Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][C:6]1[CH:35]=[CH:34][C:9]2[C:10]3[C:15]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=5)=[C:19]([Cl:32])[CH:18]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:33][C:8]=2[CH:7]=1)C.O.[OH-].[Li+]>C1COCC1.O>[Cl:32][C:19]1[CH:18]=[C:17]([NH:16][C:15]2[C:10]3[C:9]4[CH:34]=[CH:35][C:6]([CH2:5][C:4]([OH:36])=[O:3])=[CH:7][C:8]=4[S:33][C:11]=3[N:12]=[CH:13][N:14]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=1
Reactant: CCOC(=O)Cc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of {4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-benzo[4,5]thieno[2,3-d]pyrimidin-7-yl}-acetic acid ethyl ester (400 mg, 0.766 mmol) in THF (10 mL) was added a solution of lithium hydroxide monohydrate (161 mg, 3.83 mmol) in water (3 mL), and the resulting mixture was stirred at rt overnight. The solvent was evaporated, and aq. NaOH (0.2 N, 5 mL) was added to the residue, and the mixture was washed with diethyl ether (2×8 mL). The pH of the aqueous layer was adjusted to 5 by addition of 0.5 N HCl, and it was then extracted with EtOAc (3×25 mL). The combined organic layers were dried (Na2SO4) and concentrated to give the product as a slightly brown solid. (350 mg, 93%). LCMS RT=3.66 min, [M+H]+=494.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH:5]=[CH:6][CH:7]([N:16]([CH3:33])[C:17](=[O:32])[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[CH:19]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:2].ClC1C=CC=CC=1Cl>O1CCCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH:7]([N:16]([CH3:33])[C:17](=[O:32])[C:18]1[CH:19]=[C:20]([C:28]([F:30])([F:29])[F:31])[CH:21]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:23]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C=CC(Cc1ccc(Cl)cc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)CCC(Cc1ccc(Cl)cc1)N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A solution of 29 g of 4-[N'-methyl-N'-(3,5-bistrifluoromethyl-benzoyl)-amino]-5-(4-chlorophenyl)-pent-2-enoic acid ethyl ester [see example 2b)] in 300 ml of tetrahydrofuran is hydrogenated for 0.5 hour in the presence of 3 g of palladium/activated carbon (10%) and 6 g of 1,2-dichlorobenzene. The reaction mixture is then filtered and concentrated by evaporation. The residue is chromatographed (silica gel, hexane/ethyl acetate 3:1). In this way the title compound is obtained in the form of a colourless oil. 1H-NMR, 500 MHz, DMSO, 140°, delta (ppm): 7.99(s, 1H), 7.51(s, 2H), 7.30(td, 2H), 7.18(d, 2H), 4.5(b, 1H), 4.06(q, 2H), 2.9(m, 1H), 2.8(m, 4H), 2.35(m, 2H), 2.02(m, 1H), 1.90(m, 1H), 1.19(t, 3H).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][N:12]=2)[CH:5]=1.[OH-].[Na+]>CO.C1COCC1.O>[Cl:17][C:16]1[C:11]([O:10][C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=2)[C:3]([OH:19])=[O:2])=[N:12][CH:13]=[C:14]([Cl:18])[CH:15]=1
Reactant: COC(=O)c1cccc(Oc2ncc(Cl)cc2Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(Oc2ncc(Cl)cc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A mixture of 3-(3,5-dichloro-pyridin-2-yloxy)-benzoic acid methyl ester (1100 mg, 4.0 mmol) and NaOH (700 mg, 16 mmol) in methanol:THF:water (1:1:1, 6 mL) was stirred at room temperature for 8 h. Solvents were evaporated. Crude mass was taken in water (40 mL), acidified to pH 4.0 and extracted with ethyl acetate. Evaporation of ethyl acetate yielded 3-(3,5-dichloro-pyridin-2-yloxy)-benzoic acid (908 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2].[Br:15][CH:16](Br)[CH3:17].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.N#N>C(#N)C>[C:1]([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:17][CH2:16][Br:15])=[C:7]([CH3:13])[C:6]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)cc(O)c(C)c1C
Reactant: CC(Br)Br
Agent: C1COCCOCCOCCOCCOCCO1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(=O)Oc1c(C)cc(OCCBr)c(C)c1C
Yield: 34 %

Procedure:
A mixture of 4-acetoxy-2,3,5-trimethyl phenol (0.94 g, 4.82 mmol), dibromoethane (4 mL), potassium carbonate (0.80 g, 1.2 eq), 18-crown-6 (20 mg) in acetonitrile (15 mL) was stirred and heated at reflux under an atmsophere of N2 for 8 days. After this time the mixture was concentrated at reduced pressure and the residue partitioned between CH2Cl2 and 1M HCl. The organic phase was dried, filtered and concentrated at reduced pressure. The residue was purified by flash chromatography (9:1 ethyl acetate, petroleum spirit). The product was obtained as a white solid (34%) and was recrystallised from petroleum spirit as colourless needles, m.p 59-60° C. 1H NMR (CDCl3) δ6.55 (s, 1H), 4.24 (t, J=6.2 Hz, 2H), 3.64 (t, J=6.2 Hz, 2H), 2.32 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:15](=[O:16])[N:14]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:5]2[N:6]=[C:7](S(C)=O)[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[OH-].[NH4+:23]>O1CCOCC1>[NH2:23][C:7]1[N:8]=[C:9]([CH3:10])[C:4]2[CH:3]=[C:2]([Br:1])[C:15](=[O:16])[N:14]([CH:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:5]=2[N:6]=1
Reactant: Cc1nc(S(C)=O)nc2c1cc(Br)c(=O)n2C1CCCC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nc(N)nc2c1cc(Br)c(=O)n2C1CCCC1
Temperature: 110 °C
Yield: 93 %

Procedure:
To a solution of 6-bromo-8-cyclopentyl-4-methyl-2-(methylsulfinyl)pyrido[2,3-d]pyrimidin-7(8H)-one (0.80 g, 2.16 mmol) in dioxane (5 mL) was added ammonium hydroxide (30%, 2.6 mL). The mixture was then heated at 110° C. in a sealed tube for 30 minutes. The solution was concentrated in vacuo and extracted with ethyl acetate (3×30 mL). The combined organics were washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), filtered and concentrated to dryness to give the title compound as a brown crystalline solid (0.65 g, 93%).
Reaction SMILES: C(N(CCCC)CC#CC#N)CCC.[CH2:15]([N:21]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:22][C:23]#[C:24][C:25]#[N:26])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(#N)C#CCCCCCCCCCCCC.NC1C=C(CN(CCCC)CCCC)[O:52][N:51]=1>>[NH2:26][C:25]1[CH:24]=[C:23]([CH2:22][N:21]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[O:52][N:51]=1
Reactant: CCCCN(CCCC)Cc1cc(N)no1
Reactant: CCCCCCN(CC#CC#N)CCCCCC
Agent: CCCCCCCCCCCCC#CC#N
Agent: CCCCN(CC#CC#N)CCCC
Product: CCCCCCN(CCCCCC)Cc1cc(N)no1

Procedure:
When in the procedure of Example 9(a) an appropriate amount of 4-dibutylamino-2-butynenitrile or 4-dihexylaminobutynenitrile was substituted for 2-pentadecynenitrile, 3-amino-5-dibutylaminomethylisoxazole, and 3-amino-5-dihexylaminomethylisoxazole were obtained respectively, and when each of these isoxazoles was substituted for 3-amino-5-dodecylisoxazole in the procedure of Example 9(b), the following compounds were obtained:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH3:22].CCCCCC.C(OCC)(=O)C>C(#N)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:23][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:20])[CH3:22]
Reactant: CC(C)(CBr)NC(=O)OC(C)(C)C
Reactant: Oc1ccc2ccccc2c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(COc1ccc2ccccc2c1Cl)NC(=O)OC(C)(C)C
Yield: 51 %

Procedure:
To a solution of 1-chloronaphthalen-2-ol (1.5 mmol) and Cs2CO3 (3 mmol) in acetonitrile was added tert-butyl (1-bromo-2-methylpropan-2-yl)carbamate (3 mmol). The resulting mixture was heated at reflux overnight. After TLC control (n-hexane/ethyl acetate 7:3) showed the disappearance of 1-chloronaphthalen-2-ol, solvent was evaporated in vacuo and the residue was dissolved in 15 mL of ethyl acetate and washed with water (3×5 mL), brine (10 mL) and dried over Na2SO4. The evaporation of solvent afforded tert-butyl {1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-yl}carbamate as a pale oil (51% yield) which was dissolved in 5 mL of 4 M HCl solution in dioxane. The resulting mixture was stirred at room temperature for 18 h. After HPLC-MS control, the solvent was distilled off and the residue was dissolved in dichloromethane and wash 2 times with NaOH 1N to afford 1-[(1-chloronaphthalen-2-yl)oxy]-2-methylpropan-2-amine as a pale oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH3:20])[CH:18]=[N:19][C:4]=2[CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[O:32][CH3:33])#[N:22]>C(#N)C1C=CC=CC=1>[CH3:33][O:32][C:24]1[CH:25]=[C:26]([C:2]2[N:7]=[C:6]([O:8][C@@H:9]([C@@H:11]3[CH2:12][C:13](=[O:16])[NH:14][CH2:15]3)[CH3:10])[C:5]3[N:17]([CH3:20])[CH:18]=[N:19][C:4]=3[CH:3]=2)[CH:27]=[CH:28][C:23]=1[C:21]#[N:22]
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C)c12)[C@H]1CNC(=O)C1
Reactant: COc1cc(B(O)O)ccc1C#N
Solvent: N#Cc1ccccc1
Product: COc1cc(-c2cc3ncn(C)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1C#N

Procedure:
Following General Procedure B, beginning with (R)-4-((R)-1-(6-chloro-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)pyrrolidin-2-one 2.06 (41 mg, 0.139 mmol) and 4-cyano-3-methoxyphenylboronic acid (31 mg, 0.18 mmol), 2-methoxy-4-(3-methyl-4-((R)-14(R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)benzonitrile 3B.14 was synthesized.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:15][C:16]([O:18]C2C=CC([N+]([O-])=O)=CC=2)=O)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH:39]1[CH:43]=[C:42]([CH2:44][NH2:45])[N:41]=[CH:40]1.O>CN(C)C=O>[NH:39]1[CH:43]=[C:42]([CH2:44][NH:45][C:16](=[O:18])[NH:15][C@@H:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:11]([O:13][CH3:14])=[O:12])[N:41]=[CH:40]1
Reactant: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1c[nH]cn1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)NCc1c[nH]cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 226.9 %

Procedure:
1.1 g (0.37 mmol) of methyl(S)-3-(4-methoxyphenyl)-2-(4-nitrophenoxycarbonyl-amino)propanoate (cf. preparation 2-2) and 0.7 mL (0.37 mmol) of diisopropyl-ethylamine in 5 mL of dimethylformamide are added at 80° C. to a solution of 500 mg (0.37 mmol) of C-(1H-imidazol-4-yl)methylamine dihydrochloride in 15 mL of dimethylformamide. The reaction mixture is stirred for 2 hours at 80° C. The reaction is stopped by adding 30 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (eluent: 80/20 dichloromethane/methanol). 279 mg of methyl (S)-2-[3-(1H-imidazol-4-yl-methyl)-ureido]-3-(4-methoxyphenyl)propanoate in the form of a yellow oil are obtained in a yield of 63%.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:22]O)[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1cccc(Cl)c1
Product: N#Cc1ccnc(-n2nccc2OCc2cccc(Cl)c2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (3-chlorophenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 5.22 (2H, s), 5.73 (1H, d, J=1.6 Hz), 7.30-7.35 (3H, m) 7.41-7.43 (1H, m), 7.47 (1H, s), 7.57 (1H, d, J=2.0 Hz), 8.05 (1H, s), 8.72 (1H, d, J=5.2 Hz). [M+H] Calc'd for C16H11ClN4O, 311. Found, 311.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:15]([CH2:16][CH3:17])=[C:14]([S:18][C:19]2[CH:20]=[C:21]([C:27]#[N:28])[CH:22]=[C:23]([CH:26]=2)[C:24]#[N:25])[C:13]([CH2:29][CH3:30])=[N:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[CH2:29]([C:13]1[C:14]([S:18][C:19]2[CH:26]=[C:23]([C:24]#[N:25])[CH:22]=[C:21]([CH:20]=2)[C:27]#[N:28])=[C:15]([CH2:16][CH3:17])[N:11]([CH2:10][CH2:9][OH:8])[N:12]=1)[CH3:30]
Reactant: CCc1nn(CCO[Si](C)(C)C(C)(C)C)c(CC)c1Sc1cc(C#N)cc(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CCc1nn(CCO)c(CC)c1Sc1cc(C#N)cc(C#N)c1
Yield: 53.6 %

Procedure:
5-{[1-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3,5-diethyl-1H-pyrazol-4-yl]sulfanyl}isophthalonitrile (180 mg, 0.4 mmol) (Preparation 51) was treated with tetrabutylammonium fluoride (1M solution in tetrahydrofuran, 0.8 ml, 0.8 mmol) and the resulting solution was stirred for 2½ hours. The mixture was concentrated under reduced pressure to give a brown oil. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate:dichloromethane (1:4, by volume) to provide the title compound (70 mg) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]1)=[O:19].Cl>ClCCCl>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:18]([CH:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)=[O:19])=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)N1CCC(C(=O)Cl)CC1
Reactant: c1ccc(-c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)N1CCC(C(=O)c2ccc(-c3ccccc3)cc2)CC1
Yield: 41.5 %

Procedure:
A mixture of 1,1′-biphenyl (0.3 mol) and aluminum-(III)-chloride (0.6 mol) in 1,2-dichloroethane (500 ml) was stirred. A mixture of ethyl 4-(chlorocarbonyl)-1-piperidinecarboxylate (0.3 mol) in 1,2-dichloroethane (100 ml) was added dropwise over a 30-minutes period (exothermic temperature rise to 30° C.). The mixture was stirred at room temperature for 90 minutes, poured out into ice and HCl and extracted with DCM. CH3OH was added. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 42 g of ethyl 4-(4-phenylbenzoyl)-1-piperidinecarboxylate (interm. 9).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([O:20][CH3:21])=[C:5]([N:9]2[C:13]([CH2:14][NH2:15])=[CH:12][C:11]([C:16]([F:19])([F:18])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[F:22][C:23]1[CH:24]=[C:25]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:26]=[CH:27][C:28]=1[CH2:29][OH:30]>C(Cl)Cl.O>[Cl:2][C:3]1[C:4]([O:20][CH3:21])=[C:5]([N:9]2[C:13]([CH2:14][NH:15][C:32]([NH:31][C:25]3[CH:26]=[CH:27][C:28]([CH2:29][OH:30])=[C:23]([F:22])[CH:24]=3)=[O:33])=[CH:12][C:11]([C:16]([F:18])([F:19])[F:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1ccc(CO)c(F)c1)Oc1ccccc1
Reactant: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1CN
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COc1c(Cl)cccc1-n1nc(C(F)(F)F)cc1CNC(=O)Nc1ccc(CO)c(F)c1
Reaction time: 16 h
Yield: 61.2 %

Procedure:
To a stirred solution of (1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine hydrochloride (100 mg, 0.38 mmol, 1.0 eq) in DCM (5 mL) was added TEA (0.16 mL, 1.14 mmol, 3.0 eq) followed by phenyl 3-fluoro-4-(hydroxymethyl)phenyl-carbamate (131 mg, 0.38 mmol, 1.0 eq) at RT and stirred for 16 h. The reaction mixture was diluted with water (15 mL), extracted with DCM (2×15 mL). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4 and evaporated under vacuum. Crude product was purified by CC to get 1-((1-(3-chloro-2-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methyl)-3-(3-fluoro-4-(hydroxymethyl)phenyl)urea (110 mg; 61%) as off white solid (TLC system: MeOH/CHCl3 (1:9); Rf: 0.55).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:11][C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:55][C:56]([O:59][C:60]([NH:62][CH2:63][C@H:64]([NH2:69])[C:65]([O:67][CH3:68])=[O:66])=[O:61])([CH3:58])[CH3:57].Cl.C(N(CC)CC)C>CN(C=O)C>[CH3:68][O:67][C:65](=[O:66])[C@@H:64]([NH:69][C:18]([C:14]1[S:13][C:12]([NH:11][C:9](=[O:10])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)=[N:16][C:15]=1[CH3:17])=[O:20])[CH2:63][NH:62][C:60]([O:59][C:56]([CH3:55])([CH3:58])[CH3:57])=[O:61]
Reactant: COC(=O)[C@@H](N)CNC(=O)OC(C)(C)C
Reactant: Cc1nc(NC(=O)Cc2cccc(O)c2)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NC(=O)c1sc(NC(=O)Cc2cccc(O)c2)nc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 2-[2-(3-Hydroxy-phenyl)-acetylamino]-4-methyl-thiazole-5-carboxylic acid (620 mg, 2.121 mmol) in anhydrous DMF (25 mL) was added HBTU (980 mg, 2.584 mmol), HOBt (347 mg, 2.568 mmol), H-DAP(BOC)-OME HCl (810 mg, 3.18 mmol) and triethylamine (1.1 mL, 7.892 mmol). The solution was stirred at 25° C. for 1 h and concentrated at reduced pressure to remove most of the DMF. The reaction was then diluted with ethyl acetate (200 mL), washed with water (50 mL), aqueous 1N HCl (50 mL), and brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (40%-90% EtOAc in hexanes) to give (S)-3-tert-Butoxycarbonylamino-2-({2-[2-(3-hydroxy-phenyl)-acetylamino]-4-methyl-thiazole-5-carbonyl}-amino)-propionic acid methyl ester (902.1 mg, 77.7%) as a white foam. MS m/e 493.6 (M+H+).
Reaction SMILES: [N+]([C:4]1C=CC(CCN)=CC=1)([O-])=O.[CH3:13][O:14][C:15]1N=[C:19]([NH:21][C@@H:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:23]([OH:25])=[O:24])[CH:18]=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=2)[N:16]=1>>[CH3:13][O:14][C:15]1[CH:4]=[C:19]([NH:21][C@@H:22]([CH2:26][C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:23]([OH:25])=[O:24])[CH:18]=[C:17]([C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[CH:36]=2)[N:16]=1
Reactant: COc1ccc(C[C@H](Nc2cc(-c3cccc(OC)c3)nc(OC)n2)C(=O)O)cc1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Product: COc1ccc(C[C@H](Nc2cc(OC)nc(-c3cccc(OC)c3)c2)C(=O)O)cc1

Procedure:
By proceeding in a similar manner to Example 43(b) but substituting L-O-methyl tyrosine for 2-(4-nitro-phenyl)-ethylamine in Step 3 there is prepared (2S)-2-[2-Methoxy-6-(3-methoxy-phenyl)-pyrimidin-4-ylamino]-3-(4-methoxy-phenyl)-propionic acid [40.2 mg, 45%, Example 43(n)] as a solid. LC/MS: RT=2.38 minutes, MS: 410 (M+H). 1H NMR [300 MHz, (CD3)2SO]: □12 (1H, br s), 7.62 (1H, m), 7.49 (1H, m), 7.38 (1H, m), 7.18 (2H, m), 7 (1H, m), 6.8 (2H, m), 6.73 (1H, s), 4.59 (1H, m), 3.8 (3H, s), 3.78 (3H, s), 3.68 (3H, s), 3.1 (1H, m), 2.94 (1H, m). IC50=548 nM
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].[S:25]([NH2:35])(=[O:34])([C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][CH:28]=1)=[O:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCN(CC)CC>[O:16]=[C:14]([NH:33][C:30]1[CH:31]=[CH:32][C:27]([S:25](=[O:34])(=[O:26])[NH2:35])=[CH:28][CH:29]=1)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24]
Reactant: CC(C)(C)OC(=O)CN(CCCCCC(=O)O)Cc1ccccn1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CN(CCCCCC(=O)Nc1ccc(S(N)(=O)=O)cc1)Cc1ccccn1
Yield: 31 %

Procedure:
A solution of 6-((2-tert-butoxy-2-oxoethyl)(pyridin-2-ylmethyl)amino)hexanoic acid (0.6545 g, 1.95 mmol), sulfanilamide (0.362 g, 2.10 mmol) and HATU (0.798 g, 2.10 mmol) in DMF (10 mL) and Et3N (1.0 mL) was stirred at 40° C. overnight. The reaction mixture was purified by flash chromatography over silica gel eluting with MeOH/DCM to give tert-butyl 2-((6-oxo-6-(4-sulfamoylphenylamino)hexyl)(pyridin-2-ylmethyl)amino)acetate (297 mg, 31%). ESMS m/z: 491.3 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:7][C:8]1([CH3:11])[CH2:10][CH2:9]1)[C:3]([O:5]C)=[O:4].[OH-].[Na+].Cl>CCO>[OH:1][C@H:2]([CH2:7][C:8]1([CH3:11])[CH2:10][CH2:9]1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(O)CC1(C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C[C@@H](O)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of methyl 2-hydroxy-3-(1-methyl-cyclopropyl)propanoate (1.4 g, 8.1 mmol) in EtOH (10 mL) was added aqueous NaOH (2.2 mL of a 5.0 M solution, 11 mmol). The mixture was stirred at ambient temperature for 18 h. The mixture was brought to pH 2 by the addition of 6 N aqueous HCl and the solvents were removed under reduced pressure. The residue was dried under high vacuum for 18 hours. The residue was suspended in dichloromethane (15 mL) and the mixture was stirred for 1 h. The solid was removed by filtration and the filtrate solvent was removed under reduced pressure to give an oil. This material was purified using a Chiralpak AD column using 95:5:0.1 hexanes:2-propanol:TFA as the eluant. The first eluting peak was collected and after removal of the solvents under reduced pressure and drying under high vacuum for 18 h, 2(R)-hydroxy-3-(1-methyl-cyclopropyl)propanoic acid was obtained a white solid. HPLC RT=2.00 min (Method A)
Reaction SMILES: [N:1]1([C@H:6]2[CH2:11][CH2:10][C@H:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:20].O>C1COCC1>[ClH:20].[N:1]1([C@H:6]2[CH2:11][CH2:10][C@H:9]([NH2:12])[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N2CCCC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CC[C@H](N2CCCC2)CC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl trans-4-(pyrrolidin-1-yl)cyclohexylcarbamate (399 mg, 1.44 mmol) in THF (12 mL) was added aqueous 6 N HCl (6 mL) and water (6 mL) and the reaction mixture was heated at 65° C. for 18 ht. The reaction mixture was cooled and concentrated to afford the desired product (350 mg, >99%) as an off-white solid: ESI MS m/z 169 [C10H20N2+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([N:20]1[CH2:29][CH:28]([OH:30])[CH:27]([OH:31])[C@H:21]1[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[C:36]([O:44][C:45]([F:48])([F:47])[F:46])[CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:40]([C:37]1[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][C:36]=1[O:44][C:45]([F:46])([F:47])[F:48])(=[O:42])=[O:41])[C:6](=[O:11])[C:5]2([N:20]1[CH2:29][CH:28]([OH:30])[CH:27]([OH:31])[C@H:21]1[C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19]
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Reactant: COc1ccccc1C1(N2CC(O)C(O)[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3CC(O)C(O)[C@H]3C(=O)N(C)C)c3cc(Cl)ccc32)c(OC(F)(F)F)c1
Yield: 52.7 %

Procedure:
With 300 mg of the compound obtained in Step 19-7 and 215 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting material, 248 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.