Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH2:4][CH:5]([OH:9])[CH2:6][C:7]=1[CH3:8])[CH3:2].N1C=CC=CC=1.[Cl:16]/[C:17](/[C:27]([F:30])([F:29])[F:28])=[CH:18]\[C@@H:19]1[C@H:21]([C:22](Cl)=[O:23])[C:20]1([CH3:26])[CH3:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[Cl:16]/[C:17](/[C:27]([F:28])([F:29])[F:30])=[CH:18]\[C@@H:19]1[C@H:21]([C:22]([O:9][CH:5]2[CH2:6][C:7]([CH3:8])=[C:3]([CH2:1][CH3:2])[CH2:4]2)=[O:23])[C:20]1([CH3:26])[CH3:25]
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Reactant: CCC1=C(C)CC(O)C1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCC1=C(C)CC(OC(=O)[C@H]2[C@@H](/C=C(\Cl)C(F)(F)F)C2(C)C)C1
Yield: 82.9 %

Procedure:
To a mixture of (RS)-3-ethyl-4-methyl-3-cyclopenten-1-ol (115 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (92 mg) and toluene (10 ml), (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (238 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was poured into ice-cooled 5% aqueous solution of citric acid and extracted three times with diethyl ether. After the combined ether layer was washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; n-hexane/ethyl acetate=30/1) to afford 265 mg of (RS)-3-ethyl-4-methyl-3-cyclopenten-1-yl (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No. 11). Yield 83% nD27 1.4645
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1B(O)O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:28]4[CH:29]=[C:24]([Cl:23])[CH:25]=[CH:26][C:27]=4[Cl:30])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Yield: 88.9 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.43 g, 3.73 mmol) with (2,5-dichlorophenyl)boronic acid (1.07 g, 5.59 mmol) generally according to the procedure described for Intermediate 184 provided 1.49 g (88%) of (±)[7-(2,5-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1)([O-:5])=[O:4].CCN(C(C)C)C(C)C.[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30]Cl.C([O-])(O)=O.[Na+]>C(Cl)Cl.O.C(OCC)(=O)C.CCCCCC>[CH3:25][O:26][CH2:27][CH2:28][O:29][CH2:30][O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(OCCO)cc1
Reactant: COCCOCCl
Agent: N#N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COCCOCOCCOc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 65.9 %

Procedure:
Into a 100 mL 3-neck RBF, equipped with N2 Bubbler and thermo pocket 2-(4-nitrophenoxy)ethanol (10.8 g) in DCM (30 mL), and DIPEA (11.44 g) were added; the reaction mixture was cooled to 0° C. Methoxyethoxymethyl chloride (11.02 g in 20 mL DCM) was added drop wise during 10 min, and the reaction mixture was stirred at room temperature for 16 hr. The reaction was monitored on TLC using ethyl acetate:hexane (5:5) as mobile phase. After completion of the reaction, reaction mixture was poured into water and neutralized with saturated NaHCO3 solution. Product was extracted into DCM. The organic layer was washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure at 40° C. to give 10.54 g of 1-(2-((2-methoxyethoxy)methoxy)ethoxy)-4-nitrobenzene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:16]I)=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C@H:32]([CH3:47])[CH2:33][C:34]1[C:42]2[C:37](=[C:38]([C:43]([O:45][CH3:46])=[O:44])[CH:39]=[CH:40][CH:41]=2)[NH:36][CH:35]=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(#N)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:16][NH:31][C@H:32]([CH3:47])[CH2:33][C:34]2[C:42]3[C:37](=[C:38]([C:43]([O:45][CH3:46])=[O:44])[CH:39]=[CH:40][CH:41]=3)[NH:36][CH:35]=2)=[CH:11][C:10]=1[NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c(C[C@@H](C)N)c[nH]c12
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)O[C@@H](CN[C@H](C)Cc1c[nH]c2c(C(=O)OC)cccc12)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Yield: 42.4 %

Procedure:
A solution of (R)-N-[2-benzyloxy-5-(2-iodo-1-triethylsilyloxy-ethyl)phenyl]methanesulfonamide (2.09 g, 3.72 mmol), methyl (R)-3-(2-aminopropyl)-1H-indole-7-carboxylate (1.00 g, 3.72 mmol), diisopropyl-ethylamine (1.9 ml, 11.2 mmol) in tetrahydrofuran (30 ml)-acetonitrile (20 ml) is stirred at 110° C. for 18 hours in a sealed vessel. After cooling, to the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, and the mixture is extracted with ethyl acetate. The organic layer is dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (chloroform/methanol=100/1→100/4) to give the title compound (1.05 g, yield: 42%).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11]2[N:12]=[C:13]([C:25]#[N:26])[C:14](C#N)=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:5]1)([CH3:3])[CH3:2].[CH:27]([N-:29]C=O)=[O:28].[Na+].O>CC(N(C)C)=O>[C:25]([C:13]1[C:14]([NH:29][CH:27]=[O:28])=[N:15][C:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[C:11]([C:6]2[CH:7]=[CH:8][C:9](=[O:10])[N:4]([CH:1]([CH3:2])[CH3:3])[N:5]=2)[N:12]=1)#[N:26]
Reactant: O=C[N-]C=O
Reactant: CC(C)n1nc(-c2nc(C#N)c(C#N)nc2-c2ccccc2)ccc1=O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)n1nc(-c2nc(C#N)c(NC=O)nc2-c2ccccc2)ccc1=O
Temperature: 102.5 °C
Yield: 8.3 %

Procedure:
A suspension of 5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2,3-pyrazinedicarbonitrile (343 mg) and sodium diformylamide (190 mg) in DMA (1 ml) was heated at 100-105° C. for an hour. After addition of water, the reaction mixture was extracted with CHCl3, dried over MgSO4, concentrated under reduced pressure and subjected to column chromatography on silica gel. With elution of a mixture of n-hexane and EtOAc (50:50 v/v) was obtained [3-cyano-5-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-6-phenyl-2-pyrazinyl]formamide as a solid (30 mg) and with elution of a mixture of n-hexane and EtOAc (30:70 v/v) was obtained [3-cyano-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinyl]-formamide as a solid (22 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([O:11]CCCCC)=[O:10])=[CH:7][C:6]=1[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C(O)C>[CH3:3][O:4][C:5]1[CH:18]=[CH:17][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCNc1cc(C(=O)OCCCCC)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCNc1cc(C(=O)O)ccc1OC
Yield: 92 %

Procedure:
Ethanol (3 ml) and a 1N aqueous sodium hydroxide solution (3 ml) were added to pentyl 4-methoxy-3-pentylaminobenzoate (500 mg, 1.63 mmol), and the mixture was refluxed under heating for 2 hours. Ethanol was evaporated under reduced pressure. Conc. hydrochloric acid was added to neutralize this solution, and the aqueous layer was etacted 3 times with ethyl acetate (5 ml). The organic layers were combined, washed 3 times with saturated brine (5 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained crude crystals were purif ied by washing with hexane to give 4methoxy-3-pentylaminobenzoic acid (356 mg, 71%) as colorless crystals.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[OH:19][CH2:20][CH:21]1[CH2:24][CH:23]([OH:25])[CH2:22]1>>[C:13]1([C:12]#[C:11][C:8]2[CH:7]=[N:6][C:5]([O:25][C@H:23]3[CH2:24][C@H:21]([CH2:20][OH:19])[CH2:22]3)=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: OCC1CC(O)C1
Product: OC[C@H]1C[C@H](Oc2ncc(C#Cc3ccccc3)cn2)C1

Procedure:
The title compound, yellow solid, MS: m/e=281.1 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and 3-(hydroxymethyl)cyclobutanol by using Cs2CO3 as base and dioxane as solvent for 16 hours at 100° C. and by separation of the received isomers-mixture using a chiral column (Lux2 Cellulose with heptane:isopropanol 85:15 as solvent).
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:19][C:20]1[C:21]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3([CH2:58][OH:59])[CH2:57][CH2:56]3)=[CH:51][CH:50]=2)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH:38]=3)[C:34]([O:36]C)=[O:35])[N:25](COCC[Si](C)(C)C)[C:24]=2[CH:48]=1>O1CCOCC1>[Cl:19][C:20]1[C:21]([C:49]2[CH:54]=[CH:53][C:52]([C:55]3([CH2:58][OH:59])[CH2:56][CH2:57]3)=[CH:51][CH:50]=2)=[CH:22][C:23]2[N:27]=[C:26]([O:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:39])=[C:33]([CH:38]=3)[C:34]([OH:36])=[O:35])[NH:25][C:24]=2[CH:48]=1
Reactant: COC(=O)c1cc(Oc2nc3cc(-c4ccc(C5(CO)CC5)cc4)c(Cl)cc3n2COCC[Si](C)(C)C)ccc1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1COCCO1
Product: Cc1ccc(Oc2nc3cc(-c4ccc(C5(CO)CC5)cc4)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 80 °C
Reaction time: 1 h

Procedure:
TBAF (1M in THF) (0.35 mL, 0.35 mmol) was added to a solution of methyl 5-[(6-chloro-5-{4-[1-(hydroxymethyl)cyclopropyl]phenyl}-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazol-2-yl)oxy]-2-methylbenzoate (275 mg, 0.464 mmol) in dioxane (5 mL) and reaction mixture was heated at 80° C. The volatiles were removed. The resulting crude residue was dissolved in MeOH (2 ml) and 2.5 N aqueous NaOH (2 mL) and stirred at 50° C. for 1 h. Volatiles were removed and the residue was partitioned between EtOAc and water. The aqueous layer was acidified to pH=1 with 2 N aqueous HCl, and extracted with EtOAc. Combined organic layers were dried (MgSO4), filtered and concentrated. Purification by reverse phase HPLC eluting with 10-100% acetonitrile:water afforded the title compound. LC-MS calculated for C25H21ClN2O4 448.12, observed m/e 448.7 (M+H)+. Rt: 1.81/4 min. 1H NMR (500 MHz, CD3OD): δ 7.85 (s, 1H), 7.50 (s, 1H), 7.40-7.45 (m, 4H), 7.35 (d, 2H), 7.30 (s, 1H), 3.65 (s, 2H), 2.61 (s, 3H), 0.85-0.95 (q, 4H).
Reaction SMILES: [Mg].[CH3:2][CH2:3][O:4][C:5]([C@H:7]1[CH2:11][CH2:10][C:9](=[O:12])[N:8]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:6].O.Br[C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29]>O1CCCC1>[C:16]([O:15][C:13]([NH:8][C@H:7]([CH2:11][CH2:10][C:9]([C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1[F:29])=[O:12])[C:5]([O:4][CH2:3][CH3:2])=[O:6])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1C(=O)OC(C)(C)C
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCC(=O)c1cc(F)ccc1F)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium (0.569 g) in tetrahydrofuran (20 mL), 1-bromo-2,5-difluorobenzene (2.64 mL) was added dropwise at 55° C. over 15 minutes, and the reaction solution was stirred at room temperature for one hour. This solution was added dropwise to a solution of (R)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester (5.0 g) in tetrahydrofuran (25 mL) at −40° C. over 20 minutes, and the reaction solution was stirred at −40° C. to 0° C. for one hour. Water was added to the solution in small portions at 0° C., followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 5.7 g of the title compound as a colorless oil. The property values of the compound are as follows.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][OH:8].[CH3:9][S:10](Cl)(=[O:12])=[O:11].C(N(CC)CC)C.C(OC)(C)(C)C>C1(C)C=CC=CC=1.O>[CH3:9][S:10]([O:8][CH2:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)(=[O:12])=[O:11]
Reactant: OCC1CCCCO1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCCCO1
Reaction time: 2 h

Procedure:
In 200 ml of toluene, 23.2 g (200 mmol) of tetrahydropyran-2-ylmethanol were admixed with 27.5 g (240 mmol) of methanesulfonyl chloride. At 10° C., 24.3 g (240 mmol) of triethylamine were then added dropwise, and stirring was continued for 2 hours at room temperature. 200 ml of methyl tert-butyl ether and 200 ml of water were then added to the mixture and the organic phase was separated off, washed with 200 ml of water and dried. Removal of the solvent under reduced presure gave 33.7 g (87% of theory) of a clear oil. (1H-NMR (CDCl3; δ in ppm): 4.20 (d,2H); 4.05 (dd,1H); 3.60 (m,1H); 3.45 (m,1H); 3.1 (s,3H); 1.95 (m,1H); 1.45 (m,5H))
Reaction SMILES: [I-].[CH:2]1([N+:12]2([CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH2:18]>>[OH-:18].[CH:2]1([N+:12]2([CH3:17])[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O
Agent: C[N+]1(C2CCCCCCCCC2)CCCC1
Agent: [I-]
Product: [OH-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-cyclodecyl-N-methyl-pyrrolidinium iodide (45 gm; 0.128 mol) was dissolved in 150 ml water in a 500 ml plastic bottle. To the solution, 160 gm of Ion-Exchange Resin-OH (BIO RAD® AHI-X8) was added and the mixture was stirred at room temperature overnight. The mixture was filtered and the solids were rinsed with an additional 85 ml of water. The reaction afforded 0.12 mole of the SDA (N-cyclodecyl-N-methyl-pyrrolidinium hydroxide) as indicated by titration analysis with 0.1N HCl.
Reaction SMILES: [C:1]([C:3]([C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][CH:21]=1)[C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=1)=[O:10])([CH3:5])[CH3:4])#[N:2].F[C:23]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([C:3]([C:6]1[CH:7]=[C:8]([C:9]([NH:11][C:12]2[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=2)[O:18][C:23]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])=[O:10])[CH:19]=[CH:20][CH:21]=1)([CH3:5])[CH3:4])#[N:2]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(O)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.3 %

Procedure:
To a solution of 3-(1-cyano-1-methylethyl)-N-(3-hydroxyphenyl)benzamide (5.0 g, 17.8 mmol) produced in Example 1(i) and methyl 2-fluoro-5-nitrobenzoate (3.55 g, 17.8 mmol) in N,N-dimethylformamide (50 mL) was added potassium carbonate (3.68 g, 26.7 mmol), and the mixture was stirred at room temperature for 16 hr. Insoluble material was filtered off and washed with ethyl acetate (200 mL). The filtrate and washings were combined and washed successively with 5% aqueous sodium hydrogen carbonate solution (200 mL) and saturated brine (200 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (8.45 g, 98%) as a white powder.
Reaction SMILES: C([O:3][C:4]([CH:6]1[N:36](C(OC(C)(C)C)=O)[CH2:35][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24](=[O:34])[NH:25][C:26]3[CH:30]=[C:29]([CH:31]5[CH2:33][CH2:32]5)[O:28][N:27]=3)[CH:19]=[CH:18]4)[C:8]=2[CH2:7]1)=O)C.[Li+].[OH-].C(Cl)(=O)C(Cl)=O.[CH3:52][NH2:53]>C1COCC1.CCO.O.CN(C=O)C>[CH3:52][NH:53][C:4]([CH:6]1[NH:36][CH2:35][C:9]2[N:10]=[CH:11][N:12]=[C:13]([O:14][C:15]3[CH:16]=[C:17]4[C:21](=[CH:22][CH:23]=3)[N:20]([C:24](=[O:34])[NH:25][C:26]3[CH:30]=[C:29]([CH:31]5[CH2:32][CH2:33]5)[O:28][N:27]=3)[CH:19]=[CH:18]4)[C:8]=2[CH2:7]1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)C1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C4CC4)on3)c2)CN1C(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CNC(=O)C1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cc(C4CC4)on3)c2)CN1

Procedure:
To a solution of 4-[1-(5-cyclopropyl-isoxazol-3-ylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidine-6,7-dicarboxylic acid 7-tert-butyl ester 6-ethyl ester (110 mg, 0.196 mmol) in THF/EtOH/H2O (3:1:1 mL) LiOH (0.016 g, 0.392 mmol) is added and the reaction stirred until starting material is consumed. At this point the reaction is quenched with 1N HCl (2 mL) and extracted with EtOAc. After drying and evaporation, the crude product is dissolved in DCM (3 mL) at 0° C., oxalyl chloride (0.026 mL, 0.294 mmol) and DMF (2 drops) are added. At this point Methylamine (2 M in THF) (0.49 mL, 0.981 mmol) is added and the reaction stirred for 1 h at rt. After work up with water and extraction with EtOAc the crude product is dissolved in DCM (2 mL) and TFA (1 mL) is added. After removing the solvent in vacuo, and basifying with NH4OH, the product is separated using FCC eluting with DCM:MeOH:NR4OH 100:0:0 to 90:8:2. MS (ESI) m/z 474.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.21 (s, 1 H) 8.43 (s, 1 H) 8.21-8.33 (m, 1 H) 8.15 (d, J=3.79 Hz, 1 H) 7.94 (d, J=5.81 Hz, 1 H) 7.44 (d, J=2.27 Hz, 1 H) 7.12 (d, J=9.09 Hz, 1 H) 6.75 (d, J=3.03 Hz, 1 H) 6.65 (s, 1 H) 3.91-4.15 (m, 2 H) 3.61 (br. s, 1 H) 2.83-2.95 (m, 2 H) 2.66 (d, J=4.80 Hz, 3 H) 2.12-2.24 (m, 1 H) 1.03-1.17 (m, 2 H) 0.94 (dd, J=4.80, 2.53 Hz, 2 H).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)(=[O:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:7]2[NH:6][C:5]3[CH:21]=[CH:22][C:2]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:23](=[O:25])[CH3:24])=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Reactant: CC(=O)c1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 90 °C
Yield: 87.2 %

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.450 g, 1.21 mmol), 2-acetylphenylboronic acid (0.298 g, 1.82 mmol), sodium carbonate (0.771 g, 7.26 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.079 g, 0.121 mmol) in DME (10 mL) and H2O (2.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the product as a yellow oil (0.433 g, 87%).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:35][C@@H:36]([CH2:48][CH3:49])[CH:37]([C:39]1[O:40][C:41]2[C:42]([N:47]=1)=[N:43][CH:44]=[CH:45][CH:46]=2)[OH:38].CN1CCOCC1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(OCC)(=O)C.C([O-])(O)=O.[Na+].ClCCl>[CH3:1][C:2]1([CH2:7][CH:8]([CH2:12][C:13]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[O:14])[C:9]([NH:35][CH:36]([C:37]([C:39]2[O:40][C:41]3[C:42]([N:47]=2)=[N:43][CH:44]=[CH:45][CH:46]=3)=[O:38])[CH2:48][CH3:49])=[O:11])[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(CC(CC(=O)N2CCOCC2)C(=O)O)CCCC1
Reactant: CC[C@H](N)C(O)c1nc2ncccc2o1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CCC(NC(=O)C(CC(=O)N1CCOCC1)CC1(C)CCCC1)C(=O)c1nc2ncccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
2-(1-Methyl-cyclopentylmethyl)-4-morpholin-4-yl-4-oxo-butyric acid (100 mg, 0.35 mmol) was combined with EDC (250 mg, 1.3 mmol), HOBt (250 mg, 1.6 mmol), and (2S)-2-amino-1-oxazolo[4,5-b]pyridin-2-yl-butan-1-ol (100 mg, 0.48 mmol). Dichloromethane (4 mL) was added and then 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with 1N aqueous HCl, water, saturated aqueous NaHCO3 solution and brine, dried with MgSO4 and evaporated under vacuum. The crude product was dissolved in dry dichloromethane (10 mL) and Dess-Martin Periodinane (500 mg, 1.2 mmol) was added. After stirring at ambient temperature for 1 hour, the mixture was diluted with ethyl acetate (150 mL) and treated with 0.26M Na2S2O3 solution in saturated aqueous NaHCO3. The organic phase was washed with saturated aqueous NaHCO3 and brine, dried with MgSO4 and evaporated. The product was purified by flash chromatography on silica gel (hexane/ethyl acetate 1:1) to yield the title compound (40 mg; 0.085 mmol) as a mixture of diastereomers.
Reaction SMILES: [CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:8]([F:18])[CH:7]=1)[C:3]([OH:5])=[O:4].[S]>C1(OC2C=CC=CC=2)C=CC=CC=1.CC(C)=O>[CH3:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([F:18])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(C(=O)O)c1ccc(C2CCCCC2)c(F)c1
Agent: [S]
Solvent: CC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Temperature: 250 °C
Reaction time: 6 h
Yield: 45.1 %

Procedure:
A mixture of 5.00 g of α-methyl-4-cyclohexyl-3-fluorophenylacetic acid (m.p. 83° to 84° C.) and 2.3 g of sulphur in 10 ml of diphenyl ether was subjected to heating with stirring at 250° C. for 6 hours. The resulting reaction liquid was dissolved in acetone, and the insoluble substances were removed by filtration. The filtrate was poured into an aqueous sodium hydroxide solution. The resulting mixture was repeatedly washed with benzene, and hydrochloric acid was added to the aqueous layer. The crystals thus precipitated were collected by filtration, and recrystallized from a mixed benzene-n-hexane solvent to obtain 2.2 g of α-methyl-2-fluoro-4-biphenylylacetic acid (m.p. 112° to 114° C.).