Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC[N:4]1[C:8]2=[N:9][C:10]([N:13]([CH3:21])[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=[C:7]2[N:6]=[C:5]1[C:22]1[S:23][C:24]2[C:30]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:29][CH:28]=[C:27]([O:37][CH3:38])[C:25]=2[N:26]=1.Cl>>[CH3:38][O:37][C:27]1[C:25]2[N:26]=[C:22]([C:5]3[NH:4][C:8]4=[N:9][C:10]([N:13]([CH3:21])[CH2:14][CH:15]5[CH2:20][CH2:19][O:18][CH2:17][CH2:16]5)=[CH:11][CH:12]=[C:7]4[N:6]=3)[S:23][C:24]=2[C:30]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[CH:29][CH:28]=1
Reactant: COCn1c(-c2nc3c(OC)ccc(N4CCOCC4)c3s2)nc2ccc(N(C)CC3CCOCC3)nc21
Agent: Cl
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4ccc(N(C)CC5CCOCC5)nc4[nH]3)nc12
Yield: 54.2 %

Procedure:
0.03 g [3-Methoxymethyl-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-(tetrahydro-pyran-4-ylmethyl)-amine (0.056 mmol) were treated with 5N HCl (1 ml) at 90° C. for 0.5 h. The reaction mixture was concentrated, taken up in water (1 ml) and adjusted to pH 10 with ammonium hydroxide (25%), whereupon a precipitation formed. The precipitation was filtered, the crystals washed with water. After drying in vacuo, 0.015 g [2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-3H-imidazo[4,5-b]pyridin-5-yl]-methyl-(tetrahydro-pyran-4-ylmethyl)-amine (55%) was obtained as a yellow solid; M.p.: 190–195° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:14])[O:5][N:4]=1.C[O:16][C:17](=[O:30])[CH2:18][O:19][C:20]1[CH:28]=[CH:27][C:26]([SH:29])=[C:25]2[C:21]=1[CH2:22][CH2:23][CH2:24]2>>[Cl:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[O:5][N:4]=[C:3]([CH2:2][S:29][C:26]2[CH:27]=[CH:28][C:20]([O:19][CH2:18][C:17]([OH:30])=[O:16])=[C:21]3[C:25]=2[CH2:24][CH2:23][CH2:22]3)[CH:7]=1
Reactant: ClCc1cc(-c2ccccc2Cl)on1
Reactant: COC(=O)COc1ccc(S)c2c1CCC2
Product: O=C(O)COc1ccc(SCc2cc(-c3ccccc3Cl)on2)c2c1CCC2

Procedure:
The title compound was prepared in the manner analogous to Example 1F using commercially available 3-chloromethyl-5-(2-chloro-phenyl)-isoxazole and 12C. MS m/z 430 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[O:20][C@H:21]([CH3:28])[CH2:22][N:23]([CH3:27])[C:24](=[O:26])[CH3:25])[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[F:29]
Reactant: Fc1ccccc1CCl
Reactant: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Product: CC(=O)N(C)C[C@@H](C)Oc1cccc2ncnc(Nc3ccc(OCc4ccccc4F)c(Cl)c3)c12
Yield: 72 %

Procedure:
The procedure described in Example 3 was repeated using N-[(2R)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)propyl]-N-methylacetamide (obtained as described for in Example 50, preparation of starting materials) and 2-fluorobenzyl chloride to give the title compound in 72% yield; NMR spectrum (DMSO-d6) 1.37 (d, 3H), 1.94 (s, 3H), 3.04 (s, 3H), 3.30 (1H obscured by H2O), 4.20 (dd, 1H), 5.07 (m, 1H), 5.25 (s, 2H), 7.27 (m, 5H), 7.43 (m, 1H), 7.59 (t, 1H), 7.67 (dd, 1H), 7.70 (t, 1H), 8.07 (d, 1H), 8.45 (s, 1H), 9.93 (s, 1H); Mass Spectrum MH+ 509.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[CH2:2].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.F[K].C(P)(C)(C)C>C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].O1CCOCC1>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(B(O)O)cc1
Reactant: Clc1ccc(-c2ccncc2)cc1
Agent: [Pd]
Agent: CC(C)(C)P
Agent: F[K]
Solvent: C1COCCO1
Product: C=Cc1ccc(-c2ccc(-c3ccncc3)cc2)cc1
Temperature: 80 °C
Yield: 50 %

Procedure:
This Example was carried out in the same manner as Example 10, except that 23.42 g (0.158 mol) of 4-vinyl-phenyl boronic acid, 20.0 g (0.1055 mol) of 4-(4-chloro-phenyl)pyridine, 500□ of 1,4-dioxane, 27.54 g (0.474 mol, 3.3 equivalent) of fluoro-potassium, 1.69 g (0.0084 mol, 5.3 mol %) of t-butylphosphine [P( t-Bu)3)], and 2.6 g (0.0028 mol, 1.8 mol %) of palladium tris(dibenzylidene acetone) [Pd2(dba)3] were used. Finally, after the resulting solution was heated to reflux at 80° C. for 24 hours, the 4-(4′-vinyl-biphenyl-4-yl)pyridine was isolated. The yield was 50%.
Reaction SMILES: [OH:1][CH:2]([C@@H:5]1[CH2:10][C@H:9]([N:11]([CH:13]([CH3:15])[CH3:14])[CH3:12])[CH2:8][CH2:7][C@@H:6]1[N:16]1[CH2:20][CH2:19][C@H:18]([NH:21]C(=O)OCC2C=CC=CC=2)[C:17]1=[O:32])[CH2:3][CH3:4]>CO.[Pd]>[NH2:21][C@H:18]1[CH2:19][CH2:20][N:16]([C@H:6]2[CH2:7][CH2:8][C@@H:9]([N:11]([CH:13]([CH3:14])[CH3:15])[CH3:12])[CH2:10][C@H:5]2[CH:2]([OH:1])[CH2:3][CH3:4])[C:17]1=[O:32]
Reactant: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CCC(O)[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N1CC[C@H](N)C1=O
Reaction time: 4 h
Yield: 101.8 %

Procedure:
A solution of benzyl (S)-1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (267 mg) in MeOH (15 mL) was charged with 10% Pd/C, Degussa (˜100 mg). The reaction flask was evacuated and then back-filled with hydrogen; this was repeated two more times. The reaction was stirred under 60 psi of H2 for 4 h and then filtered and concentrated in vacuo to afford the desired (S)-3-amino-1-((1S,2R,4R)-2-(1-hydroxypropyl)-4-(isopropyl(methyl)amino)cyclohexyl)pyrrolidin-2-one (190 mg) as an oil.
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1B1OC(C)(C)C(C)(C)O1)[CH3:2].Br[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:27]=[C:28]([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[N:29]=2)[C:25]=1[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].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].O.C(OCC)(=O)C>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:20]1[CH:21]=[CH:22][C:23]2[N:24]([CH:27]=[C:28]([C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[N:29]=2)[C:25]=1[CH3:26])[CH3:2]
Reactant: Cc1c(Br)ccc2nc(C(F)(F)C(F)(F)F)cn12
Reactant: CCSc1ccccc1B1OC(C)(C)C(C)(C)O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCSc1ccccc1-c1ccc2nc(C(F)(F)C(F)(F)F)cn2c1C
Yield: 103.5 %

Procedure:
A mixture of 0.53 g of 2-ethylsulfanylphenylboronic acid pinacol ester, 0.65 g of 6-bromo-5-methyl-2-pentafluoroethylimidazo[1,2-a]pyridine, 0.02 g of tris(dibenzylideneacetone)dipalladium(0), 0.05 g of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylphenyl, 1.0 g of tripotassium phosphate and 3 ml of 1,4-dioxane was stirred under heat-reflux for 9 hours. Ethyl acetate and water were added to the cooled reaction mixture, and the mixture was filtered. The filtrate was extracted with ethyl acetate and then dried over anhydrous sodium sulfate. The dried matter was concentrated under reduced pressure, and then the resulting residue was applied to a silica gel column chromatography to obtain 0.79 g of 6-(2-ethylsulfanylphenyl)-5-methyl-2-pentafluoroethylimidazo[1,2-a]pyridine (Compound of Present Invention 29).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH3:18])[CH2:14][N:13]([CH3:15])[C:12](=O)[CH:11]([CH3:17])[O:10]2)[CH:6]=[CH:7][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[O-]S([O-])(=O)=O.[Mg+2]>CCOCC.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH3:18])[O:10][CH:11]([CH3:17])[CH2:12][N:13]([CH3:15])[CH2:14]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C2(C)CN(C)C(=O)C(C)O2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: COc1cccc(C2(C)CN(C)CC(C)O2)c1
Yield: 100.6 %

Procedure:
The above mixture of isomers of 6-(3-methoxyphenyl)-2,4,6-trimethyl-3-morpholinone (15.8 g) in dry ether (50 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (4.0 g) in ether (250 ml). After heating under reflux for 3 hours the reaction mixture was cooled and the complex decomposed by the cautious, successive addition of water (4 ml), 2 M sodium hydroxide (8 ml) and anhydrous MgSO4. The inorganic material was filtered off and the filtrate removed under reduced pressure affording 15 g of oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:17][C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)[S:5][C:6]=1[C:7]1[CH:8]=[C:9]([S:13](Cl)(=[O:15])=[O:14])[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:30]([CH2:32][NH2:33])[OH:31]>O1CCOCC1>[OH:31][CH2:30][CH2:32][NH:33][S:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]2[S:5][C:4]([NH:17][C:18]3[CH:23]=[N:22][CH:21]=[CH:20][N:19]=3)=[N:3][C:2]=2[CH3:1])[CH:8]=1)(=[O:15])=[O:14]
Reactant: Cc1nc(Nc2cnccn2)sc1-c1cccc(S(=O)(=O)Cl)c1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(Nc2cnccn2)sc1-c1cccc(S(=O)(=O)NCCO)c1
Reaction time: 8 h
Yield: 14.3 %

Procedure:
3-[4-Methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonyl chloride (42c) (0.251 g, 0.68 mmol) is dissolved in dioxane (10 ml). The solution is treated with 2M aqueous sodium carbonate (0.7 ml, 1.36 mmol) followed by the addition of ethanolamine (0.125 ml, 2.05 mmol). The reaction mixture is stirred overnight. The solvent is removed in vacuo and the residue is taken into water (10 ml)/ethylacetate (30 ml) and sonicated. The layers are separated then the aqueous layer is extracted with ethyl acetate (2×30 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to give a residue which is purified by prep LC-MS to give the titled compound (0.038 g, 14%)
Reaction SMILES: O.[CH3:2][N:3]([CH3:35])[CH:4]1[CH2:7][N:6]([C:8]2[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[NH:26][CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[C:10]([O:33][CH3:34])[CH:9]=2)[CH2:5]1.[NH4+].[Cl-]>[Fe].C(O)C>[CH3:35][N:3]([CH3:2])[CH:4]1[CH2:5][N:6]([C:8]2[CH:9]=[C:10]([O:33][CH3:34])[C:11]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[NH:26][CH:25]=4)[CH:21]=[CH:20][N:19]=3)=[CH:12][C:13]=2[NH2:14])[CH2:7]1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2c[nH]c3ccccc23)n1
Temperature: 105 °C
Reaction time: 3 h
Yield: 107.9 %

Procedure:
Water (4 mL) was added to a mixture of N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1H-indol-3-yl)pyrimidin-2-amine (Intermediate 167, 240 mg, 0.52 mmol), iron (175 mg, 3.13 mmol), NH4Cl (19.56 mg, 0.37 mmol) and ethanol (24 mL). The resulting mixture was stirred at 105° C. for 3 h, and was then filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and part-purified by ion exchange chromatography, using an SCX column and eluting with 0.35M methanolic ammonia. Appropriate fractions were combined and concentrated in vacuo to give the title compound (241 mg, 107%) as a brown gum which was used without further purification; m/z: ES+ MH+ 430.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[N:18]=[C:19]=[O:20].CCOC(C)=O.CCCCCC.C(Cl)Cl.CO>ClC(Cl)C>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[NH:18][C:19](=[O:20])[N:2]([CH3:1])[C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ccc(C)cc1N=C=O
Reactant: CNc1cnccn1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1ccc(C)cc1NC(=O)N(C)c1cnccn1
Temperature: 80 °C

Procedure:
To a 0.3 M stirred solution of 2-methylaminopyrazine (1 equiv.) in dichloroethane at room temperature under nitrogen was added 2-methoxy-5-methylphenylisocyanate (1 equiv.). The reaction was warmed to 80° C. overnight and then cooled to room temperature. In most cases, the product precipitated and was isolated by filtration. Alternatively the product could be isolated by silica gel chromatography using EtOAc/hexane or CH2Cl2/MeOH as eluant. 1H-NMR (400 MHz, CDCl3) δ8.57 (s, 1H), 8.32 (s, 1H), 8.31 (s, 1H), 8.17 (s, 1H), 6.80 (i, 2H), 3.90 (s, 3H), 3.56 (s, 3H), 2.32 (s, 3H). LRMS (ESI, Positive) m/e 273.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9](N1C(=O)CCC1=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:19][CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:19][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C1CCC(=O)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
N-(Benzyloxycarbonyl)succinimide (5.6 g, 22.4 mmol) was dissolved in CH2Cl2 (25 mL) and the solution was added to a cooled (0° C.) and stirred solution of diethyl aminomalonate hydrochloride (5.0 g, 23.6 mmol) and triethylamine (13.4 mL, 95 mmol) in CH2Cl2 (125 ml). The resulting solution was stirred at 0° C. for 10 min and then at rt for 1 h. The solution was washed with 10% citric acid (2×50 mL),10% sodium hydrogen carbonate (2×50 mL), and water (50 mL) and was then dried (Na2SO4) and evaporated to afford diethyl N-benzyloxycarbonylaminomalonate as a colorless oil, which crystallized upon standing at 0° C. (6.3 g) (LC/Mass + ion): 310 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)[S:6]1(=[O:23])=[O:22].[CH3:24][CH:25]1[CH2:30][NH:29][CH2:28][CH:27]([CH3:31])[NH:26]1>>[F:21][C:16]1[CH:15]=[C:14]([N:7]2[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:5]([CH2:4][CH2:3][CH2:2][N:29]3[CH2:28][CH:27]([CH3:31])[NH:26][CH:25]([CH3:24])[CH2:30]3)[S:6]2(=[O:23])=[O:22])[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: CC1CNCC(C)N1
Reactant: O=S1(=O)N(CCCBr)c2ccccc2N1c1ccc(F)c(F)c1
Product: CC1CN(CCCN2c3ccccc3N(c3ccc(F)c(F)c3)S2(=O)=O)CC(C)N1
Yield: 85.3 %

Procedure:
In an analogous manner as general procedure V, 1-(3-bromopropyl)-3-(3,4-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.2, 0.51 mmol) was treated with 2,6-dimethylpiperazine (0.21 g, 1.8 mmol) to provide 1-(3,4-difluorophenyl)-3-[3-(3,5-dimethylpiperazin-1-yl)propyl]-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (0.19 g, 85%) as a white solid:
Reaction SMILES: C(OC(N[CH:12]1[NH:16][C@@H:15]([CH3:17])[C:14]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])([OH:18])[O:13]1)=O)C1C=CC=CC=1.[OH2:27].Cl>O1CCCC1.C1(C)C=CC=CC=1>[CH2:14]([O:27][C:12]([NH:16][C@@H:15]([CH3:17])[C:14]([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[F:26])=[O:18])=[O:13])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O
Reactant: C[C@@H]1NC(NC(=O)OCc2ccccc2)OC1(O)c1ccc(F)cc1F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 92 %

Procedure:
In tetrahydrofuran (70 mL) was dissolved (4S)-2-(benzyloxycarbonyl)amino-5-(2,4-difluorophenyl)-4-methyl-5-hydroxyoxazolidine (14.0 g) prepared in Example 12, and water (50 mL) and conc. hydrochloric acid (20 mL) were added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was diluted with toluene, the aqueous layer was discarded, and the organic layer was washed with water three times. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by silica column chromatography (eluent: hexane/ethyl acetate=3/1) to give the title compound (11.7 g) as a pale yellow syrup in a yield of 92%.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)[CH:26]=[CH:25][C:3]=1[O:4][CH2:5][C:6]1[CH:10]=[N:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH:13]([CH3:24])[CH2:12]2)[N:7]=1.[ClH:34].FC1C=C(S(C)(=O)=O)C=CC=1OCC1N=CN(C2CCNCC2)N=1>>[ClH:34].[F:1][C:2]1[CH:28]=[C:27]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)[CH:26]=[CH:25][C:3]=1[O:4][CH2:5][C:6]1[CH:10]=[N:9][N:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH:13]([CH3:24])[CH2:12]2)[N:7]=1
Reactant: CC1CC(n2ncc(COc3ccc(-n4cnnn4)cc3F)n2)CCN1C(=O)OC(C)(C)C
Agent: CS(=O)(=O)c1ccc(OCc2ncn(C3CCNCC3)n2)c(F)c1
Agent: Cl
Product: CC1CC(n2ncc(COc3ccc(-n4cnnn4)cc3F)n2)CCN1

Procedure:
The title compound was synthesized from tert-butyl 4-(4-((2-fluoro-4-(1H-tetrazol-1-yl)phenoxy)methyl)-2H-1,2,3-triazol-2-yl)-2-methylpiperidine-1-carboxylate in a manner similar to that described in Intermediate 6. The title compound was isolated as a mixture of four stereoisomers.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11]S(C(C)(C)C)(=O)=O)[CH3:10])=[CH:5][C:4]=1[F:19].N1C=CC=CC=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>O1CCOCC1.CO>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([NH:11][C:26](=[O:28])[CH3:27])[CH3:10])=[CH:5][C:4]=1[F:19]
Reactant: CC(=O)OC(C)=O
Reactant: CC(NS(=O)(=O)C(C)(C)C)c1ccc(Br)c(F)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)NC(C)c1ccc(Br)c(F)c1
Reaction time: 1 h

Procedure:
20.0 mL 4N HCl in dioxane are added to 17.2 g (53.4 mmol) 2-methyl-propane-2-sulfonic acid [1-(4-bromo-3-fluoro-phenyl)-ethyl]-amide (X.1) in 150 mL MeOH. Stirring is continued for 1 h. After that time, the mixture is concentrated and the residue is triturated from diethylether (150 mL). The precipitate is filtered off, washed with diethylether and suspended in 250 mL DCM. 8.64 mL (107 mmol) pyridine and 5.29 mL (56.1 mmol) acetic anhydride are added and the mixture is stirred for 12 h at rt. After that time, the mixture is transferred to a separation funnel, washed with 1N HCl (200 mL) and sat. aq. NaHCO3-solution (200 mL) and dried over sodium sulphate. The solvent is removed by evaporation to yield the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](O)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(=O)([O-])O.[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCc1ccc(Br)cc1
Reaction time: 3 h

Procedure:
3-(4-bromophenyl)propionic acid (Aldrich) (12.25 g, 53.48 mmol) was dissolved in tetrahydrofuran (100 mL) and the solution was slowly added to lithium aluminum hydride (1.22 g, 32.09 mmol) in tetrahydrofuran (100 mL). The reaction was stirred for 3 h, then 150 mL 1 N aqueous sodium hydrogen carbonate was added, the mixture was extracted with ethyl acetate (3×150 mL) and the organic phases were dried over magnesium sulphate and concentrated in vacuo. The crude product was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14].CN(C)C=O.COC(OC)N(C)C.C(OCC)(=O)C>>[Cl:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:7])[O:8][CH:9]=[CH:12]2
Reactant: COC(=O)c1ccc(Cl)c([N+](=O)[O-])c1C
Agent: COC(OC)N(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1occc2c([N+](=O)[O-])c(Cl)ccc12
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A pressure tube was charged with methyl 4-chloro-2-methyl-3-nitrobenzoate (13 g, 57 mmol), N,N-dimethylformamide (10 mL, 200 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (26.5 mL, 200 mmol). The reaction was heated at 120° C. for 20 h. The solvents were removed and the resultant brown residue was redissolved in ethyl acetate (600 mL, 6000 mmol) and 130-270 mesh 60A silica gel (500 g, 6000 mmol) was added. The reaction was stirred with a mechanical stirrer for 8 h. The reaction was filtered, washed with ethyl acetate (400 mL). the organics were combined. and the solvents were removed under reduced pressure. The residue was purified by flash chromatography to give the desired product.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C@H:22]2[NH:27][C@@H:26]([C@H:28]([OH:30])[CH3:29])[CH2:25][O:24][CH2:23]2)=[CH:18][CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:50]([C:53]1[CH:61]=[CH:60][C:56]([C:57](O)=[O:58])=[CH:55][CH:54]=1)([O-:52])=[O:51]>C(OCC)(=O)C.O.O1CCCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C@H:22]2[NH:27][C@@H:26]([C@@H:28]([O:30][C:57](=[O:58])[C:56]3[CH:55]=[CH:54][C:53]([N+:50]([O-:52])=[O:51])=[CH:61][CH:60]=3)[CH3:29])[CH2:25][O:24][CH2:23]2)=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: C[C@@H](O)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](OC(=O)c1ccc([N+](=O)[O-])cc1)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Reaction time: 2 h
Yield: 100 %

Procedure:
Under a nitrogen atmosphere and under ice-cooling, diisopropylazodicarboxylate (1.36 mL) was added dropwise in a tetrahydrofuran solution containing (R)-1-[(3R,5R)-5-(4-chlorophenyl)morpholin-3-yl]ethanol (903 mg), triphenylphosphine (1.81 g), and 4-nitrobenzoic acid (1.16 g). Stirring was continued for 30 minutes at the same temperature and for 2 hours at room temperature. Water and ethyl acetate was added to the reaction solution, and the organic layer was partitioned. The organic layer was washed with brine and was dried over anhydrous magnesium sulfate. The solvent was removed under a vacuum, and the residue was purified by silica gel column chromatography (heptane/ethyl acetate 9/1→8/2→7/3), and the title compound (1.46 g) was obtained. The physical property values are as follows.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C@@H:11]([NH:14][NH:15][CH:16]=O)[CH2:12][CH3:13])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][N:34]([C:37]3[CH:42]=[CH:41][C:40]([NH:43][C:44](=O)[O:45]C4C=CC=CC=4)=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)=[CH:27][CH:26]=1.C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][C@H:9]([C@@H:11]([N:14]1[C:44](=[O:45])[N:43]([C:40]2[CH:39]=[CH:38][C:37]([N:34]3[CH2:33][CH2:32][N:31]([C:28]4[CH:29]=[CH:30][C:25]([OH:24])=[CH:26][CH:27]=4)[CH2:36][CH2:35]3)=[CH:42][CH:41]=2)[CH:16]=[N:15]1)[CH2:12][CH3:13])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Nc1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1)Oc1ccccc1
Reactant: CC[C@H](NNC=O)[C@H](C)OCc1ccccc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC[C@@H]([C@H](C)OCc1ccccc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Temperature: 95 °C
Reaction time: 24 h

Procedure:
A mixture of N′-((2S,3S)-2-(benzyloxy)pentan-3-yl)formohydrazide compound of formula-17 (45.5 g) obtained in example-13, dioxane (500 ml) added phenyl 4-(4-(4-hydroxyphenyl)piperazin-1-yl)phenylcarbamate compound of formula-19 (50 g) was heated to 90-100° C. Triethylamine (26 g) was added to the reaction mixture at 90-100° C. over a period of 1 hour and stirred for 24 hours at 90-100° C. After completion of the reaction, the reaction mixture was cooled to 25-30° C. and dichloromethane was added to the reaction mixture. Filtered the reaction mixture through hyflow bed and washed with dichloromethane. Water was added to the filtrate. Both organic and aqueous layers were separated and the aqueous layer was extracted with dichloromethane. Both organic layers were combined and washed with 2% sodium hydroxide solution followed by water, and then with 5% hydrochloric acid solution followed by water and 5% NaHCO3 solution washing. Distilled off the solvent from organic layer under reduced pressure to get the title compound. Isopropyl alcohol (75 ml) was added to the obtained compound and the reaction mixture was cooled to 25-30° C. The reaction mixture was stirred for 6 hours at 25-30° C. Filtered the solid, washed with isopropyl alcohol and then dried to get the title compound. Yield: 28 g; Purity by HPLC: 97.67%; Impurity-A: 0.37%