Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])[CH2:6]1)=[N+]=[N-].CP(C)C.O>C1COCC1.C(Cl)Cl>[NH2:1][CH2:4][C@@H:5]1[C@H:9]2[O:10][C:11]([CH3:13])([CH3:14])[O:12][C@H:8]2[C@H:7]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=2[O:34][CH3:35])[CH2:6]1
Reactant: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN=[N+]=[N-])[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CP(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(CNc2ncnc3c2ncn3[C@@H]2C[C@H](CN)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
A solution of 9-((3aS,4R,6R,6aR)-6-(azidomethyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-9H-purin-6-amine (1.72 g, 3.58 mmol) in THF (16 mL) was cooled to 0° C. (ice/brine bath) and treated dropwise with a 1.0 M solution of trimethylphosphine in THF (6.30 mL, 6.30 mmol). The cold bath was removed after 30 min and the reaction mixture was stirred for 1.5 h; HPLC/LC MS indicated complete consumption of the starting azide. Water (2.84 mL, 157 mmol) was added to the orange solution (gas evolution noted) and the reaction mixture was stirred for 2.75 h at rt; HPLC indicated complete conversion to the desired amine. The reaction mixture was concentrated in vacuo to afford an orange oil. The residue was taken up in CH2Cl2 (150 mL) and washed with water (2×50 mL) and brine (1×75 mL). The separated organic layer was dried (Na2SO4) and concentrated in vacuo to afford the title compound (1.6 g, 98%) as a pale yellow foam: MS (ESI+) for C23H30N6O4 m/z 455.2 (M+H)+; HPLC purity >95 area %.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1C[CH2:11][CH2:10][CH2:9]1.C(#N)C=C.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1C=CC=CC=1>[C:9]([CH2:10][CH2:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH:6]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:1]1=[O:7])#[N:8]
Reactant: C1CCNC1
Reactant: CCOC(=O)CBr
Reactant: O=C1CCCCC1
Solvent: c1ccccc1
Solvent: C=CC#N
Product: CCOC(=O)CC1CCCC(CCC#N)C1=O
Yield: 57.9 %

Procedure:
An oven dried 250 ml 1-necked round bottomed flask was charged with cyclohexanone (26.37 g, 0.27 mol) and dry benzene (50 ml). To this solution was added pyrrolidine (29 ml, 0.35 mol) over 10 min through a dropping funnel. The resultant solution was refluxed for 3 hours with azeotroping off water and then concentrated by distilling off benzene. The remaining crude enamine was dissolved in p-dioxane (100 ml) and treated with acrylonitrile (20 ml, 0.3 mol) and refluxed for 6 hours, and then slowly treated with ethyl bromoacetate (31 ml, 0.28 mol), and refluxed for further 12 hours. Then the reaction mixture was concentrated under reduced pressure, and treated with water (30 ml) and 10% sulfuric acid (50 ml) at room temperature. The resultant solution was diluted with ether (200 ml). The organic layer was separated from the aqueous layer and further extracted twice with ether (100 ml×2), combined, and washed with saturated NaCl solution (200 ml). The resulting organic layer was dried over anhydrous magnesium sulfate, and filtered, and the solvent was removed at reduced pressure to yield a crude product. Vacuum distillation at 0.1 torr afforded the desired product 2 (37.10 g, 58%) as a mixture of cis and trans stereoisomers: bp 160°-175° C. (0.1 torr); FT-IR (neat, cm-1) 2936, 2861, 2245, 1732, 1710, 1449, 1376, 1344, 1276, 1234, 1188, 1116, 1071, 1028, 989, 947, 862, 838, 748; 1H NMR (CDCl3, 400 MHz) δ 4.14 (q, J=7.1 Hz, 2H), 2.92 (m, 1H), 2.75 (dd, 16.6, 7.2 Hz, 1H), 2.56 (m, 1H), 2.45 (t, J=7.4 Hz, 1H), 2.43 (t, J=7.5 Hz, 1H), 2.17 (dd, J=16.6, 5.7 Hz, 2H), 2.22-2.05 (m, 2H), 1.96-1.78 (m, 2H), 1.55 (ddd, J=17.4, 8.8, 4.7 Hz, 1H), 1.42 (m, 2H), 1.26 (t, J=7.2 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 210.92, 172.22, 119.63, 48.92, 48.81, 47.35 (47.14 for minor), 34.80, 34.55, 34.25, 34.13, 4.93, 15.09 (14.07 for minor); MS (El, 70 eV, rel. intensity) 237 (M, 17), 208(12), 192(B), 191(59), 163(27), 150(58), 141(35), 95(20), 84(27), 67(13), 55(20), 49(14); HRMS (El) calcd. for C13H19NO3 237.1365. Found 237.1361.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[N:11][CH3:12])([NH2:10])=[O:9].C1(O[C:20](=[O:31])[NH:21][C:22]2[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](=[N:11][CH3:12])([NH:10][C:20]([NH:21][C:22]1[N:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([CH3:30])[N:23]=1)=[O:31])=[O:9]
Reactant: CN=S(N)(=O)c1ccccc1Cl
Reactant: COc1nc(C)nc(NC(=O)Oc2ccccc2)n1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CN=S(=O)(NC(=O)Nc1nc(C)nc(OC)n1)c1ccccc1Cl
Reaction time: 0.75 h
Yield: 22.5 %

Procedure:
To a solution of 196.8 mg (0.96 mmol) of 2-chloro-N'-methylbenzenesulfonimidamide and 250 mg (0.96 mmol) of phenyl(4-methoxy-6-methyl-1,3,5-triazin-2-yl)carbamate in 5 mL of dry acetonitrile was added 0.15 mL (1.0 mmol) of 1,8-diazabicyclo[5.4.0]-undec-7-ene. After 45 minutes at room temperature, 5 mL of water and 2.5 mL of 5% HCl were added. The aqueous layer was extracted with methylene chloride (3×10 mL). The organic layer was dried (Na2SO4), filtered and the solvent was removed with a rotary evaporator. The residue was triturated with ethyl acetate to give 80 mg of a white solid; m.p. 154° to 160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([CH:34]=1)[CH2:7][CH:8]1[C:14](=[O:15])[N:13]([C:16]([NH:18][CH:19]([CH2:31][CH3:32])[C:20]([NH:22][CH2:23][C:24](OC(C)(C)C)=O)=[O:21])=[O:17])[CH2:12][C:11](=[O:33])[NH:10][CH2:9]1.Cl.C(OC(=O)CN)(C)(C)C.C(OC([C:54]1(N)C=C[CH:57]=[C:56]([NH2:60])[CH2:55]1)=O)(C)(C)C>>[NH2:60][C:56]1[CH:57]=[C:23]([CH:24]=[CH:54][CH:55]=1)[NH:22][C:20]([C@H:19]([NH:18][C:16]([N:13]1[C:14](=[O:15])[CH:8]([CH2:7][C:6]2[CH:34]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[O:35][CH3:36])[CH2:9][NH:10][C:11](=[O:33])[CH2:12]1)=[O:17])[CH2:31][CH3:32])=[O:21]
Reactant: CCC(NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)NCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)C1(N)C=CC=C(N)C1
Agent: CC(C)(C)OC(=O)CN
Agent: Cl
Product: CC[C@@H](NC(=O)N1CC(=O)NCC(Cc2cc(Cl)ccc2OC)C1=O)C(=O)Nc1cccc(N)c1

Procedure:
Instead of the starting material compound of Example 220, that is, the glycine tert-butyl ester hydrochloride, 1-(tert-butoxycarbonyl)-1,3-phenylenediamine was used for the similar procedure as in Example 220 and Example 245 to obtain the title compound.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25]1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:26]2[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][CH:25]=2)=[O:34])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1c[nH]c2ccccc12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c[nH]c3ccccc23)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 1H-Indole-3-carboxylic acid.
Reaction SMILES: [C:1]([O:5][NH:6][C:7]([C:9]1[C:14]([CH3:15])=[C:13]([N+:16]([O-])=O)[CH:12]=[CH:11][CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(ONC(C1C=C(C=CC=1)N)=O)(C)(C)C>>[NH2:16][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([C:7](=[O:8])[NH:6][O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14]=1[CH3:15]
Reactant: Cc1c(C(=O)NOC(C)(C)C)cccc1[N+](=O)[O-]
Agent: CC(C)(C)ONC(=O)c1cccc(N)c1
Product: Cc1c(N)cccc1C(=O)NOC(C)(C)C
Yield: 98.9 %

Procedure:
This compound was prepared from 6-tert-butyloxycarbamoyl-2-nitrotoluene (4.60 g, 18.2 mmol) in a manner similar to that described for 3-tert-butyloxycarbamoylaniline (EXAMPLE 147), affording 4.00 g (99%) of 2-amino-6-tert-butyloxycarbamoyltoluene as a colorless oil. Data for 2-amino-6-tert-butyloxycarbamoyltoluene: 1H NMR (400 MHz, CDCl3) 7.04 (br d of ABq, JAB=8.0, JA=0, JB=7.9, 2H, 5,4-H), 6.49 (d, J=8.3, 1H. 3-H), 6.26 (br s, 1H, NH), 3.61 (br s, 2H, NH2), 2.02 (s, 3H, 1-CH3), 1.51 [s, 9H, (CH3)3CO)].
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].[CH:18](=O)[CH3:19].C(O[BH3-])(=O)C.[Na+]>C(Cl)Cl>[CH2:18]([NH:1][C:2]1[CH:13]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:11]=[CH:10][C:3]=1[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5])[CH3:19]
Reactant: CON(C)C(=O)c1ccc(C(F)(F)F)cc1N
Reactant: CC=O
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CCNc1cc(C(F)(F)F)ccc1C(=O)N(C)OC
Yield: 17.7 %

Procedure:
2-Amino-N-methoxy-N-methyl-4-trifluoromethyl-benzamide (482 mg, 1.94 mmol) was reacted with acetaldehyde (0.12 ml, 2.14 mmol) and sodium acetoxyborohydride (892 mg, 4.20 mmol) in CH2Cl2 at room temperature as described above to yield title compound (95 mg, 17%).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c([N+](=O)[O-])ccc(F)c1F
Yield: 106.7 %

Procedure:
20 g (0.114 mole) of 2,3-difluoro-6-nitrophenol (VI) were dissolved in 700 ml of acetone. 18.9 g (0.137 mole) of potassium carbonate and 34.1 g (0.24 mole) of methyl iodide were added to the solution, and the mixture was heated under reflux for 20 hours, whilst stirring. The solvent was then removed from the mixture by evaporation under reduced pressure, and the residue was extracted with ethyl acetate. The ethyl acetate extract was washed with water and dried, and the solvent was removed by evaporation under reduced pressure to give 23.0 g of 3,4-difluoro-2-methoxy-1-nitrobenzene (VII) as a yellow oil [Step (B1)].
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:17][C:18]3[CH:23]=[C:22]([NH:24][C:25]4[S:29][N:28]=[C:27]([CH3:30])[CH:26]=4)[C:21]([C:31]#[N:32])=[CH:20][C:19]=3[F:33])[C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].OO.CC(O)=[O:40]>CCO.CS(C)=O>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:17][C:18]3[C:19]([F:33])=[CH:20][C:21]([C:31]([NH2:32])=[O:40])=[C:22]([NH:24][C:25]4[S:29][N:28]=[C:27]([CH3:30])[CH:26]=4)[CH:23]=3)[C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-n4ccnc4)cc3)C(N)=O)c(F)cc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-n4ccnc4)cc3)C(N)=O)c(F)cc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)propanamide (9 mg, 0.019 mmol) in EtOH (1 mL) and DMSO (0.5 mL), aq. 1N NaOH (0.5 mL, 0.50 mmol) and aq. H2O2 (50%, 0.5 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was purified by HPLC to give the titled compound (5 mg). MS 480.3 (M+H); UV 204.7, 292.8 nm.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:14][CH2:15][C:16]([OH:18])=[O:17].Cl>CC(C)=O.[OH-].[Na+].O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:14][CH2:15][C:16]([OH:18])=[O:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Ex-26A: To a solution of 4-acetylbenzenesulfonyl chloride (0.50 g, 2.3 mmol) in acetone (7.5 mL) was added a solution of glycine (0.42 g, 5.7 mmol) in 5% aqueous sodium hydroxide (2.5 mL) and the reaction was stirred for 30 min at room temperature. The mixture was diluted with water (10 mL), acidified with a 1 N hydrochloric acid solution, and extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with brine (2×20 mL), dried over sodium sulfate, and the solvent was removed under reduced pressure. The resulting solid was dried in vacuo to afford 0.55 g (94%) of (4-acetylbenzenesulfonylamino)acetic acid as a white solid, mp 213–215° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.28 (t, 1H, J=5.4 Hz), 8.12 (d, 2H, J=8.4 Hz), 7.92 (d, 2H, J=8.4 Hz), 3.64 (d, 2H, J=5.1 Hz), 2.64 (s, 3H). Anal. Calcd. for C10H11NO5S: C, 46.69; H, 4.31; N, 5.44; S, 12.46; Found: C, 46.76; H, 4.43; N, 5.39; S, 12.16.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27](=[O:29])[CH3:28])[CH:22]=3)=[CH:17][CH:16]=2)[O:12][C:13]=1[CH3:14].C(N(CC)CC)C>ClCCl>[C:27]([C:23]1[CH:22]=[C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:11]3[O:12][C:13]([CH3:14])=[C:9]([CH2:8][CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:10]=3)=[CH:20][CH:19]=2)[CH:26]=[CH:25][CH:24]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1cccc(-c2ccc(-c3nc(CCO)c(C)o3)cc2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cccc(-c2ccc(-c3nc(CCOS(C)(=O)=O)c(C)o3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.7 %

Procedure:
Add methanesulfonyl chloride (0.110 g, 0.760 mmol) to a cool (0° C.) solution of 1-{4′-[4-(2-hydroxy-ethyl)-5-methyl-oxazol-2-yl]-biphenyl-3-yl}-ethanone (0.188 g, 0.584 mmol) and triethylamine (0.089 g, 0.88 mmol) in dichloromethane (5 mL). Warm the reaction mixture to room temperature and stir for 1 hour. Add dichloromethane and wash the crude organic layer with saturated sodium chloride solution. Dry the organic extracts over Na2SO4, filter, and concentrate to give crude methanesulfonic acid 2-[2-(3′-acetyl-biphenyl-4-yl)-5-methyl-oxazol-4-yl]-ethyl ester (0.256 g, >100%).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=O)=[CH:8][CH:7]=[CH:6][C:5]=12.[N+:12]([CH2:15][C:16](=O)[CH3:17])([O-:14])=[O:13].[F:19][C:20]([F:40])([F:39])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:38])/[CH:34]=[C:35](\[NH2:37])/[CH3:36])[CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1>C(O)(C)C>[F:40][C:20]([F:19])([F:39])[C:21]1[CH:22]=[C:23]([N:27]2[CH2:32][CH2:31][N:30]([C:33]([C:34]3[CH:10]([C:9]4[C:4]5[C:5](=[N:1][O:2][N:3]=5)[CH:6]=[CH:7][CH:8]=4)[C:15]([N+:12]([O-:14])=[O:13])=[C:16]([CH3:17])[NH:37][C:35]=3[CH3:36])=[O:38])[CH2:29][CH2:28]2)[CH:24]=[CH:25][CH:26]=1
Reactant: CC(=O)C[N+](=O)[O-]
Reactant: O=Cc1cccc2nonc12
Reactant: C/C(N)=C/C(=O)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Solvent: CC(C)O
Product: CC1=C(C(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)C(c2cccc3nonc23)C([N+](=O)[O-])=C(C)N1

Procedure:
7.4 g (50 mmol) of 2.1.3-benzoxadiazole-4-aldehyde, 10 g (0.1 mol) of nitroacetone and 15.6 g (50 mmol) of 3-aminocrotonic acid 4-(3-trifluoromethylphenyl)piperazide are heated in isopropanol at 60° C. for 6 hours. The product crystallizes after part of the solvent has been evaporated off, and is recrystallized from a little isopropanol.
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]CC)=[O:43])=[CH:37][CH:36]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>C(O)C>[CH2:1]([C:3]1[O:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[CH:37][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4coc(CC)n4)cc3OC)c(C)o2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccc(CC(=O)O)cc4)oc3C)c(OC)c2)co1
Temperature: 50 °C
Reaction time: 1 h
Yield: 56.8 %

Procedure:
To a mixture of ethyl {4-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (360 mg), tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.6 mL) and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid was added to the reaction mixture for neutralization, and the mixture was extracted with ethyl acetate. The residue was recrystallized from ethyl acetate-hexane and the precipitated crystals were collected by filtration to give {4-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-oxazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid (196 mg, yield 37%) as colorless crystals. melting point: 117-119° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11](N(OC)CC)=[O:12])=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:24][Mg]Br>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][C:11](=[O:12])[CH3:24])=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: CCN(OC)C(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.5 %

Procedure:
To a solution of 2-(2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-N-methoxy-N-ethyl-acetamide (200 mg, 0.60 mmol) in THF (4 mL) at −78° C. was added methylmagnesium bromide (1.28 mL, 1.79 mmol, 1.4 M solution in THF/toluene) and the resulting mixture warmed to RT and stirred for 3 hours. The resulting mixture was quenched with 1M HCl and extracted with ethyl acetate. The combined organic extracts were washed with brine, then dried (Na2SO4) and concentrated in vacuo affording 1-(2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-propan-2-one as a white solid (146 mg, 80%). LCMS: RT=2.90 min, [M+H]+=306/308/310.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](=[O:6])[CH3:5].C1C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]=O)=[CH:22][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:16][O:17][C:18]1[CH:19]=[CH:20][C:21]([CH:24]2[O:9][CH2:8][C:3]([C:4]([CH3:5])=[O:6])([CH3:7])[CH2:2][O:1]2)=[CH:22][CH:23]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CC(=O)C(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C2OCC(C)(C(C)=O)CO2)cc1

Procedure:
3,3-bis(Hydroxymethyl)butanone (39.6 g), benzene (200 ml), anisaldehyde (40.8) and toluene-p-sulphonic acid (200 mg) were heated under reflux in a Dean and Stark water trap until the theoretical amount of water had separated. The solution was concentrated in vacuo and the solid residue was crystallised from isopropyl acetate as a white crystalline solid m.p. 112°-114°, cis isomer.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Cr]([O-])([O-])=O.[Cu+2]>[C:12]([C:9]1[CH:8]=[C:7]([CH2:16][CH2:17][CH:18]([OH:20])[CH3:19])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: CCO
Product: CC(O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 3 h

Procedure:
4-(3,5-di-t-butyl-4-hydroxyphenyl) butane-2-ol was prepared by catalytic hydrogenation of 84.8 grams of 4-(3,5-di-t-butyl-4-hydroxyphenyl) butane-2-one in 400 milliliters of ethanol solvent in the presence of 10 grams of copper chromite catalyst at 150° C, and 1000 pounds per square inch pressure in a one-liter autoclave. Reduction was complete in three hours. The catalyst was filtered off and the filtrate was evaporated. The residue was crystallized by the addition of hexane to yield 82.9 grams of a white solid product (97 percent yield) having a melting point between 64° C and 66° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH:10]=[N:9]1)([O-])=O.[H][H]>[Pd].C1COCC1.CO>[NH2:1][C:4]1[CH:5]=[C:6]([CH:33]=[CH:34][CH:35]=1)[CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:25]=[CH:26][CH:27]=4)[CH:20]=3)[NH:15][CH:14]=2)[CH:10]=[N:9]1
Reactant: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc([N+](=O)[O-])c5)c4)c3c2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(N)c5)c4)c3c2)c1
Yield: 16.1 %

Procedure:
N-(3-(3-(1-(3-nitrobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methane sulfonamide (Example-7) (80 mg, 0.163 mmol), was reduced by palladium on carbon (8 mg, 10% W/W) in THF/MeOH (2/2 mL) under positive pressure of hydrogen using a bladder. The catalyst filtered off and concentrated to get crude compound. This was then purified by preparative TLC using 10% ethyl acetate in hexanes as eluent yielded 12 mg (16% yield) of pure titled compound. 1H NMR (DMSO-d6, 400 MHz): δ11.85 (s, 1H), 9.83 (s, 1H), 8.47-8.46 (d, 1H), 8.33-8.32 (m, 2H), 7.92 (s, 1H), 7.775-7.770 (d, 1H), 7.53-7.44 (m, 3H), 7.24-7.22 (d, 1H), 6.96-6.94 (t, 1H), 6.46-6.42 (m, 2H), 5.20 (s, 2H), 5.10 (b, 2H), 3.05 (s, 3H). MS: m/z=459.3 (M+1), HPLC: 92.06% (method B).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]([CH3:17])([CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)=[O:8])[CH3:2].Br[CH2:20][CH2:21][CH2:22][Cl:23].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][C:6]([CH3:17])([CH3:16])[C:7]([C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:20][CH2:21][CH2:22][Cl:23])=[CH:13][CH:14]=1)=[O:8])[CH3:2]
Reactant: ClCCCBr
Reactant: CCOC(=O)CC(C)(C)C(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CC(C)(C)C(=O)c1ccc(OCCCCl)cc1

Procedure:
The product from step 2 (1.0 g, 4.2 mmol), 1-bromo-3-chloropropane (1.0 g, 8 mmol) and K2CO3 in acetonitrile (20 mL) was heated to reflux for 24 h. The reaction was cooled, filtered, concentrated to an oil and purified by ISCO silica gel chromatography (10% EtOAc/hexanes) to give 0.7 g.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][CH:12]1[CH2:17][NH:16][CH2:15][CH:14]([CH3:18])[NH:13]1>C(#N)C>[CH3:11][CH:12]1[NH:13][CH:14]([CH3:18])[CH2:15][N:16]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:17]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC1CNCC(C)N1
Solvent: CC#N
Product: CC1CN(c2ccc([N+](=O)[O-])cc2)CC(C)N1
Temperature: 90 °C
Yield: 68 %

Procedure:
1-Fluoro-4-nitro-benzene (1.00 g, 8.75 mmol) and 2,6-dimethyl-piperazine (1.20 g, 10.5 mmol) are dissolved in 100 ml of acetonitrile forming a yellow homogeneous mixture. Mixture is heated at 90° C. overnight. Mixture is reduced on rotovap to afford the product as an orange solid (1.40 g, 65%); 1H NMR (DMSO-d6) δ 1.00 (d, J=6.3 Hz, 6H), 2.37-2.80 (m, 5H), 3.87 (dd, J=2.1, 12.4 Hz, 2H), 7.00 (d, J=9.5 Hz, 2H), 8.00 (d, J=9.5 Hz, 2H).