Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>O>[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)CNCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)O)cc1
Temperature: 80 °C
Yield: 48.2 %

Procedure:
Iminodiacetic acid (200 g, 1.50 mol) was dissolved in water (3 L) and sodium hydroxide (180 g, 4.5 mol) was added in small portions with stirring. After stirring for 15 minutes, p-toluenesulfonyl chloride (286.5 g, 1.5 mol) was added in small portions. The reaction mixture was heated to 80° C. for one hour, giving a clear solution. At the end of this time, the reaction solution was cooled in an ice bath to 10°--15° C., and concentrated HCl (110 ml) was added, precipitating the product as a white solid. This solid was filtered and washed with cold water, then dried in a vacuum oven at 55° C., giving 207.7 g (0.723 mol, 48.2% yield): mp 195°-196° C . (lit.* mp 191° C.); 1H NMR (DMSO-d6, 300 MHz) δ 2.38 (s, 3H), 3.66 (s, 4H), 7.39 (d, J=8.7 Hz, 2H), 7.65 (d, J=8.1 Hz); 13C NMR (DMSO-d6, 75 MHz) δ 20.90, 53.98, 126.55, 129.79, 136.70, 143.17, 171.77.
Reaction SMILES: [CH2:1]([C:3]1[NH:11][C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[N:4]=1)[CH3:2].[H-].[Na+].Br[CH2:24][CH2:25][CH2:26][CH3:27]>C(OCC)(=O)C>[CH2:24]([N:4]1[C:3]([CH2:1][CH3:2])=[N:11][C:10]2[C:5]1=[N:6][CH:7]=[N:8][C:9]=2[C:12]1[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=1[CH3:20])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCBr
Reactant: CCc1nc2ncnc(-c3c(C)cc(C)cc3C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCCn1c(CC)nc2c(-c3c(C)cc(C)cc3C)ncnc21
Reaction time: 1 h
Yield: 26.7 %

Procedure:
A solution of 8-ethyl-6-(2,4,6-trimethylphenyl)purine (200 mg, 0.75 mmol) in anhydrous dimethylfomamide (5 mL) was cooled to 0° C., and treated with sodium hydride dispersion in mineral oil (72 mg 50% w/w, 1.50 mmol). After 1 hour, bromobutane (0.10 mL, 0.90 mmol) was added by syringe, and the mixture was allowed to stir for 12 hours. It was poured into ethyl acetate (120 mL), and was washed with water (3×120 mL) and brine (100 mL). The aqueous layers were back-extracted in sequence with ethyl acetate (120 mL), and the extracts were combined, dried over anhydrous sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, 20:80 ethyl acetate-hexane) to afford the title product as a viscous oil (64.2 mg, 0.20 mmol, 27%). TLC R, 0.20 (30:70 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 8.96 (1H, s), 6.95 (2H, s), 4.25 (2H, t, J=7.5 Hz), 2.93 (2H, q, J=7.7 Hz), 2.32 (3H, s), 2.04 (6H, s), 1.91-1.86 (2H, m), 1.50-1.38 (2H, m), 1.39 (3H, t, J=7.7 Hz), 1.01 (3H, t, J=7.5 Hz). MS(NH3 -CI): m/e 325 (3), 324 (23), 323 (100).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([O:27][CH3:28])[CH:26]=1)[CH2:22][NH2:23]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:23][CH2:22][C:21]2[CH:24]=[C:25]([O:27][CH3:28])[CH:26]=[C:19]([O:18][CH3:17])[CH:20]=2)[N:3]=1
Reactant: COc1cc(CN)cc(OC)c1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COc1cc(CNc2nc(Cl)nc3c2ncn3C2CCCC2)cc(OC)c1

Procedure:
2-Chloro-6-[(3,5-dimethoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 3,5-dimethoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C1COCC1.[C:6]1([CH2:12][OH:13])[CH:11]=[CH:10][CH:9]=[CH:8]C=1.[OH-].[Na+].[Cl:16][C:17]1[C:22]([O:23][CH2:24][CH:25]2[CH2:27][O:26]2)=[CH:21][CH:20]=[CH:19][N:18]=1>O>[Cl:16][C:17]1[C:22]([O:23][CH2:24][CH:25]([OH:26])[CH2:27][O:13][CH2:12][CH2:6]/[CH:11]=[CH:10]\[CH:9]=[CH2:8])=[CH:21][CH:20]=[CH:19][N:18]=1
Reactant: OCc1ccccc1
Reactant: Clc1ncccc1OCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=C/C=C\CCOCC(O)COc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
A mixture of THF (915 ml), benzenemethanol (2.96 mol) and NaOH (2.36 mol) was stirred at room temperature for 30 minutes (cooling was required to keep the temperature below 25° C.). Intermediate (19) (1.97 mol) was added. The reaction mixture was stirred at room temperature for 4 days. Water was added dropwise (cooling required) and the mixture was extracted with ethyl acetate. The organic layer was dried, filtered and the solvent was evaporated. The residue was combined with analogously obtained fraction, then purified by HPLC over silica gel (eluent: hexane/ethyl acetate (60/40)). The desired fractions were collected and the solvent was evaporated, yielding 38% of 1-[(2-chloro-3-pyridinyl)oxy]-3-[(3Z)-3,5-hexadienyloxy]-2-propanol (intermediate 20).
Reaction SMILES: [C:1]([CH2:11][CH2:12][C:13]([OH:15])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S(Cl)([Cl:18])=O>CN(C)C=O>[C:1]([CH2:11][CH2:12][C:13]([Cl:18])=[O:15])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Cl)CCC(=O)OCc1ccccc1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
A solution of 5 grams of beta-carbobenzyloxypropionic acid (IV) in 50 ml. of thionyl chloride containing 0.5 ml of anhydrous dimethylformamide is allowed to stand, sheltered from moisture, for two days. The excess thionyl chloride is distilled off under a high vacuum, and the residue, which is a yellow oil, is heated in a flask to 110°C under an abs. pressure of 0.4 mmHg in order to strip the head fractions. The undistilled residue is taken up with ethyl ether, decolorized with charcoal, filtered and concentrated again. There are obtained about 3.48 grams (64% of theory) of (V) which is employed as such for the following stage.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[C:7]1[CH:8]=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C.[CH3:21][C:22]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:23]=1[O:24][CH2:25][CH2:26][CH2:27][C:28]([CH3:33])([CH3:32])[C:29](Cl)=[O:30]>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][N:3]=[C:2]1[C:7]1[CH:8]=[C:9]([NH:13][C:29](=[O:30])[C:28]([CH3:32])([CH3:33])[CH2:27][CH2:26][CH2:25][O:24][C:23]2[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:22]=2[CH3:21])[CH:10]=[CH:11][CH:12]=1
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Cl)c1
Reactant: Nc1cccc(C2=NCCCO2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc(C3=NCCCO3)c2)c1
Temperature: 0 °C

Procedure:
To an ice cold solution of 3-(5,6-dihydro-4H-1,3-oxazin-2-yl)benzenamine, 8.8 g (0.05 mol), (Journal of the American Chemical Society, Vol. 59, pp. 2259-2261, (1937)) and triethylamine, 10 ml, in dichloromethane, 300 ml, is added 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride, 13.4 g (0.05 mol), (U.S. Pat. No. 4,285,951). The mixture is worked up to give 18.8 g of N-[3-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenyl]-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide after recrystallization from diisopropyl ether; mp 114°-115° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[F:13][C:14]1[CH:27]=[C:26]([OH:28])[CH:25]=[CH:24][C:15]=1[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:13][C:14]1[CH:27]=[C:26]([O:28][C:2]2[CH:11]=[N:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=3)[N:3]=2)[CH:25]=[CH:24][C:15]=1[O:16][CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1F
Temperature: 100 °C

Procedure:
A mixture of 2,6-dichloroquinoxaline (0.99 g 0.005 mole), ethyl 2-(2-fluoro-4-hydroxyphenoxy)propionate (1.14 g, 0.005 mole), anhydrous potassium carbonate (0.76 g, 0.0055 mole) and dimethylformamide (20 ml) was stirred and heated at 100° C. for 2 hours. The mixture was cooled and then poured into water (200 ml) to give a white precipitate which was collected by filtration. Recrystallization from ethanol gave the product, ethyl 2-[2-fluoro-4-(6-chloroquinoxalin-2-yloxy)phenoxy]propionate, as colourless crystals (1.3 g; 66%), mp 110° C. Proton magnetic resonance spectrum (CDCl3, δ in ppm); 1.3, t, 3H (CH2CH3); 1.7, d, 3H (CHCH3); 4.3, q, 2H (OCH2CH3); 4.8, q, 1H (CHCH3); 6.9-7.5, m, 3H (phenoxy ring); 7.8, bs, 2H (C7, C8 of quinoxaline); 8.2, bs, 1H (C5 of quinoxaline); 8.8, s, 1H (C3 of quinoxaline).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]1([NH2:12])[CH2:11][CH2:10][S:9][CH2:8][CH2:7]1)=[O:5].[OH:13][C:14]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:2][O:3][C:4]([C:6]1([NH:12][C:16](=[O:17])[C:15]2[CH:19]=[CH:20][CH:21]=[C:22]([CH3:23])[C:14]=2[OH:13])[CH2:7][CH2:8][S:9][CH2:10][CH2:11]1)=[O:5]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: COC(=O)C1(N)CCSCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C1(NC(=O)c2cccc(C)c2O)CCSCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.2 %

Procedure:
To a solution of HCl salt of 4-amino-tetrahydro-thiopyran-4-carboxylic acid methyl ester (529 mg, 2.5 mmol), 2-hydroxy-3-methyl-benzoic acid (380 mg, 2.5 mmol), HATU (1.14 g, 3.0 mmol) in anhydrous DMF (20 mL) is added DIPEA (1.66 mL, 10 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (30 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 10-80% EtOAc in heptane) to give a pure product (27) as white solid (102 mg, 13%).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[C:14]([F:26])[CH:13]=3)[CH:6]=[N:5][C:4]=2[CH:3]=1.[C:27]([C:29]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]1)#[CH:28]>>[F:26][C:14]1[CH:13]=[C:12]([N:7]2[C:8](=[O:11])[C:9]3[S:10][C:2]([C:28]#[C:27][C:29]4([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:3][C:4]=3[N:5]=[CH:6]2)[CH:17]=[CH:16][C:15]=1[O:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=c1c2sc(Br)cc2ncn1-c1ccc(OCCN2CCCC2)c(F)c1
Reactant: C#CC1(O)CCCC1
Product: O=c1c2sc(C#CC3(O)CCCC3)cc2ncn1-c1ccc(OCCN2CCCC2)c(F)c1

Procedure:
6-Bromo-3-[3-fluoro-4-(2-pyrrolidin-1-ylethoxy)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one was reacted with 1-ethynylcyclopentanol by method R.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.Cl[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][N:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc(C=O)cc2)cn1
Yield: 35 %

Procedure:
A mixture of 25 g of 2-methyl-5-pyridinol, 32 g of 4-chlorobenzaldehyde, 75 g of potassium carbonate and 200 ml of dimethylformamide was heated under refluxing for 6 hours with stirring. After cooling, the mixture was filtered and the filtrate was concentrated. The resulting oily substance was dissolved in diethyl ether, and the solution was washed successively with an aqueous solution of sodium hydroxide and water, and dried over magnesium sulfate. The solvent was then distilled off and the resulting oily substance was dissolved in isopropyl alcohol. To the solution was added concentrated hydrochloric acid, and the resulting hydrochloride was filtered and recrystallized from a mixture of methanol and ethyl acetate to obtain colorless needles. The crystals were added to an aqueous solution of sodium carbonate and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off to obtain an oily substance which crystallized upon standing. The crystals were recrystallized from hexane to obtain 17 g (35% yield) of 4-(2-methyl-5-pyridyloxy)benzaldehyde as colorless prisms having a melting point of 45°-46° C. and a boiling point of 133° C./2 mmHg (bath temperature).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:22][CH2:21]4)[CH:19]=3)=[C:11](N)[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2].[C:30](N1C2C(=CC(C3C=CC(S(C)(=O)=O)=CC=3)=C(OC)C=2)N(C(OC(C)C)=O)C[C@@H]1C)(=[O:32])C>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:21][CH2:22]4)[CH:19]=3)=[C:11]([O:32][CH3:30])[CH:12]=2)[N:7]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:6][C@@H:5]1[CH3:29])(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1-c1ccc(S(C)(=O)=O)cc1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O
Reactant: CC(=O)N1c2cc(N)c(-c3cnn(C4CC4)c3)cc2N(C(=O)OC(C)C)C[C@@H]1C
Product: COc1cc2c(cc1-c1cnn(C3CC3)c1)N(C(=O)OC(C)C)C[C@H](C)N2C(C)=O

Procedure:
Isopropyl (S)-4-acetyl-7-(1-cyclopropyl-1H-pyrazol-4-yl)-6-methoxy-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate was synthesized from isopropyl (S)-4-acetyl-6-amino-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate according to the procedure described above for isopropyl (S)-4-acetyl-6-methoxy-3-methyl-7-(4-(methylsulfonyl)phenyl)-3,4-dihydroquinoxaline-1(2H)-carboxylate (Example 244). MS (ESI, pos. ion) m/z 413 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].[I:18]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[C:10](=[CH:15][CH:14]=[C:13]([O:16][CH3:17])[CH:12]=2)[NH:9][C:8]=1[I:18])(=[O:3])[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc2[nH]cc(CCNC(C)=O)c2c1
Solvent: ClC(Cl)Cl
Product: COc1ccc2[nH]c(I)c(CCNC(C)=O)c2c1
Temperature: -20 °C
Reaction time: 4.5 h

Procedure:
To a solution of melatonin (2.32 g: 10 mM) in chloroform (70 ml) cooled at -20° C. there is added N-iodosuccinimide (NIS:2.25 g; 10 nM); the reaction mixture is stirred at -20° C. for 4.5 hours.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[CH:4]=[O:5].[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C.[OH-].[Na+].O>[N+:10]([C:7]1[CH:6]=[C:3]([C:2]([S:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[CH:4]=[O:5])([O-:12])=[O:11]
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=Cc1cc([N+](=O)[O-])ccc1Sc1ccccc1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A solution of 480 g of 2-chloro-5-nitro-benzaldehyde in 3.2 litres of ethanol is treated dropwise under a nitrogen atmosphere at 30°-40° C with stirring within 4 hours with a solution of 320 g of thiophenol in 120 g of sodium hydroxide, 2 litres of ethanol and 440 ml of water. The mixture is stirred for a further 30 minutes at 60° C, then cooled to 0° C and filtered. There is obtained crude crystalline 3-nitro-6-(phenylthio)-benzaldehyde of melting point 96°-100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([OH:23])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[C:9]([F:25])[CH:10]=[C:11]([F:24])[CH:12]=3)=[CH:4][CH:3]=1.[CH3:28][C@H](NC)[C@H](O)C1C=CC=CC=1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:19]3[CH:18]([CH2:20][C:21]([O:23][CH3:28])=[O:22])[CH2:17][CH2:16][CH2:15][C:14]=3[C:13]3[C:8]2=[C:9]([F:25])[CH:10]=[C:11]([F:24])[CH:12]=3)=[CH:4][CH:3]=1
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Reactant: O=C(O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(F)cc(F)cc21
Product: COC(=O)CC1CCCc2c1n(Cc1ccc(Cl)cc1)c1c(F)cc(F)cc21

Procedure:
Following the method of Example 18, Step II to Step IV, but using 9-p-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid from Example 30, Step III and using 1(-)ephedrine in Step III, there is obtained the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([C@@H:21]2[CH2:23][C@H:22]2[C:24](O)=[O:25])=[C:5]2[C:19]([CH3:20])=[N:18][NH:17][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])#[N:2].[NH2:27][CH:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29]1.N1(O)C2C=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:1]([C:3]1[C:4]([C@@H:21]2[CH2:23][C@H:22]2[C:24]([NH:27][CH:28]2[CH2:29][CH2:30][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:32][CH2:33]2)=[O:25])=[C:5]2[C:19]([CH3:20])=[N:18][NH:17][C:6]2=[N:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[F:16])#[N:2]
Reactant: Cc1n[nH]c2nc(-c3ccc(O)cc3F)c(C#N)c([C@@H]3C[C@H]3C(=O)O)c12
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1n[nH]c2nc(-c3ccc(O)cc3F)c(C#N)c([C@@H]3C[C@H]3C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 51.9 %

Procedure:
To 200 mg (0.57 mmol) of (1R,2R)-2-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-yl)cyclopropane carboxylic acid diluted in 4 ml of anhydrous dimethylformamide are added, at 0° C., 121 mg (0.57 mmol) of tert-butyl 4-aminopiperidine-1-carboxylate, 76 mg (0.62 mmol) of N,N-dimethylpyridine-4-amine (DMAP), 110 mg (0.62 mmol of N,N-dimethyl-N-[(methylimino)methylene]propane-1,3-diamine hydrochloride (EDCI) and 84 mg (0.62 mmol) of 1H-benzo[d][1,2,3]triazole-1-ol (HOBT). The reaction mixture is stirred 20 h at room temperature. The solvent is concentrated, water is added and the product extracted several times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on silica (cyclohexane/ethyl acetate eluent: 5:5 to 3:7) to give 158 mg of tert-butyl 4-((1R,2R)-2-(5-cyano-6-(2-fluoro-4-hydroxyphenyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yl)cyclopropanecarboxamido)piperidine-1-carboxylate in the form of a white solid.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:7]2.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:7]2
Reactant: CCOC(=O)CBr
Reactant: O=C1c2ccc(F)cc2CC1c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(c2ccc(F)cc2)Cc2cc(F)ccc2C1=O
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 73.8 %

Procedure:
To a solution of 0.720 g (0.018 mol) of 60% sodium hydride suspended in 50 mL DMF at 10° C. was added dropwise 4.0 g (0.0164 mol) of the product from step B dissolved in 25 mL DMF. The reaction mixture was stirred at 10° C. for 20 min. and 3.1 g (0.0164 mol) ethyl bromoacetate was added all at once. The reaction was heated at 60° C. for 15 min, cooled to room temperature, poured into 200 mL 10% HCl, extracted with ethyl acetate (3×50 mL), washed with brine (1×100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to afford 4.0 g of a viscous oil. 1H NMR (CDCl3) δ: 1.10 (t, 3H), 3.18 (s, 2H), 3.63 (s, 2H), 4.18 (q, 2H), 6.95-7.30 (m, 6H), 7.80 (dd, 1H). IR (neat): 1720, 1676 cm-1 .
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:24])[CH:15]=2)=[O:12])[CH2:4]1.[CH:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:36]([N:37]=[C:38]=[O:39])=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][CH:26]=1>C1COCC1>[C:31]1([C:28]2[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=2)[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=1[NH:37][C:38](=[O:39])[N:2]([CH:3]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[C:16]([CH3:24])[CH:15]=2)=[O:12])[CH2:4]1)[CH3:1]
Reactant: O=C=Nc1ccccc1-c1ccccc1
Reactant: CNC1CCN(CCNC(=O)Nc2cc(C)nc3ccccc23)C1
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(N(C)C(=O)Nc3ccccc3-c3ccccc3)C2)c2ccccc2n1
Reaction time: 18 h

Procedure:
To a solution of 1-[2-(3-methylamino-pyrrolidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea (0.03 mmol) in THF (0.3 mL) is added a solution of 2-biphenyl isocyanate (0.09 mmol) in THF (0.6 mL). The reaction is allowed to stir for 18 h, and then is quenched with water (0.1 mL), and stirred for an additional 0.5 h. The reaction mixture is evaporated. The residue is taken up in a mixture of formic acid/TFA (1:1; 1 mL), and purified by preparative HPLC.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:17]([CH2:18][CH2:19][O:20]CC3C=CC=CC=3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1.[H][H]>[Pd].CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[N:17]([CH2:18][CH2:19][OH:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CN1CCN(Cc2nc3cccnc3n2CCOCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCN(Cc2nc3cccnc3n2CCO)CC1
Yield: 46.1 %

Procedure:
A mixture of 16.7 parts of 2-[(4-methyl-1-piperazinyl)methyl]-3-[2-(phenylmethoxy)ethyl]-3H-imidazo[4,5-b]pyridine and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 3 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane. The product was filtered off and dried, yielding 5.84 parts (46.1%) of 2-[(4-methyl-1-piperazinyl)methyl]-3H-imidazo[4,5-b]pyridine-3-ethanol; mp. 89.5° C. (compound 129).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3](=O)[CH:4]=[CH:5][C:6](=[CH:11][N:12]1CCCC1)[CH:7]([S:9][CH3:10])[CH3:8].C(N(CC)CC)C.Cl.N[OH:29]>C1(C)C=CC=CC=1>[CH3:10][S:9][CH:7]([C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:19])([F:18])[F:1])=[N+:12]([O-:29])[CH:11]=1)[CH3:8]
Reactant: CSC(C)C(C=CC(=O)C(F)(F)F)=CN1CCCC1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CSC(C)c1ccc(C(F)(F)F)[n+]([O-])c1
Temperature: 12.800000190734863 °C
Reaction time: 1 h

Procedure:
403 mg (0.37 mmol) of the 27 wt % 1,1,1-trifluoro-6-(methylthio)-5-(pyrrolidine-1-ylmethylene)hept-3-en-2-one (4) in toluene was added to a 25 mL three-neck round bottom flask equipped with a reflux condenser and vented to a bleach scrubber. To this mixture was added 34 mg (0.34 mmol) of triethylamine in one portion. The reaction mixture was cooled to about 12.8° C. and then 24 mg (0.34 mmol) of hydroxylamine hydrochloride was added in one portion. The reaction mixture was slowly heated to 85° C. and stirred for one hour and forty-five minutes. The reaction mixture was then cooled to ambient temperature. This mixture was split into many fractions for instrumental analysis and purification. A portion of the reaction mixture was partitioned between toluene and water. Both the organic and aqueous layers were analyzed by LC/MS. Both layers were confirmed to have a peak with molecular consistency for 5-(1-(methylthio)ethyl)-2-(trifluoromethyl)pyridine N-oxide (C9H10F3NOS). Calculated m/z=237.04. Found m/z=237.04.