Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:10]2[CH:11]=[CH:12][C:13](B(O)O)=[N:14][CH:15]=2)[CH:7]=[CH:8][CH:9]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:21]=1.C(Cl)Cl>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:19][C:20]1[CH:25]=[C:24]([C:12]2[CH:13]=[N:14][CH:15]=[C:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=3)[CH:11]=2)[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[N:21]=1
Reactant: Clc1cc(Cl)nc(-c2ccccn2)n1
Reactant: COc1cccc(-c2ccc(B(O)O)nc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: ClCCl
Solvent: COCCOC
Product: COc1cccc(-c2cncc(-c3cc(Cl)nc(-c4ccccn4)n3)c2)c1
Temperature: 25 °C

Procedure:
A solution of 5-(3-methoxy-phenyl)-pyridine boronic acid hydrochloride (Int. D) (1 eq, 59 mg) in DME (1 ml) and 2M sodium carbonate (0.4 ml) is treated with 4,6-dichloro-2-pyridin-2-yl-pyrimidine (Int. C) (1 eq, 50 mg) and placed under an atmosphere of argon. PdCl2(dppf).DCM (0.1 eq. 16 mg) is added and the reaction mixture is heated using microwave radiation at 90° C. for 1 h. After cooling to room temperature, the mixture is partitioned between EtOAc/water and the organic portion is separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA) and the appropriate fractions are combined and concentrated in vacuo. The residue is loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are concentrated in vacuo and dried under vacuum overnight to afford the title compound [M+H]+=375/377.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:5]=1
Reactant: CCCCCBr
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCCOc1cccc(C(=O)OC)c1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
To 3-hydroxybenzoic acid methyl ester (25 g) and potassium carbonate (25 g) in N,N-dimethylformamide (300 ml) were added 1-bromopentane (25 ml) and the mixture was stirred for 7 hours at 80° C. the reaction mixture was added to a mixture of water and ethyl acetate. The organic layer was taken and dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was evaporated under reduced pressure to give 3-amyloxybenzoic acid methyl ester (35 g).
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].S([O-])([O-])(=O)=O.[NH4+].[NH4+].P([O-])(O)(O)=O.[K+].S([O-])([O-])(=O)=O.[Mg+2].Cl>>[ClH:1].[NH2:2][C@@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8]
Reactant: NCCCCC(N)C(=O)O
Agent: Cl
Agent: O=P([O-])(O)O
Agent: O=S(=O)([O-])[O-]
Product: NCCCC[C@@H](N)C(=O)O
Reaction time: 0.17 h

Procedure:
Into a shaking flask having a volume of 500 ml was charged 100 ml of a medium (pH 7.0) comprising 2% of DL-lysine monohydrochloride, 0.2% of ammonium sulfate, 0.1% of potassium dihydrogen phosphate, 0.05% of magnesium sulfate and 0.02% of a yeast extract, and the medium was sterilized at 120° C. for 10 minutes. A loopful of Yarrowia lipolytica IFO 1209 was inoculated into the medium, and cultured at 30° C. for 168 hours with shaking. The cell was removed by centrifuging 1000 ml of the above culture broth to obtain a supernatant. After the supernatant was adjusted to have pH 6.0 with hydrochloric acid, ultrafiltration was carried out in order to remove protein and others, whereby a filtrate was obtained. After activated carbon was added to the filtrate to effect decolorization, the filtrate was concentrated under reduced pressure, and 200 ml of ethanol was added to 20 g of the concentrate to obtain 5.8 g of D-lysine monohydrochloride as crude crystals. 5.8 ml of water was added to the crude crystals, and the crude crystals were dissolved by heating, and then recrystallized by cooling to obtain 2.9 g of crystals of D-lysine monohydrochloride.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][N:14]=3)[CH:11]=2)[N:6]([C:27](=[O:29])[CH3:28])[C@@H:5]([CH3:30])[CH2:4]1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:38][C:34]1[CH:33]=[C:32]([NH:2][C@H:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[O:20])=[CH:15][N:14]=4)[CH:11]=3)[N:6]([C:27](=[O:29])[CH3:28])[C@@H:5]([CH3:30])[CH2:4]2)[CH:37]=[CH:36][CH:35]=1
Reactant: Clc1cccc(Br)c1
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](N)C[C@@H]1C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)N4CCOCC4)cn3)cc2[C@H](Nc2cccc(Cl)c2)C[C@@H]1C
Temperature: 120 °C
Yield: 9.2 %

Procedure:
1-((2S,4R)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone hydrochloride (for a preparation see Intermediate 65) (120 mg, 0.278 mmol), 1-bromo-3-chlorobenzene (0.065 mL, 0.557 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (21.9 mg, 0.056 mmol), tris(dibenzylideneacetone)dipalladium(0) (25.5 mg, 0.028 mmol) and sodium tert-butoxide (37.5 mg, 0.390 mmol) were combined in 1,4-dioxane (2 mL) and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 120° C. for 25 mins. The reaction mixture was partitioned between water (50 mL) and DCM (3×50 mL). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue which was purified by MDAP (HpH) to give 1-((2S,4R)-4-((3-chlorophenyl)amino)-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (13 mg, 0.026 mmol, 9.2% yield).
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]([F:25])([F:24])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[N:15][C:14]([N:17]3[CH2:23][CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[H-].[Na+].[Cl:35][CH:36]([CH3:38])[CH3:37]>C1COCC1.CN(C)C=O>[ClH:35].[ClH:1].[CH:36]([N:20]1[CH2:21][CH2:22][CH2:23][N:17]([C:14]2[N:15]=[N:16][C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([F:24])([F:3])[F:25])=[CH:6][CH:7]=3)=[CH:12][CH:13]=2)[CH2:18][CH2:19]1)([CH3:38])[CH3:37]
Reactant: FC(F)(F)c1ccc(-c2ccc(N3CCCNCC3)nn2)cc1
Reactant: CC(C)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)N1CCCN(c2ccc(-c3ccc(C(F)(F)F)cc3)nn2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.9 %

Procedure:
4-[6-(4-Trifluoromethylphenyl)pyridazin-3-yl][1,4]diazepane, dihydrochloride (0.028 g, 0.071 mmol) was suspended in THF (4 mL) and triethylamine (0.022 g, 0.21 mmol) was added. Sodium hydride (0.0085 g, 0.35 mmol) was added and the reaction mixture was stirred at rt for 20 min. Dry N,N-dimethylformamide (1 mL) and 2-chloropropane (0.056 g, 0.71 mmol) was added and the reaction mixture was heated 30 min at 160° C. and 30 min at 180° C. in a microwave oven. The reaction mixture was purified on a silicagel column (0.04-0.063 mesh) using dichloromethane/MeOH (9:1) as eluent. This afforded a crude oil containing several components that was purified further by preparative HPLC using Method B. This afforded 9 mg of an oil which was dissolved into MeOH. Addition of HCl in diethyl ether afforded 6.5 mg (21%) of the title compound as an oily dihydrochloride.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].O>C(Cl)(Cl)Cl>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[N:10]([CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[C:32](=[O:34])[CH3:33])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)N(CC1CCN(C(=O)OC(C)(C)C)CC1)[C@@H]1C[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 81.8 %

Procedure:
To a solution of tert-butyl 4-((trans-2-phenylcyclopropyl)amino)methyl)piperidine-1-carboxylate (Example 1, 80 mg, 0.242 mmol) in chloroform (5 mL) was added triethylamine (0.067 mL, 0.484 mmol) followed by acetyl chloride (0.022 mL, 0.315 mmol). The solution was stirred for 1 hour, and then water (5 mL) was added. The layers were separated and the organic layer was washed with brine, dried over MgSO4 and filtered. The solution was then evaporated. tert-Butyl 4-((N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-1-carboxylate (80 mg, 0.198 mmol, 82% yield) was isolated as yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.30-7.37 (m, 2H), 7.21-7.28 (m, 1H), 7.08 (d, J=7.07 Hz, 2H), 4.03-4.25 (m, 2H), 3.53 (dd, J=7.58, 13.64 Hz, 1H), 3.06-3.25 (m, 1H), 2.78-2.87 (m, 1H), 2.61-2.77 (m, 2H), 2.22 (td, J=2.65, 4.86 Hz, 1H), 2.18 (s, 3H), 1.82-1.98 (m, 1H), 1.54-1.72 (m, 2H), 1.47 (s, 9H), 1.36-1.45 (m, 2H), 1.06-1.25 (m, 2H); LC-MS Rt=1.09 min; MS (ESI): 373.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][NH:12][C@@H:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:14][CH:15]=[CH2:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([CH3:31])[CH:30]=1)[C:25](Cl)=[O:26]>>[CH2:1]([O:8][C:9]([NH:11][N:12]([C@@H:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:14][CH:15]=[CH2:16])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([CH3:31])[CH:30]=[C:22]([CH3:21])[CH:23]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: C=CC[C@@H](NNC(=O)OCc1ccccc1)C(C)(C)C
Product: C=CC[C@@H](N(NC(=O)OCc1ccccc1)C(=O)c1cc(C)cc(C)c1)C(C)(C)C

Procedure:
Briefly, benzyl carbazate (compound A) was reacted with pivaldehyde to give (E)-N′-(2,2-dimethyl-propylidene)-hydrazinecarboxylic acid benzyl ester (compound B). Compound B was reacted with (S,S)-2-allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]oxazasilolidine (Compound C; see Leighton et al., J. Am. Chem. Soc. 125:9596 (2003) and WO 03/074534) to give (R)—N′-(1-tert-butyl-but-3-enyl)-hydrazinecarboxylic acid benzyl ester (compound D). Compound D was reacted with 3,5-dimethyl benzoyl chloride to give (R)—N′-(1-tert-butyl-but-3-enyl)-N′-(3,5-dimethyl-benzoyl)-hydrazinecarboxylic acid benzyl ester (compound B). Compound E was hydrogenated to give (R)-3,5-dimethyl-benzoic acid N-(1-tert-butyl-butyl)-hydrazide (compound F). Compound F was reacted with 2-ethyl-3-methoxybenzoyl chloride to give Compound 1. The crude material was triturated first with ether (2% ethanol) and then with 1:1 hexanes:ether in a fritted glass Büchner funnel. The product was then washed with deionized water with thorough mixing and allowed to dry in air. Compound 1 was isolated as a white powder.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22][C:21](=O)[CH2:20]1)[CH3:18].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=5)(=[O:37])=[O:38])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22][C:21](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:20]1)[CH3:18]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC[C@@H]1CC(=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C=C1C[C@@H](CC)[C@@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1
Yield: 89.3 %

Procedure:
To a slurry of sodium hydride (0.227 g, 5.67 mmol, 60% dispersion in oil) in THF (30 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (1.18 mL, 5.90 mmol). After about 30 min a solution of (cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (2.00 g, 4.72 mmol) in THF (1.0 mL) was added. After about 4 h EtOAc and sat NaHCO3 were added. The organic layer was separated concd in vacuo and purified by flash chromatography on silica gel eluting with 20-100% EtOAc in DCM to afford ethyl 2-((cis)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate (2.08 g, 89%): LC/MS (Table 1, Method c) Rt=2.52-2.56 min; MS m/z: 494 (M+H)+ as a mixture of diastereomers and ethyl 2-((cis)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate (0.150 g, 9%), as a mixture of diastereomers: LC/MS (Table 1, Method a) Rt=1.85-1.89; MS m/z: 340 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([CH2:10][N:11]([CH2:25][CH2:26][CH3:27])[C:12]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:13]=2[CH:14]=[N:15]O)[CH2:9][CH2:8]1.O.[OH-].[Na+]>O1CCCC1>[NH2:15][CH2:14][C:13]1[CH:17]=[C:18]([C:21]([F:23])([F:24])[F:22])[CH:19]=[CH:20][C:12]=1[N:11]([CH2:10][CH:7]1[CH2:9][CH2:8]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=NO
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium aluminum hydride (1.4 g) is suspended in tetrahydrofuran (50 ml) and thereto is added dropwise a 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde oxime (5.7 g) in tetrahydrofuran (20 ml) under ice-cooling, and the mixture is stirred at room temperature overnight. To the reaction solution are added water (1.4 ml), a 2N-aqueous sodium hydroxide solution (2.8 ml) and water (2.8 ml) successively under ice-cooling, and the insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (chloroform:ethyl acetate=10:1) to give (2-aminomethyl-4-trifluoromethyl-phenyl)-cyclopropylmethyl-propyl-amine as a crude product (5.1 g).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:21]([OH:23])=O)[N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.CCN=C=NCCCN(C)C.[NH2:35][C:36]1[N:37]=[C:38]([C:42]([O:44][CH3:45])=[O:43])[N:39]([CH3:41])[CH:40]=1>CN(C=O)C.CN(C1C=CN=CC=1)C>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([C:21]([NH:35][C:36]3[N:37]=[C:38]([C:42]([O:44][CH3:45])=[O:43])[N:39]([CH3:41])[CH:40]=3)=[O:23])[N:18]([CH3:20])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: COC(=O)c1nc(N)cn1C
Reactant: Cn1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(NC(=O)c2cc(-c3ccc(N)cc3)cn2C)cn1C
Reaction time: 6 h

Procedure:
0.3 gm of boc protected 6 (0.94 mmol, 1.2 eq) was dissolved in DMF (5 mL) to which 2.0 eq of EDCI and 2.5 eq of DMAP were added. The mixture was allowed to stir for 30 minutes after which commercially available methyl 4-amino-1-methyl-1H-imidazole-2-carboxylate (0.121 g, 0.79 mmol, 1.0 eq) was added. The reaction mixture was allowed to stir for a further 6 hour at which point TLC showed completion of reaction. The reaction was quenched by pouring it onto a mixture of ice/water mixture and the resulting mixture was extracted with ethyl acetate (3×150 mL). The combined extracts were sequentially washed saturated aqueous NaHCO3 (50 mL), water (50 mL), brine (50 mL) and finally dried over MgSO4. Excess ethyl acetate was evaporated by rotary evaporator under reduced pressure and the crude product (0.48 gm) was used for the boc deprotection step to afford 11. For boc deprotection, the crude intermediate was dissolved in a small volume of MeOH and 4M HCl in dioxane (5 mL) was added slowly to the stirring solution. The reaction mixture was stirred for 2 hours at which point TLC showed completion of reaction. Excess solvent was evaporated under vacuum to obtain a brown coloured solid (11). The solid product was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give pure 11. Yield 0.35 gm, 81% over two steps.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[S:15][C:16](Cl)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:25]1([OH:31])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH-].[K+].CN(C=O)C>CCOC(C)=O.O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[S:15][C:16]([O:31][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCC3)sc1Cl
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(C)=O)CCC3)sc1Oc1ccccc1
Temperature: 70 °C
Yield: 71.3 %

Procedure:
To ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-chlorothiazole-4-carboxylate (1J) (0.250 g, 0.69 mmol), phenol (0.129 g, 1.4 mmol), and KOH (0.284 g, 2.1 mmol) was added DMF (10 mL). The reaction mixture was allowed to heat to 70° C. for 72 hours. The reaction mixture was cooled to rt and diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography on silica gel eluting with a gradient of 0 to 80% EtOAc in hexanes to provide 0.208 g (72%) ethyl 2-(1-acetyl-1,2,3,4-tetrahydroquinolin-7-yl)-5-phenoxythiazole-4-carboxylate (21A): LC/MS (APCI): m/z 424.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]([CH3:23])([CH3:22])[CH2:19][CH2:20][NH2:21].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:21][CH2:20][CH2:19][C:18]([CH3:23])([CH3:22])[CH3:17])[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)CCN
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)CCNC(=O)[C@@H]1C[C@H]2C[C@H]2N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (300 mg, 1.32 mmol), 3,3-dimethyl-butylamine (134 mg, 1.32 mmol) and HBTU (751 mg, 1.98 mmol) in CH2Cl2 (9 mL) under a nitrogen atmosphere was added DIPEA (0.922 mL, 5.28 mmol). The reaction mixture was stirred at RT for 16 h. CH2Cl2 and water were added, the phases were separated and the aqueous layer extracted with CH2Cl2 (×2). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual material was purified by flash chromatography on silica gel (c-hexane/AcOEt 1-0 to 0-1) to give the title compound. TLC, Rf (EtOAc)=0.85.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.CO.[OH-].[Li+].Cl>O.O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[C:7]2[C:12]=1[N:11]=[C:10]([CH2:17][CH3:18])[C:9]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)=[C:8]2[O:27][CH:28]([F:30])[F:29]
Reactant: CCc1nc2c(Cl)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2c(Cl)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(F)cc1

Procedure:
A solution of [8-chloro-4-difluoromethoxy-2-ethyl-3-(4-fluorobenzyl)quinolin-5-yloxy]acetic acid methyl ester (0.060 g), methanol (1.5 mL), tetrahydrofuran (1.5 mL), water (1.0 mL) and lithium hydroxide (0.01 g) was stirred at room temperature for 1 hour. The mixture was acidified by the addition of 1.0 M aqueous hydrochloric acid, extracted with ethyl acetate and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by preparative reverse-phase HPLC using a gradient of acetonitrile in water gave title compound as a yellow solid, 0.022 g.
Reaction SMILES: [OH:1][CH:2]([C:6]1[C:7]([CH:12]([CH3:14])[CH3:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>N1C=CC=CC=1>[CH3:15][S:16]([O:1][CH:2]([C:6]1[C:7]([CH:12]([CH3:14])[CH3:13])=[N:8][CH:9]=[N:10][CH:11]=1)[CH:3]([CH3:5])[CH3:4])(=[O:18])=[O:17]
Reactant: CC(C)c1ncncc1C(O)C(C)C
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)c1ncncc1C(OS(C)(=O)=O)C(C)C
Temperature: 0 °C
Yield: 90.5 %

Procedure:
8.3 g (43 mmol) of 5-(1-hydroxy-2-methylpropyl)-4-isopropylpyrimidine was dissolved in 10 ml of pyridine, and under cooling with ice, 9.8 g (86 mmol) of methylsulfonyl chloride was dropwise added. The reaction mixture was reacted at room temperature for 2 hours, and then, 100 ml of ice water was added, followed by extraction with ethyl acetate. The obtained organic layer was washed with an aqueous citric acid solution and water and then dried over anhydrous magnesium sulfate. Ethyl acetate was distilled off under reduced pressure to obtain 10.6 g (yield: 90%) of 5-(1-methylsulfonyloxy-2-methylpropyl)-4-isopropylpyrimidine.