Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN(C)CCCN=C=NCC.[CH2:39]([CH:41]([CH2:44][CH3:45])[CH2:42][NH2:43])[CH3:40].CN(C)C=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:39]([CH:41]([CH2:44][CH3:45])[CH2:42][NH:43][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])=[CH:6][CH:5]=1)=[O:2])[CH3:40]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C(=O)O)cc23)c(OC)c1
Reactant: CCC(CC)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(CC)CNC(=O)c1ccc2cccc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Yield: 77 %

Procedure:
A mixture of methyl 4-(7-carboxynaphth-1-ylmethyl)-3-methoxybenzoate (342 mg), 4-dimethylaminopyridine (358 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (560 mg), and 2-ethylbutylamine (198 mg), was dissolved in 3:1 methylene chloride:dimethylformamide (distilled over CaH2) (4 ml) and stirred for 18 h. Methylene chloride was added and the solution was washed (1N hydrochloric acid, brine), dried (MgSO4) and evaporated to give a yellow foam. Recrystallization from 1:2 methylene chloride:hexane (30 ml) gave methyl 4-[7-(2-ethylbutylcarbamoyl)naphth-1-ylmethyl]-3-methoxybenzoate (326 mg, 77%) as a colorless solid; mp 129.5°-130.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9](OC3CCOCC3)[C:10]=2[N:11]=1.[CH:19]1([SH:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]=[CH:7][N:8]=[C:9]([S:25][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:10]=2[N:11]=1
Reactant: SC1CCCCC1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Clc1ccc2ncnc(SC3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
To a solution of 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1 g, 0.500 mmol) in ACN (2.500 ml) were added cyclohexanethiol (0.058 g, 0.500 mmol) and K2CO3 (0.069 g, 0.500 mmol) at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with water and extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1N aq. NaOH and then washed with 1N aq. HCl. The organic layers were dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(cyclo hexylthio)pyrido[3,2-d]pyrimidine (0.129 g, 92%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.36-1.42 (1H, m), 1.48-1.69 (5H, m), 1.80-1.86 (2H, m), 2.14-2.20 (2H, m), 4.10-4.16 (1H, m), 7.73 (1H, d, J=8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.98 (1H, s).
Reaction SMILES: [Na].[F:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[N:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21](=O)[CH:22]([CH2:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=5)[C:14]4=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:5][CH:4]=1.[CH3:31][C:32](=[O:35])[CH:33]=[CH2:34]>CCO>[F:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:17]3[N:16]=[C:15]4[CH2:18][CH2:19][CH2:20][C:21]5[C:22]([CH2:23][C:24]6[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=6)([CH2:34][CH2:33][C:32](=[O:35])[CH:31]=5)[C:14]4=[CH:13][C:12]=3[CH:11]=[N:10]2)=[CH:7][CH:8]=1
Reactant: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc2C1Cc1ccccn1
Reactant: C=CC(C)=O
Agent: [Na]
Solvent: CCO
Product: O=C1C=C2CCCc3nc4c(cnn4-c4ccc(F)cc4)cc3C2(Cc2ccccn2)CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 49.7 %

Procedure:
Sodium (1.09 g, 47.4 mmol) and EtOH (355 mL) were stirred together until a solution was formed then 1-(4-fluorophenyl)-5-(pyridin-2-ylmethyl)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6(1H)-one (115, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (16.47 g, 42.6 mmol) was added. The mixture was heated to about 60° C. then but-3-en-2-one (4.14 mL, 50.2 mmol) was added over about 50 min. The mixture was stirred at about 60° C. for about 90 min then it was cooled and concentrated under reduced pressure. The material was partitioned between EtOAc (250 mL) and water (150 mL) then the aqueous layer was extracted with EtOAc (100 mL). The combined organics were washed with brine (30 mL) then dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified on silica gel (330 g) using a gradient from 0-100% EtOAc in DCM. Product fractions were combined and concentrated under reduced pressure to yield rac-9-(4-fluorophenyl)-12b-(pyridin-2-ylmethyl)-1,5,6,7,9,12b-hexahydrobenzo[3,4]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-3(2H)-one (116, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (9.28 g, 50%); LC/MS, method 3, Rt=1.61, 2.40 min, MS m/z 439 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.83 (s, 1H), 8.43 (s, 1H), 8.36-8.28 (m, 3H), 7.61-7.57 (m, 1H), 7.44-7.36 (m, 2H), 7.18-7.11 (m, 2H), 5.97 (s, 1H), 3.88 (d, J=13.4 Hz, 1H), 3.67 (d, J=13.5 Hz, 1H), 3.27-3.15 (m, 1H), 2.98-2.93 (m, 1H), 2.87-2.74 (m, 1H), 2.48-2.40 (m, 1H), 2.39-2.27 (m, 1H), 2.23-2.09 (m, 2H), 1.94-1.75 (m, 2H), 1.56-1.49 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1.C(N(CC)CC)C>ClCCl>[C:9]([N:12]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1)([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
A solution of 35.6 ml of benzylchloroformate in 200 ml of dichloromethane was added dropwise to a mixture of 10 g of (racemic)-3-pyrrolidinol, 48.3 ml of triethylamine and 725 ml of dichloromethane which was cooled to 0° C. The mixture was stirred for 48 hours at room temperature. The dichloromethane solution was extracted with 5% hydrochloric acid and 5% aqueous sodium bicarbonate. The acid and bicarbonate washes were combined, salted with sodium chloride and extracted with 2×750 ml of ethyl acetate. The combined organic extracts were dried and concentrated, giving 22.7 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol. A mixture of 2.5 g of (racemic)-N-carbobenzyloxy-3-pyrrolidinol, 2.0 ml of methyl iodide and 5.1 g of silver oxide in 50 ml of dimethylformamide was stirred at room temperature for 2 days. The mixture was diluted with ether and then filtered. The filtrate was concentrated to a small volume. The ether solution was washed with water, dried and concentrated to dryness in vacuo. The residue was purified by chromatography (silica gel) to give 2.4 g of (racemic)-N-carbobenzyloxy-3-methoxypyrrolidine as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[CH2:3][CH:4]([C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[CH:19][CH:18]=1)[NH:5][C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:1][CH:2]([CH3:30])[CH2:3][CH:4]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:28][CH:29]=1)[NH:5][C:6]1[C:15]([CH3:16])=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: Cc1cc2ccccc2nc1NC(CC(C)C)c1ccc(C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2ccccc2nc1NC(CC(C)C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl(+/−)-4-(3-methyl-1-((3-methylquinolin-2-yl)amino)butyl)benzoate (325 mg, 0.803 mmol) in dichloromethane (8.0 mL) was added trifluoroacetic acid (0.62 mL, 8.0 mmol). The solution was stirred at room temperature for 17 hours then concentrated under reduced pressure. Toluene (3 mL) was added, and the solution was again concentrated under reduced pressure to remove excess trifluoroacetic acid to give (+/−)-4-(3-methyl-1-((3-methylquinolin-2-yl)amino)butyl)benzoic acid trifluoroacetic acid salt as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.26 (s, 1H), 8.06 (d, J=8.4 Hz, 2H), 7.84 (d, J=7.8 Hz, 1H), 7.80-7.75 (m, 1H), 7.75-7.69 (m, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.55-7.48 (m, 1H), 5.50 (dd, J=5.0, 9.5 Hz, 1H), 2.56 (s, 3H), 2.24-2.14 (m, 1H), 1.92-1.75 (m, 2H), 1.08 (d, J=6.4 Hz, 3H), 1.05 (d, J=6.2 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:20])=[CH:4][C:5]([F:19])=[C:6]([N:8]2[C:16](=[O:17])[C:11]3=[CH:12][CH2:13][CH2:14][CH2:15][N:10]3[C:9]2=[O:18])[CH:7]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[Cl:20][C:3]1[C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:7][C:6]([N:8]2[C:16](=[O:17])[C:11]3=[CH:12][CH2:13][CH2:14][CH2:15][N:10]3[C:9]2=[O:18])=[C:5]([F:19])[CH:4]=1
Reactant: Nc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Yield: 72.8 %

Procedure:
To a pyridine (5 mL) solution of 2-(5-amino-4-chloro-2-fluorophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1, 3[2H, 7H]-dione (0.50 g, 1.69 mmol) was added methanesulfonyl chloride (0.14 mL, 1.86 mmol) with stirring under cooling in an ice-water bath and the reaction mixture was stirred for 2 hours at 0° C. The resulting mixture was quenched with 1N hydrochloric acid (60 mL) and extracted with ethyl acetate (20 mL×3 times). The organic layer combined was washed with saturated sodium chloride solution (20 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/1) to obtain a white solid of 2-(4-chloro-2-fluoro-5-methanesulfonylaminophenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.46 g, yield:73.0%).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](O)=[O:4].ClC(Cl)(Cl)C([O-])=O.[Na+].C([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=O>CN(C=O)C>[Cl:1][C:2]([Cl:7])([Cl:6])[CH:3]([CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)[OH:4]
Reactant: O=C(O)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: O=C([O-])C(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C(O)C(Cl)(Cl)Cl)CC1
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
Placed 2,2,2-trichloroacetic acid (5.746 g, 35.17 mmol) in DMF (5 mL) and added slowly sodium 2,2,2-trichloroacetate (6.519 g, 35.17 mmol). The reaction was stirred for 10 minutes and tert-butyl 4-formylpiperidine-1-carboxylate (5.00 g, 23.44 mmol) was added. The reaction was stirred for 40 minutes then quenched with saturated sodium bicarbonate and filtered. The solids were washed with water and dried. The product was triturated with water and filtered to give the title compound (5.734 g, 73.53% yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[C:9]1([C:2]2[CH:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: c1ccc(-c2cc(-c3ccccc3)ncn2)cc1
Yield: 38 %

Procedure:
First, 5.02 g of 4,6-dichloropyrimidine, 8.29 g of phenylboronic acid, 7.19 g of sodium carbonate, 0.29 g of bis(triphenylphosphine)palladium(II) dichloride (abbreviation: Pd(PPh3)2Cl2), 20 mL of water, and 20 mL of acetonitrile were put into a recovery flask equipped with a reflux pipe, and the air in the flask was replaced with argon. This reaction container was heated by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. Here, there were further put 2.08 g of phenylboronic acid, 1.79 g of sodium carbonate, 0.070 g of Pd(PPh3)2Cl2, 5 mL of water, and 5 mL of acetonitrile into the flask, and the mixture was heated again by irradiation with microwaves (2.45 GHz, 100 W) for 60 minutes. After that, water was added to this solution and an organic layer was extracted with dichloromethane. The obtained solution of the extract was washed with water and dried with magnesium sulfate. The solution after drying was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane as a developing solvent, so that a pyrimidine derivative Hdppm (yellow white powder, 38% in yield) was obtained. Note that for the irradiation with microwaves, a microwave synthesis system (Discover, manufactured by CEM Corporation) was used. A synthesis scheme (a-1) of Step 1 is shown below.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(N(CC)CC)C.CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][C:11]=1[O:17][CH3:18])[N:8]=[CH:7][CH:6]=[C:5]2[O:4][C:3]1[CH:19]=[CH:20][C:21]([CH3:23])=[CH:22][C:2]=1[NH:1][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3N)c2cc1OC
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(C)cc3Nc3ccccc3)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
4-(2-Amino-4-methylphenoxy)-6,7-dimethoxyquinoline (52 mg) was dissolved in triethylamine/N,N-dimethylformamide (0.5 ml/2.5 ml), and phenylboronic acid (100 mg) and copper acetate (250 mg) were added to the solution which was then stirred at room temperature overnight. The reaction solution was filtered, and the solvent was removed therefrom by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. Next, the ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (50 mg, yield 76%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[CH:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Br)(Br)([Br:16])=O.C([O-])(O)=O.[Na+]>>[Br:16][C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH3:1])[N:3]=1
Reactant: CCOC(=O)c1ccc(=O)[nH]c1C
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)c1ccc(Br)nc1C
Temperature: 130 °C
Reaction time: 4 h
Yield: 93.1 %

Procedure:
Ethyl 2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (2.0 g, 11 mmol) and POBr3 (8.9 g, 31 mmol) were mixed in one 100 mL flask, and the mixture was stirred at 130° C. for 4 hrs. The reaction mixture was cooled to room temperature and 50 g of ice water was added. The mixture was neutralized to pH=9 with aqueous NaHCO3 solution, extracted twice with EtOAc, dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2.5 g (93% yield) of the desired product. LC-MS found: 244.1 (M+H)+.
Reaction SMILES: C([N:3](CC)CC)C.[C:8]1(C)[C:9]([C:14](Cl)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1.C(OCC)(=O)C>C(Cl)Cl>[C:14]([NH2:3])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1
Yield: 337.5 %

Procedure:
To a solution of 391 mg (1 mmol) of 2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine in 3 mL of anhydrous methylene chloride, was added 0.42 mL (3 mmol) of triethylamine, then at room temperature, 0.12 mL (0.9 mmol) of ortho-toluoyl chloride was added. After 15 hours at room temp ethyl acetate was added, washed with 5% critic acid, saturated sodium bicarbonate, brine, dried, filtered and concentrated to afford 420 mg of crude material. This was chromatgraphed on 40 g of silica gel using 50% ethyl acetate/hexane to afford 368 mg of pure benzamide, N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl) amino]-1S-(phenylmethyl)propyl]-2-methyl, m/e=516 (M+Li).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].[C:14](=O)([O-])[O-].[K+].[K+].C(=O)(OC)OC>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[CH:6]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [K+]
Solvent: COC(=O)OC
Solvent: CN(C)C=O
Product: COC(=O)c1cn(C)c2ccccc12
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 151.9 %

Procedure:
Indole-3-carboxylic acid methyl ester (5.0 g, 28.54 mmol), potassium carbonate (2.5 g), N,N-dimethylformamide (35 mL) and dimethyl carbonate (7.2 mL, 85 mmol) were combined and the stirred mixture was heated to reflux (˜130° C.). Within 3.5 h, the reaction had gone to completion as determined by HPLC analysis. After the reaction mixture was cooled to ˜3° C., ice cold water (100 mL) was slowly added. The resulting slightly off-white solid was recovered by filtration and was washed with water (2×50 mL). The solid was not purified further, but was dried in vacuo at 45° C. for 24 h to provide 5.2 g of 1-methylindole-3-carboxylic acid methyl ester (96.3% yield).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[NH:15][N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH:26]1[CH2:28][C:27]1([F:30])[F:29]>CN(C)C=O>[F:29][C:27]1([F:30])[CH2:28][CH:26]1[CH2:25][N:15]1[C:16](=[O:17])[N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[CH:13]=[N:14]1
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Reactant: FC1(F)CC1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-n2cnn(CC3CC3(F)F)c2=O)nc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate (9.36 g, 36.8 mmol) in anhydrous N,N-dimethylformamide (150 mL) was added cesium carbonate (23.90 g, 73.70 mmol). The reaction mixture was stirred at ambient temperature for 30 min, followed by the addition of bromomethyl-2,2-difluorocyclopropane (6.00 g, 35.10 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was heated at 40° C. for 3 h and filtered. The solid was washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to dryness. The residue was triturated with ethyl acetate (50 mL) to afford the title compound as a yellow solid (10.8 g, 98%): mp 146-148° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 4.23 (t, J=7.1 Hz, 2H), 3.97-3.77 (m, 2H), 2.54 (s, 3H), 2.20-2.04 (m, 1H), 1.73-1.60 (m, 1H), 1.48-1.37 (m, 1H), 1.26 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.8, 156.6, 154.0, 149.9, 132.2, 118.2, 114.4 (t), 61.6, 42.8 (d), 20.7 (t), 17.2, 14.9 (t), 14.5; MS (ES+) m/z 345.9 (M+1).
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].[CH:26]1([CH2:29][O:30][C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=2[O:40][CH:41]([F:43])[F:42])[C:34](O)=[O:35])[CH2:28][CH2:27]1>>[CH:26]1([CH2:29][O:30][C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][C:39]=2[O:40][CH:41]([F:42])[F:43])[C:34]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)=[O:35])[CH2:28][CH2:27]1
Reactant: O=C(O)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc(OC(F)F)c(OCC5CC5)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-(cyclopropylmethoxy)-4-(difluoromethoxy)benzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) to yield the title compound.
Reaction SMILES: O=[C:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCN(CC)CC.Cl.[NH2:24][OH:25]>C1COCC1>[OH:25][N:24]=[C:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCOCC(=O)C1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCOCC(=NO)C1
Temperature: 25 °C
Yield: 102.2 %

Procedure:
A solution of tert-butyl 6-methylene-1,4-oxazepane-4-carboxylate 38.2 (1.23 g, 5.74 mmol) in 1,4-dioxane (20 mL) and H2O (20 mL) was treated with sodium periodate (2.46 g, 11.49 mmol) and a solution of 2.5% OsO4 in t-BuOH (0.36 mL, 0.028 mmol). The reaction mixture was stirred at room temperature for 18 hrs. The resulting yellow-white suspension was diluted with H2O and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo to provide a brown oil (1.30 g) that was used immediately without further purification. The crude tert-Butyl 6-oxo-1,4-oxazepane-4-carboxylate (4.4 g, 20.4 mmol) was dissolved in THF (100 mL) and treated with Et3N (11.4 mL, 81.8 mmol) and hydroxylamine hydrochloride (3.1 g, 45.0 mmol). The mixture was stirred at room temperature over the weekend. The mixture was concentrated in vacuo to dryness and the residue was suspended between EtOAc and water. The aqueous layer was extracted with EtOAc. The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to yield (4.8 g) of a semisolid product 38.3. LCMS m/z=253.1 [M+Na], 461.3 [2M] with two equal peaks observed (oxyme steroisomers presumably). Used without further purification.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]2[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=2)[CH3:34])=[O:22])[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=1
Reactant: Cc1ccc(-c2cc(OC3COCC3O)cc(C(=O)O)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(OC3COCC3O)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(4-hydroxytetrahydrofuran-3-yloxy)-4′-methylbiphenyl-3-carboxylic acid (35 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a white solid.