate (266 mg) was added trifluoroacetic acid (3.0 mL), and the solution was stirred at room temperature for 23 hours. The solution was then stirred at 40° C. for 2 hours and trifluoroacetic acid (2.0 mL) was further added. The solution was stirred at 50° C. for 3 hours. The trifluoroacetic acid was distilled off by azeotropic distillation with xylene. Water and chloroform were added to the residue and the solution was neutralized with saturated aqueous sodium hydrogencarbonate solution. The solution was extracted with 20% ethanol/chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then, the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography (silica gel, chloroform:methanol=85:15) to give the title compound (75 mg).
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[C:15]=1[N:23]=[C:24]=[N:25][C:26]1[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=1[CH:35]([CH3:37])[CH3:36])([CH3:13])[CH3:12]>C1COCC1>[CH:35]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([CH:32]([CH3:34])[CH3:33])[C:26]=1[NH:25][C:24](=[N:23][C:15]1[C:14]([CH:11]([CH3:13])[CH3:12])=[CH:19][CH:18]=[CH:17][C:16]=1[CH:20]([CH3:22])[CH3:21])[O:8][N:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([CH3:37])[CH3:36]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=Nc1c(C(C)C)cccc1C(C)C
Reactant: ON=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1N=C(Nc1c(C(C)C)cccc1C(C)C)ON=C1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82 %

Procedure:
To a solution of cyclohexanone oxime (1.13 g, 0.01 mol) in dry THF (25 ml) is added finely powdered NaOH (0.04 g) and bis(2,6-diisopropylphenyl)carbodiimide (3.65 g, 0.01 mol). The mixture is then stirred 4 h at room temperature under argon. The turbid mixture is thereafter filtered and evaporated under reduced pressure. The solid residue is crystallized from dichloromethane-hexane to afford 3.9 g of the title compound as a colorless solid, mp. 150-152° C.
Reaction SMILES: [CH2:1]([NH:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:8]([N:13]([C:19]([O:21][CH2:22][C:23]#[CH:24])=[O:20])[C:14](=[O:18])[C:15](Cl)=[O:16])[C:9]([CH3:12])([CH3:11])[CH3:10].O>C1(C)C=CC=CC=1>[CH2:1]([N:4]([CH2:5][CH:6]=[CH2:7])[C:15](=[O:16])[C:14]([N:13]([CH2:8][C:9]([CH3:11])([CH3:10])[CH3:12])[C:19]([O:21][CH2:22][C:23]#[CH:24])=[O:20])=[O:18])[CH:2]=[CH2:3]
Reactant: C=CCNCC=C
Reactant: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: C#CCOC(=O)N(CC(C)(C)C)C(=O)C(=O)N(CC=C)CC=C
Yield: 85.8 %

Procedure:
3.88 g (0.4 mole) of diallylamine are added dropwise to 5.35 g (0.02 mole) of 97% pure N-neopentyl-N-2-propinyloxycarbonyloxamic acid chloride in 50 ml of toluene. During this addition, the internal temperature is kept at 20° C. by external cooling with ice. When the dropwise addition has ended, 30 ml of water are added, the organic phase is separated off and the latter is washed twice with water, dried over sodium sulphate and finally concentrated in vacuo. 5.5 g (86% of theory) of N,N-diallyl-N'-neopentyl-N'-2-propinyloxycarbonyl-oxalic acid diamide of refractive index nD20 =1.4878 are obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:26][N:27]([CH3:37])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:31]([C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([N:27]([CH3:37])[CH3:26])[CH:29]=4)=[O:32])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(N(C)C)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 3-(dimethylamino)benzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19]C)[CH:15]=2)[C:10]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22].Cl.B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>CCOCC.C(Cl)(Cl)Cl.C(O)(C)C.C(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:19])[CH:15]=2)[C:10]=1[C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[CH:25][CH:24]=1)=[O:22]
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3cccc(F)c3F)ccc2c1
Agent: BrB(Br)Br
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cccc(F)c2F)ccc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.6 %

Procedure:
Charge a flask with [2-(2,3-difluoro-phenyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (1.3 g, 2.6 mmol) and add 200 mL methylene chloride followed by 25 mL of HCl in ether (1 M) and evaporate to dryness. Dissolve the solid in 200 mL methylene chloride and chill the solution in ice. Add to this solution boron tribromide (4.0 mL, 42.4 mmol) with swirling. Stir the dark solution at room temperature for 1 hour at which point all the starting material is gone. Pour this into a two phase mixture consisting of saturated sodium bicarbonate aqueous phase and a 3/1 mixture of chloroform/isopropanol organic phase and extract using a separatory funnel. Separate the organic phase and dry over 3 Å molecular sieves. Purify on a silica column eluting with 0-10% methanol/methylene chloride, collecting the first fraction that contains the product to give 400 mg of the title compound (32%).
Reaction SMILES: CO[C:3](=O)[C@H:4]([NH:6][C:7](=[O:22])[C@@H:8]([NH:11][C:12](OCC1C=CC=CC=1)=[O:13])[CH2:9][OH:10])C.C1CCCCC=1>[Pd].CO>[OH:10][CH2:9][C@@H:8]1[NH:11][C:12](=[O:13])[C@@H:4]([CH3:3])[NH:6][C:7]1=[O:22]
Reactant: COC(=O)[C@@H](C)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCCCC1
Product: C[C@H]1NC(=O)[C@H](CO)NC1=O
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To (R)-2-((S)-2-benzyloxycarbonylamino-3-hydroxy-propionylamino)-propionic acid methyl ester (172 g, 0.53 mol) was added 10% Pd/C (8.6 g), MeOH (530 mL) and cyclohexene (344 mL) under nitrogen. The mixture was heated to reflux for 17 h. MeOH (500 mL) was added and the reflux continued for 1 h. The hot reaction mixture was filtered through a pad of celite, cake washing with hot MeOH (2×500 mL). The combined filtrates were concentrated. The resulting solid was slurried in 2-butanone (400 mL) and petrol (400 mL) was added gradually over 10 min. After stirring for 30 min, the solids were filtered, cake washed with 2:1 petrol/2-butanone (300 mL). The filter cake was dried in vacuo at 40° C., to give the title compound (68.3 g) as an off white solid. 1H NMR (DMSO-d6): 8.08 (1H, s), 7.90 (1H, s), 5.11 (1H, t), 3.92 (1H, q), 3.80-3.71 (1H, m), 3.71-3.60 (1H, m), 3.58-3.47 (1H, m), 1.24 (3H, d).
Reaction SMILES: Br[C:2]1[C:3]([O:9][CH2:10][C@H:11]2[CH2:13][C@@H:12]2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][N:15]=2)=[N:4][C:5]([CH3:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:30]2[CH:34]=[N:33][N:32]3[CH2:35][CH2:36][CH2:37][C:31]=23)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C1COCC1.O.CCOC(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([C@H:12]2[CH2:13][C@@H:11]2[CH2:10][O:9][C:3]2[C:2]([C:30]3[CH:34]=[N:33][N:32]4[CH2:35][CH2:36][CH2:37][C:31]=34)=[CH:7][N:6]=[C:5]([CH3:8])[N:4]=2)=[N:15][CH:16]=1
Reactant: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2Br)nc1
Reactant: CC1(C)OB(c2cnn3c2CCC3)OC1(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc([C@H]2C[C@@H]2COc2nc(C)ncc2-c2cnn3c2CCC3)nc1
Temperature: 100 °C

Procedure:
A mixture of 5-bromo-4-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-2-methylpyrimidine (2-3) (120 mg, 0.3 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole (OO2) (104 mg, 0.4 mmol), tripotassium phosphate (145 mg, 0.7 mmol), S-Phos (14 mg, 0.03 mmol), and Pd(OAc)2 (3.9 mg, 0.02 mmol) in THF (1.5 mL) and water (0.3 mL) was heated at 100° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (10 mL), washed with sodium bicarbonate (2 mL) and brine (2 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-45% acetonitrile in water with 0.1% TFA modifier) to afford the title compound as a colorless gum. 1H NMR (500 MHz, DMSO): δ 8.51 (s, 1 H), 8.14 (d, J=2.9 Hz, 1 H), 7.84 (s, 1 H), 7.31-7.22 (m, 2 H), 4.53 (dd, J=11.3, 6.4 Hz, 1 H), 4.25 (dd, J=11.3, 8.2 Hz, 1 H), 4.04 (t, J=7.3 Hz, 2 H), 3.78 (s, 3 H), 2.97 (t, J=7.3 Hz, 2 H), 2.50 (s, 3 H), 2.39-2.32 (m, 2 H), 2.19 (dd, J=8.4, 4.7 Hz, 1 H), 1.79 (m, 1 H), 1.17 (dt, J=8.6, 4.5 Hz, 1 H), 1.06 (dd, J=8.6, 4.9 Hz, 1 H); HRMS m/z (M+H) 378.1921 found, 378.1925 required.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:20][CH2:21][CH2:22][OH:23])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl-].[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([O-])(=[O:40])=[O:39])=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([O:20][CH2:21][CH2:22][O:23][S:38]([C:35]3[CH:36]=[CH:37][C:32]([CH3:42])=[CH:33][CH:34]=3)(=[O:40])=[O:39])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CCC(OCCO)(c2ccc(Br)cc2)C1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOC2(c3ccc(Br)cc3)CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ambient solution of Example 54C (0.450 g, 1.17 mmol), triethylamine (0.178 mL, 1.28 mmol), and 4-dimethylaminopyridine (0.005 g, 0.041 mmol) in dichloromethane (3 mL) was added p-toluenesulfonate chloride (0.224 g, 1.17 mmol). The reaction was stirred at room temperature for 8 h and was then partitioned between water (10 mL) and diethyl ether (10 mL). The layers were separated, and the aqueous was extracted with additional diethyl ether (2×10 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC (10% ethyl acetate in hexane to 25% ethyl acetate in hexane) to give the title product. MS (ESI) m/z 541 [M+H]+.