Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([NH:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][N:23]([C:25](=[O:28])[CH:26]=[CH2:27])[CH2:22]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([O:29]C)[CH:3]=1.B(Br)(Br)Br.CO.CCN(CC)CC>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([NH:11][CH2:12][C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:24][N:23]([C:25](=[O:28])[CH:26]=[CH2:27])[CH2:22]3)[CH2:17][CH2:16]2)=[O:14])=[C:4]([OH:29])[CH:3]=1
Reactant: C=CC(=O)N1CC(N2CCN(C(=O)CNc3cc(C(C)C)c(Cl)cc3OC)CC2)C1
Agent: BrB(Br)Br
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)N1CC(N2CCN(C(=O)CNc3cc(C(C)C)c(Cl)cc3O)CC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 1-(3-(4-(2-(4-chloro-5-isopropyl-2-methoxyphenylamino)acetyl)piperazin-1-yl)azetidin-1-yl)prop-2-en-1-one (77 mg, 0.18 mmol) in DCM (15 mL) at −60° C., BBr3 (443 mg, 1.8 mmol) was added dropwise and the resulting mixture was stirred at RT for 1 h. The mixture was cooled to −60° C., MeOH was added dropwise and then basified with Et3N to adjust the pH to 8-9. The mixture was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (25 mg, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ: 9.50 (bs, 1H), 6.62 (s, 1H), 6.470 (s, 1H), 6.30 (m, 1H), 6.10 (dd, J=2.4, 17.2 Hz, 1H), 5.68 (dd, J=2.0, 10.4 Hz, 1H), 5.14 (m, 1H), 4.25 (m, 1H), 4.06 (m, 1H), 3.96 (m, 1H), 3.91 (m, 2H), 3.78 (m, 1H), 3.54 (m, 4H), 3.17 (m, 2H), 2.35 (m, 4H), 1.21 (m, 6H). ESI-MS m/z: 421.4[M+H]+.
Reaction SMILES: [I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11](Cl)(=[O:13])=[O:12])[CH:3]=1.[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([O:23][CH3:24])=[C:20]([CH:22]=1)[NH2:21].N1C=CC=CC=1>ClCCl>[I:1][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([S:11]([NH:21][C:20]2[CH:22]=[C:16]([CH3:15])[CH:17]=[CH:18][C:19]=2[O:23][CH3:24])(=[O:13])=[O:12])[CH:3]=1
Reactant: COc1ccc(C)cc1N
Reactant: O=S(=O)(Cl)c1cc(I)c2occc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C)cc1NS(=O)(=O)c1cc(I)c2occc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-iodo-1-benzofuran-5-sulfonyl chloride (10.75 g, 31 mmol; Intermediate 56) in dichloromethane (200 mL) was added 5-methyl-2-methoxyaniline (4.25 g, 31 mmol) and pyridine (7.4 mL, 93 mmol) and allowed to stir at ambient temperature overnight. The dark red solution was washed with water, separated, dried and filtered through a plug of silica to remove most of the red impurity, and finally concentrated. Yield: 13.51 g (99%) red solid. HPLC 90% RT=2.58 min (System A; 30-80% MeCN over 3 min), 1.75 min (System C; 2-95% MeCN over 2 min). 1H NMR (400 MHz, CDCl3) δ ppm 2.23 (m, 3H) 3.52 (s, 3H) 6.54 (d, J=8.30 Hz, 1H) 6.79 (dd, J=8.42, 1.59 Hz, 1H) 6.86 (d, J=2.20 Hz, 1H) 6.96 (s, 1H) 7.31 (d, J=1.71 Hz, 1H) 7.71 (d, J=2.20 Hz, 1H) 7.95 (d, J=1.71 Hz, 1H) 8.04 (d, J=1.71 Hz, 1H). MS (ESI) for C16H14INO4S m/z 444 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][CH3:21].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1>O1CCCC1.CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:20]([CH3:21])[CH3:19])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reactant: CNC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CO
Product: CN(C)C(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.5 %

Procedure:
(4′-Bromobiphenyl-4-yl)acetic acid (1.0 g, 3.4 mmol) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and methanol (20 mL), and dimethylamine hydrochloride (0.42 g, 5.2 mmol), 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (1.3 g, 4.7 mmol) and N-methylmorpholine (0.95 mL, 8.6 mmol) were added, followed by stirring at room temperature for 18 hours. After the reaction solution was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: dichloromethane/ethyl acetate), and a fraction corresponding to the Rf value=0.55 (dichloromethane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.82 g, 2.6 mmol) as a white solid (yield 75%).
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:11][CH2:12][N:13]1[C:17](=[O:18])[C:16]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:15]2[C:14]1=[O:23].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]([CH:4]1[CH2:9][CH2:8][N:7]([CH2:11][CH2:12][N:13]2[C:14](=[O:23])[C:15]3[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]2=[O:18])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: CC(C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C1CCN(CCN2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
A solution of 4-isopropylpiperidine (3.3 g, 20.2 mmol), N-(2-bromoethyl)phthalimide (5.4 g, 21.3 mmol), potassium carbonate (5.9 g, 45.4 mmol) and acetonitrile (100 ml) and was heated under reflux for 2.5 hours and then stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The organic layer was separated and the aqueous layer was extracted with further ethyl acetate (100 ml). The combined organic extracts were dried over anhydrous sodium sulphate and the solvent was removed by evaporation under reduced pressure. The resulting oil was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane changing to dichloromethane:diethyl ether (50:50, by volume) changing to diethyl ether to afford the title compound (3.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[O:15]=[C:16]1[N:20]([C:21]2[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=2)[CH2:19][CH2:18][O:17]1>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([N:20]3[CH2:19][CH2:18][O:17][C:16]3=[O:15])=[CH:29][CH:28]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(N2CCOC2=O)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCOC2=O)cc1

Procedure:
A mixture of 1 g of methyl 4-iodobenzoate, 399 mg of 2-oxozolidone, 1.1 g of potassium carbonate, 34 mg of N,N′-dimethylethylenediamine and 73 mg of copper iodide in 10 mL of toluene was heated to 150° C. in a sealed microwave reactor for 2 h. The reaction mixture was diluted with ethyl acetate, washed with H2O, dried (MgSO4) and evaporated. Purified by silica gel chromatography (20-70% ethyl acetate/hexane) to afford methyl 4-(2-oxooxazolidin-3-yl)benzoate. 530 mg of methyl 4-(2-oxooxazolidin-3-yl)benzoate was hydrolyzed via Procedure M to give 4-(2-oxooxazolidin-3-yl)benzoic acid. 70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-oxooxazolidin-3-yl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxooxazolidin-3-yl)benzamide. MS (Q1) 394.2 (M)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([SiH2:15][O:16][C:17]([CH3:32])([CH3:31])[C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([CH2:29][OH:30])[CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[C:11]([SiH2:15][O:16][C:17]([CH3:31])([CH3:32])[C:18]1[CH:19]=[C:20]([CH:26]=[C:27]([CH:29]=[O:30])[CH:28]=1)[C:21]([O:23][CH2:24][CH3:25])=[O:22])([CH3:12])([CH3:13])[CH3:14]
Reactant: CCOC(=O)c1cc(CO)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(C=O)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Temperature: 25 °C
Yield: 100.6 %

Procedure:
0.64 ml of oxalyl chloride was added at −60° C. to a solution of 0.76 ml of dimethyl sulphoxide in 10 ml of CH2Cl2. After 5 minutes 2 g of ethyl 3-(tert-butyl-dimethyl-silanyloxymethyl)-5-hydroxymethyl-benzoate (Example 31.1) in 20 ml of CH2Cl2 were addded over 5 minutes in a manner such that the temperature did not exceed −60° C. After 15 minutes 4.295 m triethylamine were added. The reaction mixture was left too warm to room temperature and was worked up by extraction and yielded 2.0 g of ethyl 3-(tert-butyl-dimethyl-silanyloxymethyl)-5-formyl-benzoate.
Reaction SMILES: [OH:1][C@@H:2]([CH2:33]O)[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=3)=[CH:18][C:17]2=[O:31])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1.[CH3:35]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.O[C@@H](CO)CN1C=CC(NC(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=N1>ClCCl>[OH:1][C:2]([CH3:33])([CH3:35])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:32])[C@@H:11]([N:16]2[CH2:20][C:19]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH3:30])[CH:23]=3)=[CH:18][C:17]2=[O:31])[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:5]1
Reactant: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCOc1cccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.2 %

Procedure:
A solution of (S)-2-[4-(3-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 162, 300 mg, 0.90 mmol) in dichloromethane (20 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (154 mg, 0.99 mmol) and 1-hydroxybenzotriazole (128 mg, 0.95 mmol). The reaction mixture was stirred at 25° C. for 1 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 168 mg, 1.08 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 40 g; (20% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(3-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (217 mg, 51%) as a yellow powder: HR-ES-MS m/z calculated for C25H34N4O5 [M+H]+ 470, observed 471; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.04 (br. s., 3H), 1.06 (br. s., 3H), 1.31 (t, J=6.8 Hz, 3H), 1.38-1.64 (m, 2H), 1.67-1.84 (m, 1H), 3.89 (s, 2H), 4.04 (q, J=6.8 Hz, 2H), 4.16 (d, J=18.1 Hz, 1H), 4.56 (d, J=18.1 Hz, 4.68 (s, 1H), 4.86 (s, 1H), 4.87-4.93 (m, 1H), 6.44 (d, J=1.8 Hz, 1H), 6.78-6.92 (m, 3H), 7.35 (t, J=8.3 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 10.79 (s, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O.[C:12]([CH:14]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[C:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:13].[OH-].[Na+]>O1CCCC1.O1CCCC1.O>[NH2:13][CH2:12][CH:14]([C:15]1([OH:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[C:22]1[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=1
Reactant: N#CC(c1ccc(Cl)cc1)C1(O)CCCCC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: NCC(c1ccc(Cl)cc1)C1(O)CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium aluminum hydride (3.5 g.) was suspended in ice cold tetrahydrofuran (125 ml.) and concentrated sulphuric acid (2.5 ml.) added cautiously, with stirring. After one hour, 1-[cyano(p-chlorophenyl)methyl]cyclohexanol (15 g., 0.06 mole) was dissolved in tetrahydrofuran (100 ml.) and added rapidly dropwise with vigorous stirring and cooling. After a further two hours, a tetrahydrofuran-water mixture (1:1; 30 ml.) was added followed by 10% sodium hydroxide solution (50 ml.). The tetrahydrofuran was decanted and the residue washed well with diethyl ether and ethylacetate. The combined organic solution was dried over anhydrous potassium carbonate and evaporated to an oil (12 g.)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[N:14]=[CH:15][C:16]([C:17]([NH2:19])=[O:18])=[C:12]3[NH:11][CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:22](N1C=CN=C1)(N1C=CN=C1)=[S:23]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]3[C:12]4[N:11]([C:22](=[S:23])[NH:19][C:17](=[O:18])[C:16]=4[CH:15]=[N:14]3)[CH2:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(=S)n2c3c1cnn3C(c1cccc(F)c1)=CC2
Temperature: -78 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A mixture of 63.0 g of 7-(3-fluorophenyl)-4,5-dihydropyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 11) and 2.5 liters of dry tetrahydrofuran is stirred and cooled to -78° C. in a dry ice-acetone bath, then 18.0 g of sodium hydride (60 percent dispersion in mineral oil) is added in one portion This mixture is stirred at -78° C. for 1.5 hours then 40.0 g of 1,1'-thiocarbonyldiimidazole is added and stirring is continued at -78° C. for 2 hours. The mixture is allowed to warm to room temperature and is stirred for 48 hours and then the reaction is quenched with 2.5 liters of water and neutralized with 5 percent aqueous hydrochloric acid. The crystalline solid that forms is collected, washed with ether and dried to give 54.6 g of the desired product as cream colored crystals, mp 298-300° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O>CO.[Pd]>[NH:12]1[CH:13]=[CH:14][C:10]([C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)=[N:11]1
Reactant: O=[N+]([O-])c1cccc(-c2cc[nH]n2)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc(-c2cc[nH]n2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.3 %

Procedure:
To a solution of 3-(3-nitrophenyl)-1H-pyrazole 12.A (490 mg, 2.59 mmol, available from Oakwood) in methanol (5 mL) was added 10% Pd on carbon by weight (100 mg). The air was evacuated from the reaction flask and was replaced with hydrogen. The resulting slurry was stirred overnight at room temperature. The reaction mixture was filtered, and the mother liquor condensed to afford 3-(1H-pyrazol-3-yl)benzenamine 12.B (397 mg, 96% yield).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:35]([O:37]C)=[O:36])=[C:21]([C:23]3[N:28]=[C:27]([N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:26]=[CH:25][N:24]=3)[N:22]=2)[CH2:14][C@@H:13]1[O:39][CH3:40])=[O:10].[OH-].[Li+]>O1CCCC1.O>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:35]([OH:37])=[O:36])=[C:21]([C:23]3[N:28]=[C:27]([N:29]4[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]4)[CH:26]=[CH:25][N:24]=3)[N:22]=2)[CH2:14][C@@H:13]1[O:39][CH3:40])=[O:10]
Reactant: COC(=O)c1sc(N2CC[C@@H](NC(=O)c3[nH]c(C)c(Cl)c3Cl)[C@@H](OC)C2)nc1-c1nccc(N2CCCCC2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H]1CN(c2nc(-c3nccc(N4CCCCC4)n3)c(C(=O)O)s2)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.7 %

Procedure:
To a stirred solution of methyl 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate (Example 184, 35 mg. 0.06 mmol) in tetrahydrofuran (5 mL) was added a solution of lithium hydroxide (9.6 mg, 0.23 mmol) in water (1 mL). The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated to dryness. The resulting residue was diluted with water (2 mL) and the aqueous layer was extracted with diethyl ether (2×10 mL). The aqueous layer was acidified to pH 4-5 with 2N HCl solution, solid obtained was filtered and dried to yield 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylic acid 27 mg (79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:12]2[CH:13]=[N:14][C:15]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]3)=[N:16][CH:17]=2)([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.Cl.O1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]([C:12]2[CH:13]=[N:14][C:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[N:16][CH:17]=2)([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(C)(CO)c3ccc(F)cc3)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@](CO)(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 29.3 %

Procedure:
To a mixture of tert-butyl 4-(5-(2-(4-fluorophenyl)-1-hydroxypropan-2-yl)pyrimidin-2-yl)piperazine-1-carboxylate (450 mg, 1.08 mmol) in DCM (20 mL) was added 4 M HCl/1,4-dioxane (3 mL). After stirred at RT for 15 h, the reaction mixture was concentrated, the residue was diluted by aq. NaHCO3 (20 mL) and extracted with DCM. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated. The residue was separated by chiral Prep-HPLC to give (R)-2-(4-fluorophenyl)-2-(2-(piperazin-1-yl)pyrimidin-5-yl)propan-1-ol (100 mg, 29%) as a white solid. MS (ES+) C17H21FN4O requires: 316. found: 317 [M+H]+. Chiral HPLC, Column: IC 4.6*150 mm 5 um, Co-Solvent: EtOH:Hexane=1:1 (0.1% DEA), RT=4.22 min.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][NH2:22].[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:22][CH2:21][CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[Cl:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccccc1Cl
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
0.38 ml of 4-tert-butylbenzaldehyde (2.25 mmol) and 0.215 ml 2-(2-chloro-phenyl)-ethylamine (1.5 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 85 mg (2.25 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 4 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 465 mg light yellow oil (97%). MS (ISP) 302.3 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][C:16]4=[O:21])=[CH:11][C:8]=3[O:9][CH2:10][C@H:5]2[C@H:4]([C:22]([OH:24])=O)[O:3]1.Cl.[Cl:26][C:27]1[S:31][C:30]([NH2:32])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:26][C:27]1[S:31][C:30]([NH:32][C:22]([C@H:4]2[C@H:5]3[N:6]([C:7]4[CH:14]=[CH:13][C:12]([N:15]5[CH2:20][CH2:19][O:18][CH2:17][C:16]5=[O:21])=[CH:11][C:8]=4[O:9][CH2:10]3)[C:2](=[O:1])[O:3]2)=[O:24])=[CH:29][CH:28]=1
Reactant: Nc1ccc(Cl)s1
Reactant: O=C(O)[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(Nc1ccc(Cl)s1)[C@@H]1OC(=O)N2c3ccc(N4CCOCC4=O)cc3OC[C@@H]12
Yield: 60.3 %

Procedure:
Using compound (3R,3 aS)-1-oxo-7-(3-oxomorpholin-4-yl)-1,3,3a,4-tetrahydrobenzo[b]oxazolo[3,4-d][1,4]oxazin-3-carboxylic acid (90 mg, 0.269 mmol), 5-chlorothiophene-2-amine hydrochloride (55 mg, 0.323 mmol), HATU (154 mg, 0.404 mmol), and TEA (95.3 mg, 0.943 mmol) as starting materials, preparation following the method as described in Example 11 (g) afforded white solid 73 mg, yield: 60.34%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[O:10][CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccccc1B(O)O
Reactant: Fc1cc(I)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: COCCOC
Product: COc1ccccc1-c1ccnc(F)c1
Temperature: 80 °C
Yield: 54.9 %

Procedure:
To a solution of 2-fluoro-4-iodo-pyridine (0.5 g, 2.24 mmol) and (2-methoxyphenyl)boronic acid (0.34 g, 2.24 mmol) in DME/water 2:1 (15 mL) was added Pd(PPh3)2Cl2 (20 mg, 0.028 mmol) and K2CO3 (20 mg, 0.15 mmol). The mixture was heated at 80° C. for 6 hours. It was diluted with DCM, washed with water, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, DCM/MeOH 100:0 to 90:10) to give the title compound A3 (0.25 g, 55%). MS (ES) C12H10FNO requires: 203. found: 204 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31](=O)[O:32]C(C)=C)([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([O:8][C:9]([F:14])([F:13])[CH:10]([F:12])[F:11])[CH:7]=1.[NH2:37][C:38]1[S:39][CH:40]=[CH:41][N:42]=1.CN1CCCC1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@:15]([NH:30][C:31]([NH:37][C:38]2[S:39][CH:40]=[CH:41][N:42]=2)=[O:32])([C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:5]=[C:6]([O:8][C:9]([F:13])([F:14])[CH:10]([F:12])[F:11])[CH:7]=1
Reactant: C=C(C)OC(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Reactant: Nc1nccs1
Agent: CN1CCCC1
Solvent: C1CCOC1
Product: O=C(Nc1nccs1)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1
Temperature: 150 °C
Yield: 40.6 %

Procedure:
(R)-prop-1-en-2-yl 1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylcarbamate (15 mg, 0.029 mmol) and 2-aminothiazole (8.2 mg, 0.082 mmol, 2.8 eq), and N-methylpyrrolidine (0.9 μl, 0.3 eq) were stirred in THF (0.3 mL) in a microwave vial. The reaction mixture was heated at 150° C. for 20 min under microwave irradiation. After cooling, the solvent was evaporated. The residue was purified by reverse phase HPLC (20-90% CH3CN in H2O with 0.1% TFA) to give pure (R)-1-(1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)-3-(thiazol-2-yl)urea as white solids (6.5 mg, yield: 40.6%). 1H NMR (400 MHz, CDCl3-D) δ ppm 7.29 (m, 1H), 7.23-7.18 (m, 3H), 7.16 (t, J=8.0 Hz, 2H), 7.02 (t, J=8.5 Hz, 2H), 6.94-6.89 (m, 4H), 6.71 (d, J=6.82 Hz, 2H), 5.86 (tt, J=47.1, 2.9 Hz, 1H), 3.84-3.75 (m, 2H); LC-MS (ESI) 552.28 (M+H), retention time=4.12 min (10-90% MeOH in H2O with 0.1% TFA in a 4-min run).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([CH:9]1[C:14](=[O:15])[O:13][C:12]([CH3:17])(C)OC1=O)=[O:8])=[N+:2]=[N-:3].OCC[C:22]#[N:23].C(=O)=O>C(Cl)Cl>[C:22]([CH2:17][CH2:12][O:13][C:14](=[O:15])[CH2:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])#[N:23]
Reactant: CC1(C)OC(=O)C(C(=O)CCCN=[N+]=[N-])C(=O)O1
Reactant: N#CCCO
Agent: O=C=O
Solvent: ClCCl
Product: N#CCCOC(=O)CC(=O)CCCN=[N+]=[N-]

Procedure:
5-(4-Azidobutanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione was heated with 3-hydroxypropionitrile (5.25 g, 72.0 mmol) at 80° C. until no more CO2 was released. The reaction mixture was diluted with CH2Cl2 (100 ml), washed with water (100 ml) and brine (100 ml). After drying and evaporation of solvent, the product was purified by chromatography (SiO2, CHCl3:MeOH=95:5), 4-azidobutanoylacetic acid 2-cyanoethyl ester was obtained as a yellowish oil (2.86 g, 53.2%).