Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].[C:8]([C@H:12]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[C:20]([C:31]([F:34])([F:33])[F:32])=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([CH:29]=O)[CH:23]=[CH:22]3)[CH2:14][CH2:13]1)([CH3:11])([CH3:10])[CH3:9].C(O)C.C([BH3-])#N.[Na+]>>[C:8]([C@H:12]1[CH2:17][CH2:16][C@H:15]([O:18][C:19]2[C:20]([C:31]([F:32])([F:33])[F:34])=[C:21]3[C:26](=[CH:27][CH:28]=2)[CH:25]=[C:24]([CH2:29][NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])[CH:23]=[CH:22]3)[CH2:14][CH2:13]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C=O)ccc3c2C(F)(F)F)CC1
Reactant: NCCS(=O)(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(CNCCS(=O)(=O)O)ccc3c2C(F)(F)F)CC1
Temperature: 25 °C

Procedure:
Taurine (0.03737 g, 0.2986 mmol) was added to a solution of 6-(trans-4-tert-butylcyclohexyloxy)-5-(trifluoromethyl)-2-naphthaldehyde (0.1130 g, 0.2986 mmol) in Ethanol (3.00 mL, 51.4 mmol) and the mixture was refluxed for 1 hour. The mixture was cooled to room temperature and Sodium cyanoborohydride (0.02252 g, 0.3583 mmol) was added. The mixture was then refluxed overnight. The reaction mixture was cooled to room temperature, washed with saturated aqueous citric acid solution (4 ml), then concentrated to dryness under reduced pressure. The resulting solid was washed with water and filtered. The residue was washed with water (10 mL), ether (10 mL) and hexane (10 mL) consecutively, then filtered. The residue was purified by prep HPLC to give the title compound. ESI-MS(M+H+): 488.3; 1H NMR (400 MHz, DMSO-d6) Shift 8.46-8.52 (m, 1H), 7.83-7.88 (m, 1H), 7.73-7.80 (m, 2H), 7.35-7.40 (m, 2H), 4.21-4.30 (m, 1H), 4.02 (br. s., 2H), 2.88 (t, J=6.78 Hz, 2H), 2.50 (d, J=13.80 Hz, 2H), 1.77-1.85 (m, 2H), 1.43-1.52 (m, 2H), 1.00-1.13 (m, 2H), 0.67-0.92 (m, 3H), 0.53 (s, 9H).
Reaction SMILES: [Na].[C:2]([NH:5][CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3].[CH:17](=[O:22])/[CH:18]=[CH:19]/[CH2:20][CH3:21]>CCO>[C:2]([N:5]1[CH:17]([OH:22])[CH2:18][CH:19]([CH2:20][CH3:21])[C:6]1([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:4])[CH3:3]
Reactant: CC/C=C/C=O
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)C(CC)CC(O)N1C(C)=O
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Sodium (4.02 g, 0.175 mol) was dissolved in a stirred solution of diethyl acetamidomalonate (235.4 g, 1.19 mol) in abs EtOH (1.4 L) at ambient temperature under argon. The reaction mixture was cooled to 0° C., and trans-2-pentenal (100 g, 1.08 mol) was added dropwise maintaining the reaction temperature at <5° C. After the addition, the reaction was allowed to warm to room temperature, stirred for 4 h, then quenched with acetic acid (28 mL). The solution was concentrated in vacuo, and the residue dissolved in EtOAc (1.5 L), washed with 10% NaHCO3 solution (2×300 mL), brine, and dried (MgSO4). The solution was filtered and concentrated to 700 mL, then heated to reflux and treated with hexane (1 L). On cooling, the title compound precipitated and was collected, mp 106°-109° C. 1H NMR (CD3OD) δ 5.65 (d, 1H, J=5 Hz), 4.1-4.25 (m, 4H), 2.7-2.8 (m, 1H), 2.21 (s, 3H), 2.10 (dd, 1H, J=6, 13, Hz),1.86-1.97 (m, 2H), 1.27 (t, 3H, J=7 Hz), 1.23 (t, 3H, J=7 Hz), 1.1-1.25 (m, 1H), 0.97 (t, 3H, J=7 Hz).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:12]=[C:13]([C:22]2[N:23]=[C:24]3[N:28]([CH:29]=2)[CH2:27][CH2:26][S:25]3)[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]=1[OH:17])([CH3:10])([CH3:9])[CH3:8].Cl.NO.[CH3:33][N:34](C)C=O>C(Cl)CCl.N1C=CC=CC=1>[C:33]([C:29]1[N:28]2[C:24]([S:25][CH2:26][CH2:27]2)=[N:23][C:22]=1[C:13]1[CH:14]=[C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:16]([OH:17])=[C:11]([C:7]([CH3:8])([CH3:9])[CH3:10])[CH:12]=1)#[N:34]
Reactant: CN(C)C=O
Reactant: CC(C)(C)c1cc(-c2cn3c(n2)SCC3)cc(C(C)(C)C)c1O
Agent: Cl
Agent: NO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(-c2nc3n(c2C#N)CCS3)cc(C(C)(C)C)c1O

Procedure:
To a mixed solution of 0.5 g of dimethylformamide and 10 ml of ethylene dichloride was added dropwise a solution of 0.9 g of oxalyl chloride in 5 ml of ethylene dichloride under ice-cooling. After allowing to stand the mixture for 15 minutes at room temperature, a solution of 2 g of 6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole dissolved in a mixture of 3 ml of dimethylformamide and 10 ml of ethylene dichloride was added dropwise to the solution and the resultant mixture was stirred for 2 hours. Then, a solution of 0.5 g of hydroxylamine hydrochloride dissolved in a mixture of 1.5 ml of dimethylformamide and 0.6 ml of pyridine was added to the reaction mixture and the resultant mixture was refluxed overnight. The reaction mixture was washed with 30 ml of an aqueous 5% sodium hydrogen carbonate solution, dried, and then concentrated. The residue thus formed was purified by silica gel column chromatography using chloroform as the eluent and further recrystallized from ethanol to provide 0.33 g of 5-cyano-6-(3,5-di-tert-butyl-4-hydroxyphenyl)-2,3-dihydroimidazo[2,1-b]thiazole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:9]([CH2:12][C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[CH3:20])(=[O:11])=[O:10])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.C(Cl)(Cl)(Cl)[Cl:22].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([S:9]([CH:12]([Cl:22])[C:13]2[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=2[CH3:20])(=[O:11])=[O:10])=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cc1ccc(C)c(CS(=O)(=O)c2c(Cl)ccc[n+]2[O-])c1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C)c(C(Cl)S(=O)(=O)c2c(Cl)ccc[n+]2[O-])c1
Temperature: 15 °C

Procedure:
To a suspension of 2.2 g (0.01 mole) of 3-chloro-2-[[1-(2,5-dimethylphenyl)-methyl]sulfonyl]pyridine-N-oxide in 10 ml of dimethylformamide (DMF) was added 2 g (0.013 mole) of carbon tetrachloride. The mixture was cooled to 15° C. and then treated with 0.5 g (0.013 mole) of NaOFl. The mixture was stirred and allowed to warm to room temperature for two hours. It was then poured into cold water and the solid was filtered off, having a melting point of 125-127° C. Infrared and NMR spectra were consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)(=[O:28])=[O:27])[CH2:9][C:10]([NH:12][C@@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=O)[CH:19]=3)[CH2:14]2)=[O:11])=[CH:4][CH:3]=1.[CH:39](C1C=C2C(=CC=1)C[C@H](N)CC2)=C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:25][S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=2)(=[O:27])=[O:28])[CH2:9][C:10]([NH:12][C@@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH:23]=[CH2:39])[CH:19]=3)[CH2:14]2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=Cc1ccc2c(c1)CC[C@@H](NC(=O)C[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)C2
Reactant: C=Cc1ccc2c(c1)CC[C@@H](N)C2
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: C=Cc1ccc2c(c1)CC[C@@H](NC(=O)C[C@@H](NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1)C2

Procedure:
A solution of 3-(R)-(4-fluoro-phenyl)-N-(6-formyl-1,2,3,4-tetrahydro-naphthalen-2-(R)-yl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (391 mg, 1 mmol), crude (6-vinyl-1,2,3,4-tetrahydro-naphthalen-2-(R)-yl)-amine (190 mg, 1.1 mmol), HOBt (135 mg, 1 mmol) and EDC (191 mg, 1 mmol) in 2 mL of DMF was stirred overnight at RT. After quenching with Sat. NaHCO3 solution, the reaction mixture was extracted with EtOAc. The combined organic phase was washed brine, dried over Na2SO4, and evaporated in vacuo. Flash chromatography (SiO2, hexane/EtOAc=1:2) gave the desired compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:17][C:16]=2[CH3:28])=[CH:11][C:10]=1[CH2:29][OH:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[C:32]1[CH:45]=[CH:44][C:35]2[C@H:36]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:37][O:38][C:34]=2[CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][C@@H:23]3[CH2:27][CH2:26][O:25][CH2:24]3)=[CH:17][C:16]=2[CH3:28])=[CH:11][C:10]=1[CH2:29][O:30][C:32]1[CH:45]=[CH:44][C:35]2[C@H:36]([CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:37][O:38][C:34]=2[CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Cc1cc(O[C@@H]2CCOC2)cc(C)c1-c1ccc(OCc2ccccc2)c(CO)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C[C@@H]1COc2cc(OCc3cc(-c4c(C)cc(O[C@@H]5CCOC5)cc4C)ccc3OCc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.5 %

Procedure:
(R)-(4-(Benzyloxy)-2′,6′-dimethyl-4′-((tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methanol 36a (637 mg, 1.69 mmol) was dissolved in 20 mL of dichloromethane, followed by addition of methyl (S)-2-(6-hydroxyl-2,3-dihydrobenzofuran-3-yl)acetate (423 mg, 2.03 mmol) and triphenylphosphine (532 mg, 2.03 mmol). The reaction solution was cooled down to 0° C., followed by addition of diisopropyl azodicarboxylate (411 mg, 2.03 mmol), then warmed up to room temperature and stirred for 12 hours. The resulting solution was concentrated under reduced pressure to obtain the crude title compound methyl 2-((S)-6-((4-(benzyloxy)-2′,6′-dimethyl-4′-(((R)-tetrahydrofuran-3-yl)oxy)biphenyl-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetate 36b (1 g) as a brown oil, which was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:32]C)=[C:6]([C:8]([CH3:31])([CH3:30])[CH2:9][C:10]([C:26]([F:29])([F:28])[F:27])([OH:25])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][OH:24])=[N:18]3)[CH:7]=1.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:32])=[C:6]([C:8]([CH3:30])([CH3:31])[CH2:9][C:10]([C:26]([F:27])([F:28])[F:29])([OH:25])[CH2:11][NH:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]=[CH:16][C:17]([CH2:23][OH:24])=[N:18]3)[CH:7]=1
Reactant: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CC(O)(CNc1cccc2nc(CO)ccc12)C(F)(F)F)c1cc(F)ccc1O
Reaction time: 20 h

Procedure:
290 mg (0.62 mmol) of 4-(5-fluoro-2-methoxyphenyl)-1-(2-(hydroxymethyl)quinolin-5-ylamino)-4-methyl-2-(trifluoromethyl)pentan-2-ol in 7.0 ml of dichloromethane is mixed at room temperature with 12.5 ml (12.5 mmol) of a 1 M boron tribromide solution. After 20 hours at room temperature, the reaction is brought to a halt by adding methanol. The solvent is removed in a vacuum, the residue is taken up in saturated sodium bicarbonate solution and ethyl acetate, extracted with ethyl acetate, and the combined organic phases are dried on sodium sulfate. After the solvent is removed and after purification on silica gel with hexane-ethyl acetate (0-70%) as well as with ethyl acetate-methanol (0-10%), 160 mg (51% of theory) of the product is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[CH2:10][NH:11][CH:12]1[CH:19]2[CH2:20][C:15]3([C:22]([O:24]C)=[O:23])[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]3)[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9](=[O:26])[CH2:10][NH:11][CH:12]1[CH:19]2[CH2:20][C:15]3([C:22]([OH:24])=[O:23])[CH2:16][CH:17]([CH2:21][CH:13]1[CH2:14]3)[CH2:18]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C12CC3CC(C1)C(NCC(=O)OCc1ccccc1)C(C3)C2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CNC1C2CC3CC1CC(C(=O)O)(C3)C2)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of methyl 4-{[2-(benzyloxy)-2-oxoethyl]amino}-adamantane-1-carboxylate thus obtained (3.30 g) in tetrahydrofuran (20 ml), methanol (10 ml) and 8M aqueous sodium hydroxide (10 ml) were added and stirred at room temperature for 3 hours. After the reaction mixture was concentrated, the resulting residue was diluted with 1M aqueous sodium hydroxide and washed with diethyl ether. The resulting aqueous layer was diluted with 12M aqueous hydrochloric acid and extracted with chloroform. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give 4-{[2-(benzyloxy)-2-oxoethyl]amino}-adamantane-1-carboxylic acid (2.95 g) as a light-brown viscous substance.
Reaction SMILES: [NH:1]1[C:6]2[CH:7]=[CH:8][S:9][C:5]=2[C:4](=[O:10])[O:3][C:2]1=O.[NH:12]([CH2:14]C(O)=O)[CH3:13]>CS(C)=O.C(OCC)(=O)C>[CH3:13][N:12]1[C:4](=[O:10])[C:5]2[S:9][CH:8]=[CH:7][C:6]=2[NH:1][C:2](=[O:3])[CH2:14]1
Reactant: O=c1[nH]c2ccsc2c(=O)o1
Reactant: CNCC(=O)O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN1CC(=O)Nc2ccsc2C1=O
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
A mixture of 30.0 g (177 mmol) of 2H-thieno[3,2-d][1,3]-oxazine-2,4(1H)-dione and 17.3 g (195 mmol) of sarcosine in 100 ml of dimethyl sulphoxide is stirred at 110° C. for 1.5 hours. The dark brown coloured solution is poured into ca 600 ml of ice/water. The separated oil is taken up in ca 200 ml of ethyl acetate and the aqueous phase is evaporated in vacuo until crystallisation begins. The mixture is cooled in an ice-bath for ca 3 hours and the separated material is filtered off under suction and washed with a small amount of water. After drying on a rotary evaporator, there is obtained 3,4-dihydro-4-methyl-2H-thieno[3,2-e][1,4]diazepine-2,5(1H)-dione of melting point 270°-272° C.
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:52]([F:53])=[CH:51][CH:50]=[CH:49][C:48]=2[F:54])=[N:44][C:43]=1[C:55]([OH:57])=O)=[O:40])([CH3:37])([CH3:36])[CH3:35].[NH2:58][C:59]1[CH:60]=[N:61][N:62]([CH2:78][C:79]2[CH:84]=[CH:83][C:82]([O:85][CH3:86])=[CH:81][CH:80]=2)[C:63]=1[N:64]1[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])[CH2:66][C@@H:65]1[CH3:77].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:34]([O:38][C:39]([NH:41][C:42]1[S:46][C:45]([C:47]2[C:48]([F:54])=[CH:49][CH:50]=[CH:51][C:52]=2[F:53])=[N:44][C:43]=1[C:55]([NH:58][C:59]1[CH:60]=[N:61][N:62]([CH2:78][C:79]2[CH:84]=[CH:83][C:82]([O:85][CH3:86])=[CH:81][CH:80]=2)[C:63]=1[N:64]1[CH2:69][CH2:68][N:67]([C:70]([O:72][C:73]([CH3:75])([CH3:76])[CH3:74])=[O:71])[CH2:66][C@@H:65]1[CH3:77])=[O:57])=[O:40])([CH3:36])([CH3:37])[CH3:35]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Reactant: COc1ccc(Cn2ncc(N)c2N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2ncc(NC(=O)c3nc(-c4c(F)cccc4F)sc3NC(=O)OC(C)(C)C)c2N2CCN(C(=O)OC(C)(C)C)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 45.1 %

Procedure:
A solution of PyBOP (328 mg, 0.63 mmol) and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid from Example 25 (176 mg, 0.50 mmol) in DCM (5 mL) was stirred at room temperature for 30 min. A solution of Intermediate 33 (S)-tert-butyl 4-(4-amino-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate (181 mg, 0.45 mmol) and DIPEA (0.13 mL, 0.72 mmol) in DCM (5 mL) was added and the mixture stirred at room temperature for 65 hr. The mixture was diluted with DCM (40 mL) and washed with water (15 mL). The organic layer was separated, passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave (S)-tert-butyl 4-(4-(5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)thiazole-4-carboxamido)-1-(4-methoxybenzyl)-1H-pyrazol-5-yl)-3-methylpiperazine-1-carboxylate as a yellow solid (150 mg). This solid was re-dissolved in DCM (10 mL) and TFA (2 mL) was added before being heated at 65° C. for 2.5 hr. The mixture was concentrated under reduced pressure before being re-dissolved in 7 N ammonia in MeOH (20 mL) and heated in a sealed pressure vessel behind a blast shield at 55° C. for 16 hr. The mixture was concentrated under reduced pressure, re-dissolved in MeOH and passed through an SCX column, washing with DCM and MeOH and eluting with 3-10% 7 N ammonia in MeOH/DCM to give 174 as an off-white solid (60 mg, 32% over two steps). 1H NMR (400 MHz, d4-MeOD) δ 8.03 (s, 1H), 7.51-7.41 (m, 1H), 7.16 (t, J=8.9 Hz, 2H), 3.20-3.14 (m, 1H), 3.08-2.98 (m, 5H), 2.64 (dd, J=12.7, 9.4 Hz, 1H), 0.93 (d, J=6.2 Hz, 3H). LCMS (ES+) m/z 420 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([O:8][CH2:20][CH:19]=[CH2:18])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCOc1cccc(OC(C)=O)c1
Temperature: 80 °C
Yield: 56.9 %

Procedure:
Resorcinol monoacetate (10.0 g, 65.7 mmoles) in anhydrous DMF (100 mL) was treated with K2CO3 (18.2 g, 131 mmoles) and allyl bromide (6.83 mL, 78.9 mmoles). The mixture was heated at 80° C. overnight, cooled to room temperature, and diluted with ethyl acetate. The mixture was washed with H2O, brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, 8% to 10% ethyl acetate:hexanes) to provide the title compound as a colorless oil (7.19 g, 57%). MS (DCI) m/z 193 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C@@H:12]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][C@@H:15]2[O:29][C:30]([CH3:33])([CH3:32])[O:31][C@@H:14]2[C@H:13]1[O:34]C(=O)C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C(OCC)(=O)C>CO>[CH2:1]([O:8][NH:9][C:10]([C@@H:12]1[N:17]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:16][C@@H:15]2[O:29][C:30]([CH3:32])([CH3:33])[O:31][C@H:14]2[C@H:13]1[OH:34])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H]3OC(C)(C)O[C@@H]3[C@@H](OC(C)=O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc(S(=O)(=O)N2C[C@@H]3OC(C)(C)O[C@H]3[C@@H](O)[C@@H]2C(=O)NOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.8 %

Procedure:
The above compound (4) (1.85 g) was dissolved in methanol (25 mL) and 28% NaOMe (668 mg) was added, and then the mixture was stirred at room temperature for 2 hours. Furthermore, 28% NaOMe (334 mg) was added and, after stirring at room temperature for 3 hours, the reaction solution was mixed with ethyl acetate (150 mL) and then washed with 0.5N hydrochloric acid and saturated saline. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure, and then the resulting residue was purified by silica gel medium pressure column chromatography (ethyl acetate:cyclohexane=2:3) to obtain the titled compound (1.36 g) as a syrup.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O[CH2:28][C@@H:29]2[O:31][CH2:30]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:16]([O:17][CH2:28][C@@H:29]2[O:31][CH2:30]2)=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: O=Cc1cccc(O)c1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OC[C@H]2CO2)c1OCc1ccccc1
Temperature: 60 °C
Yield: 19 %

Procedure:
A mixture of 2-benzyloxy-3-hydroxybenzaldehyde (60.0 g), (R)-glycidyl 4-toluenesulphonate (60.0 g) and potassium carbonate (74 g) in dry dimethylformamide (600 ml) was stirred and heated at 60° C. for 14 hours. After cooling the solvent was removed in vacuo , water (250 ml) added, and the mixture extracted with ether (2×200 ml), then ethyl acetate (2×400 ml). The combined extracts were washed with brine (2×500 ml) and dried over magnesium sulphate. The solvent was removed in vacuo and the residue purified by flash chromatography on silica, pre-adsorbing onto silica first by evaporation from a solution in dichloromethane, then eluting with a 3:1 mixture of petroleum ether (b.p. 40-60° C.) and ether. Appropriate fractions were combined and the solvent removed in vacuo to give (R)-2-benzyloxy-3-(2,3-epoxypropoxy)benzaldehyde (14.22 g). A further crop of product (33.37 g) was obtained by extraction of the silica employed in the chromatography with ether (6×500 ml), followed by concentration of the combined extracts to a volume of -500 ml and cooling overnight, filtering, then washing the precipitate with a 1:1 mixture of petroleum ether (b.p. 40-60° C.) and ether. The solvent was removed from the filtrate in vacuo and the residue purified by flash chromatography by the method described above, giving a third crop (9.68 g) of product. Combined yield of product 57.27 g.
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:6](=[O:11])[CH:7]=[C:8]([CH3:10])[N:9]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:32]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:32][C:7]1[C:6](=[O:11])[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:4]([S:3][CH2:1][CH3:2])=[N:9][C:8]=1[CH3:10]
Reactant: BrBr
Reactant: CCSc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCSc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of 4′-{[2-(ethylthio)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (3.83 g) and sodium acetate (0.87 g) in acetic acid (40 mL) was added bromine (0.54 mL), and the mixture was stirred for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (4.66 g, 99%) as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH2:37])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[NH:37][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH3:16])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2N)CC1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (S)-2-benzyloxycarbonylaminopropionic acid (230 mg, 1.03 mmol), 4-(2-aminophenylamino)piperidine-1-carboxylic acid tertbutyl ester (200 mg, 0.686 mmol), HOBt (102 mg, 0.755 mmol), 4-methylmorpholine (166 μL, 1.51 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (197 mg, 1.03 mmol) in DCM (7 mL) was stirred at RT for 3 h. The reaction mixture was then diluted with additional DCM and the organic layer was washed with water, then dried and concentrated in vacuo affording 4-[2-((S)-2-benzyloxycarbonylaminopropionylamino)phenylamino]piperidine-1-carboxylic acid tertbutyl ester as a purple/brown oil (436 mg, quantitative). LCMS: RT 3.66 min [M+H]+ 497.2.