Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:33]([O:37][C:38]([N:40]([CH:53]([CH3:55])[CH3:54])[CH2:41][C@H:42]([C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[C:43](O)=[O:44])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:52][C:49]1[CH:50]=[CH:51][C:46]([C@H:42]([C:43]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][N:25]=[C:26]([O:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:19]=34)[CH2:13][CH2:14]2)=[O:44])[CH2:41][N:40]([CH:53]([CH3:54])[CH3:55])[C:38](=[O:39])[O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[CH:47][CH:48]=1
Reactant: OCC(O)COc1n[nH]c2nccc(N3CCNCC3)c12
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2ccnc3[nH]nc(OCC(O)CO)c23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
DIEA (0.0514 mL, 0.295 mmol) was added to 3-(4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)propane-1,2-diol dihydrochloride (0.030 g, 0.0737 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0252 g, 0.0737 mmol, see Example B) and TBTU (0.0284 g, 0.0885 mmol) in DCM (1 mL) and stirred at room temperature for 2 hours. The reaction was concentrated to dryness. The resulting residue was dissolved in THF:MeOH (2 mL, 1:1), and a LiOH solution (1 mL, 2M) was added. The solution was stirred for 30 minutes, followed by the addition of ether (20 mL). The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by column chromatography (ethyl acetate:MeOH, 20:1) to give tert-butyl(2S)-2-(4-chlorophenyl)-3-(4-(3-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and 2N HCl in ether (1 mL) was added. The resulting solid was collected by filtration to give (2S)-2-(4-chlorophenyl)-1-(4-(3-(2,3-dihydroxypropoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (0.014 g, 33%). MS APCI (+) m/z 517.2 detected.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[CH3:11][C:12]([CH3:26])=[CH:13][CH2:14][CH2:15]/[C:16](/[CH3:25])=[CH:17]/[CH2:18][CH2:19][C:20]([OH:24])([C:22]#[CH:23])[CH3:21]>[Pd].[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[OH:24][C:20]([CH2:19][CH2:18][CH:17]=[C:16]([CH2:15][CH2:14][CH:13]=[C:12]([CH3:26])[CH3:11])[CH3:25])([CH:22]=[CH2:23])[CH3:21]
Reactant: C#CC(C)(O)CC/C=C(\C)CCC=C(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCCCCC
Product: C=CC(C)(O)CCC=C(C)CCC=C(C)C
Yield: 90.6 %

Procedure:
Further, 0.5 ml of quinoline and 20 g of 0.25% Pd-Lindlar catalyst was added in a solution of 1,280 g of the said dehydronerolidol in 2,000 ml of n-hexane and the mixture was hydrogenated at room temperature and normal pressure. After post-treatment, the reaction mixture was subjected to vacuum distillation to give 1,170 g of nerolidol having b.p. 105° - 110° C. (0.5 mmHg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22](=[O:23])[C:21]3[S:24][CH:25]=[CH:26][C:20]=3[NH:19][C:18]2=[O:27])[CH2:11][CH2:10]1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[C:28]([N:19]1[C:20]2[CH:26]=[CH:25][S:24][C:21]=2[C:22](=[O:23])[N:17]([CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])[CH2:14][CH2:13]2)[C:18]1=[O:27])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccccc1N1CCN(CCn2c(=O)[nH]c3ccsc3c2=O)CC1
Product: COc1ccccc1N1CCN(CCn2c(=O)c3sccc3n(C(C)=O)c2=O)CC1
Yield: 57 %

Procedure:
A solution of 3-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]thieno[3,2-d]pyrimidine-2,4-dione (2.6 g, 6.73 mmol) in acetic anhydride (30 ml) was heated to reflux for 5 hours. Acetic anhydride was removed in vacuo. The residue was dissolved in toluene, and the toluene was removed in vacuo. This process was repeated twice to remove any residual acetic anhydride. The residue was purified by flash chromatography on silica gel 60 (60 g) using 2.5% methanol in methylene chloride as eluant to give the product (1.65 g, 57% yield) as an off-white solid, mp 156°-158° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:15]1([CH2:20][C:21](O)=O)[CH:19]=[CH:18][N:17]=[CH:16]1.P(Cl)(Cl)(Cl)=O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N:15]1([CH2:20][C:21]2[N:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:3]3=[N:4][CH:5]=[CH:6][CH:7]=[C:2]3[N:1]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Nc1cccnc1Nc1ccccc1
Reactant: O=C(O)Cn1ccnc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: c1ccc(-n2c(Cn3ccnc3)nc3cccnc32)cc1
Yield: 26.9 %

Procedure:
To a solution of 3-amino-2-anilinopyridine (2.0 g) and 2-(imidazol-1-yl)acetic acid (1.56 g) in pyridine (20 ml) was dropwise added phosphorus oxychloride (1.91 g) and the mixture was refluxed for 30 minutes. The reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined extract was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent was removed under reduced pressure to give a residue, which was subjected to column chromatography on silica gel (20 g) eluting with a mixture of dichloromethane and ethanol. The fractions containing the desired compound were combined and evaporated in vacuo. The resultant crystal was recrystallized from a mixture of ethyl acetate and n-hexane to give 2-(imidazol-1-yl)methyl-3-phenyl-3H-imidazo[4,5-b]pyridine (0.8 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:14][CH:15]=3)=[CH:4][CH:3]=1.I[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([S:37][CH3:38])[N:32]=1>C1(C)C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:31]3[CH:36]=[CH:35][N:34]=[C:33]([S:37][CH3:38])[N:32]=3)[C:10]3[C:11]([N:29]=2)=[N:12][C:13]([N:16]2[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:20][CH2:21]2)=[CH:14][CH:15]=3)=[CH:6][CH:7]=1
Reactant: CSc1nccc(I)n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3[nH]c(-c4ccc(F)cc4)nc3n2)CC1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CSc1nccc(-n2c(-c3ccc(F)cc3)nc3nc(N4CCN(C(=O)OC(C)(C)C)CC4)ccc32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
KN(TMS)2 (812 mg, 3.85 mmol) in toluene (3.85 ml) is added at 0° C. to a solution of 2-(4-Fluorophenyl)-5-(4-tert.butoxycarbonyl-1-piperazinyl)imidazo[4,5-b]pyridine (1.4 g, 3.5 mmol) in DMF (7 ml). After stirring at room temperature for 30 min., 4-iodo-2-methylthiopyrimidine (970 mg, 3.85 mmol) in toluene (3.85 ml) is added and the reaction stirred at room temperature for 1 h. Toluene is evaporated, the reaction mixture heated to 120° C. for 18 h, poured on water and extracted with ethyl acetate (containing 5% EtOH) three times. The combined organic phases are washed with brine, dried over Na2SO4, filtered and evaporated to dryness. Purification over SiO2 (acetone/hexanes 20/80) renders the title compound (950 mg, 52%) as colorless foam.
Reaction SMILES: [H-].[Na+].C[O:4][C:5](=[O:17])[CH2:6][C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[CH3:16].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]#[N:30]>C1COCC1.C1COCC1.CN(C=O)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([N:9]2[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:15]3[C:7]([CH2:6][C:5]([OH:4])=[O:17])=[C:8]2[CH3:16])(=[O:26])=[O:27])=[CH:21][C:20]=1[C:29]#[N:30]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2cccnc2n1S(=O)(=O)c1ccc(Cl)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred, ice-cooled (0° C.) suspension of sodium hydride (15.8 mg of a 60% dispersion in mineral oil, 0.411 mmol) in dry THF (2 ml) under an inert atmosphere of Argon is added dropwise (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester ((0.06 g, 0.294 mmol) in THF/DMF (4 ml of a 3:1 mixture). The reaction mixture is stirred at 0° C. for 45 minutes and then treated with 4-chloro-3-cyano-benzenesulfonyl chloride (97.1 mg, 0.411 mmol) in dry THF (3 ml). Stirring continued at 0° C. for 15 minutes and then the reaction mixture is poured onto water (30 ml) and extracted with ethyl acetate (100 ml). The organic portion is separated and washed brine (50 ml), dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with iso-hexane/ethyl acetate (0%-20% ethyl acetate) to yield the titled product. (MH+ 404)
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([CH3:17])([S:7]([CH2:10][CH2:11][CH2:12][C:13](F)(F)F)(=[O:9])=[O:8])[CH3:6])C.[CH3:19][Si](C)(C)[O-].[K+].Cl>C1COCC1>[CH3:17][C:5]([S:7]([CH2:10][CH2:11][CH:12]([CH3:13])[CH3:19])(=[O:8])=[O:9])([CH3:6])[C:4]([OH:3])=[O:18]
Reactant: CCOC(=O)C(C)(C)S(=O)(=O)CCCC(F)(F)F
Reactant: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)CCS(=O)(=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 109 %

Procedure:
To a solution of 170 g (0.59 mol) of 2-methyl-2-(4,4,4-trifluoro-butane-1-sulfonyl)-propionic acid ethyl ester in THF (3.4 L) are added 225.4 g (1.76 mol) of potassium trimethylsilanolate in portions over 0.5 h. The reaction is stirred at room temperature for 18 h. The reaction mixture is acidified with 2 M aq. HCl solution (2 L) to pH 2 and extracted with DCM (2×2 L). The combined organic extracts are dried (Na2SO4) and filtered. The filtrate is concentrated under reduced pressure to afford 143 g of 2-methyl-2-(3-methyl-butane-1-sulfonyl)-propionic acid.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH:13]=[C:12]([O:19]CC)[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.O>[CH2:1]([S:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH2:13][C:12](=[O:19])[C:11]=2[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1=CCCc2cnc(SCc3ccccc3)nc21
Solvent: CC(=O)O
Solvent: O
Product: O=C1CCCc2cnc(SCc3ccccc3)nc21
Yield: 74 %

Procedure:
1.5 g (5 mmol) of 2-(benzylthio)-8-ethoxy-5,6-dihydroquinazoline were dissolved in 50 mL of acetic acid and 3 mL of water. The solution was stirred at refluxing temperature for 4 hours. The solvent was then removed under vacuum, the residue partitioned between dichloromethane and a NaHCO3 saturated solution. The organic layer was dried over anhydrous Na2SO4 and concentrated, giving 1.0 g (74% yield) of the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][NH2:27])[CH2:23][O:22]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][NH:27][S:16]([C:14]2[S:15][C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:17])[CH2:23][O:22]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CC1(C)OCC(CN)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCC3COC(C)(C)O3)s2)s1
Reaction time: 1 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (110 mg; 0.33 mmol; 1 eq), is dissolved in DCM (10 ml). 2.2-Dimethyl-1,3-dioxolane-4-methanamine (216 mg; 1.65 mmol; 5 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After one hour, the solvents are evaporated. The crude product is dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is dissolved in DCM (3 ml). Title compound precipitates with addition diethyl ether, affording after filtration, Compound (14) as a white powder (65 mg; 46%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](N)CC3)c[nH]c12
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(C)=O)CC3)c[nH]c12

Procedure:
Starting from trans-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A182) and acetyl chloride the title compound was obtained as colorless solid.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:7][C:6]=1[CH:21]1[CH2:23][CH2:22]1)C.CC(C[AlH]CC(C)C)C>C1COCC1>[CH:21]1([C:6]2[C:5]([CH2:4][OH:3])=[CH:10][CH:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=3)[N:7]=2)[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1

Procedure:
0.193 g (0.576 mmol) of the above prepared 2-cyclopropyl-6-(4-trifluoromethyl-phenyl)-nicotinic acid ethyl ester in 3.0 ml of abs. THF was cooled down to 0° C. and reacted with 1.5 ml of DIBAL-H-solution (1.0 M in toluene, 2.6 eq.) for 1 h. Careful quenching with ice, filtration over Celite, separation of the layers, reextraction of the aqueous phase with AcOEt, washing of the combined organic layers with NH4Cl, and drying over magnesium sulfate was followed by evaporation of the solvents. The crude product was finally purified by flash chromatography (SiO2, hexane/AcOEt=7/3) to deliver 0.128 g of the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30]#[N:31])[CH:25]=3)[CH2:20][CH2:19]2)=[N:6][CH:7]=1.CO.N.[SH2:36]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:32])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:29]=[CH:28][N:27]=[C:26]([C:30](=[S:36])[NH2:31])[CH:25]=3)[CH2:20][CH2:19]2)=[N:6][CH:7]=1
Reactant: N#Cc1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Reactant: S
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: NC(=S)c1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Reaction time: 48 h
Yield: 70 %

Procedure:
A pressure tube was charged with N-(5-chloropyridin-2-yl)-2-[1-(2-cyanopyridin-4-yl)piperidin-4-ylmethylamino]benzamide (50 mg, 0.11 mmol) and 1:2 methanol:tetrahydrofuran (3 mL); and the solution was treated with ammonia(g), sealed, and allowed to stir for 2 days. The mixture was then treated with hydrogen sulfide (g), sealed and allowed to stir for 2 days. The mixture was concentrated and the residue purified by column chromatography (SiO2: 2% methanol in methylene chloride) affording 38 mg (70%) of the title compound.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][N+:22]([O-])=O)[CH:18]=3)[NH:13][CH:12]=2)[CH2:7][CH2:6]1.C=O.O>CN(C=O)C>[CH3:4][N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH:21]([NH2:22])[CH2:1][OH:2])[CH:18]=3)[NH:13][CH:12]=2)[CH2:7][CH2:6]1
Reactant: C[O-]
Reactant: CN1CC=C(c2c[nH]c3ccc(CC[N+](=O)[O-])cc23)CC1
Agent: C=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC=C(c2c[nH]c3ccc(CC(N)CO)cc23)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 56.7 %

Procedure:
Sodium methoxide (0.30 g) was added to a solution of the product from step (d) (1.5 g) in DMF (15 ml) at 0° C. To the resulting solution was added dropwise a suspension of paraformaldehyde (0.19 g) in DMF (20 ml). The resulting mixture was stirred at 0° C. for 1.5 hours, then poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried and evaporated in vacuo to give a yellow oil which was eluted through a silica column using DCM/EtOH/NH4OH (50:8:1) as eluant to give the desired product as an off-white solid (0.85 g) which was recrystallised from ethanol.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:50])=[CH:28]\[CH2:29][O:30]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:21]=1[CH3:51])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C>[Si:1]([O:18][CH2:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[C:22](/[C:27](/[CH3:50])=[CH:28]\[CH2:29][OH:30])[C:21]=1[CH3:51])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C/C(=C/COC(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Solvent: CC(=O)O
Product: C/C(=C/CO)c1ccc(C)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C
Yield: 28.4 %

Procedure:
A solution of 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-1-methyl-3-trityloxy-1-propenyl)benzene (500 mg) in acetic acid (5 ml) was heated at 60° C. for 10 hours. The cooled reaction mixture was concentrated in vacuo and ethyl acetate was added thereto. The mixture was washed with aqueous sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacua. The residue was purified by flash silica gel chromatography eluted with n-hexane-ethyl acetate to give 1-tert-butyldiphenylsilyloxymethyl-2,6-dimethyl-3-((Z)-3-hydroxy-1-methyl-1-propenyl)benzene (92 mg) as colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[N:18]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>N1C=CC=CC=1>[N:18]1([C:24]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]2)=[O:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCC(OC(=O)N2CCOCC2)CC1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
Benzyl 4-hydroxypiperidine-1-carboxylate (65 μL) is dissolved in pyridine (2 mL), treated with morpholine-4-carbonyl chloride (500 μL) and stirred for 6 hours at 50° C. Morpholine-4-carbonyl chloride (75 μL) is added and the mixture is stirred for 12 hours at 80° C. Again morpholine-4-carbonyl chloride (500 μL) is added and the mixture is stirred for 12 hours at 80° C. The mixture is partitioned between ethylacetate and hydrochloric acid (1 M). The organic phase is dried (MgSO4) and concentrated. The residue is purified by HPLC on reversed phase to give the title compound. LC (method 1): tR=0.96 min; Mass spectrum (ESI+): m/z=349 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([N+:19]([O-:21])=[O:20])=[C:12]([CH:15]=[C:16](F)[CH:17]=3)[C:13]#[N:14])[CH:5]=2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CCCCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([N+:19]([O-:21])=[O:20])=[C:12]([CH:15]=[C:16]([NH:31][C@H:29]([C:26]4[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=4)[CH3:30])[CH:17]=3)[C:13]#[N:14])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: N#Cc1cc(F)cc(Nc2cc(C3CC3)[nH]n2)c1[N+](=O)[O-]
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1cc(C#N)c([N+](=O)[O-])c(Nc2cc(C3CC3)[nH]n2)c1)c1ccc(F)cc1
Temperature: 230 °C
Yield: 88.7 %

Procedure:
A mixture of 3-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-nitrobenzonitrile (Method 98, 3.50 g, 12.2 mmol), (S)-1-(4-fluoro-phenyl)ethylamine (1.87 g, 13.4 mmol), and DIEA (2.6 ml, 14.6 mmol) in n-BuOH (20 ml) was heated in a sealed tube at 230° C. for 2 hours. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane-EtOAc=1:2) to give the title compound as a yellow solid (4.4 g, 89%). 1H NMR (400 MHz) 12.38 (s, 1H), 10.12 (b, 1H), 8.07 (d, J=6.4 Hz, 1H), 7.34 (m, 2H), 7.16 (m, 2H), 6.89 (b, 1H), 6.77 (s, 1H), 5.63 (m, 1H), 4.55 (m, 1H), 1.90 (m, 1H), 1.45 (d, J=6.8 Hz, 3H), 0.97 (m, 2H), 0.70 (m 2H). MS: Calcd.: 406; Found: [M+H]+ 407.
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH2:16][CH:17]([CH3:19])[CH3:18])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)[CH2:29][CH2:28]1
Reactant: CC(C)Cc1cc(CCC=O)n(-c2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cc1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
121 mg (92%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-isobutyl-1H-pyrazol-5-yl)propanal (80 mg, 0.312 mmol), 1-(2-fluorophenyl)piperazine (56 mg, 0.312 mmol), DIPEA (0.082 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].Cl[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[N:10]=[C:9]([S:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=2[F:24])[N:8]=1>>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][S:15][C:9]1[N:8]=[C:7]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[C:11]([O:13][CH3:14])[N:10]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CS(N)(=O)=O
Product: COc1cc(NS(C)(=O)=O)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared from methane sulfonamide (0.11 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.25 g) according to the procedure outlined in Example 1, step iv). The crude material was purified by column chromatography using EtOAc/isohexane (2:8) as eluent. Yield: 0.12 g.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[N:11][N:10]([CH2:13][CH2:14]Br)[C:9](=[O:16])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:17][CH:18]([C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:24][CH:23]=1)[CH2:19][NH:20][CH3:21].C(N(CC)CC)C>C(O)C>[OH:17][CH:18]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][CH:27]=1)[CH2:19][N:20]([CH3:21])[CH2:14][CH2:13][N:10]1[C:9](=[O:16])[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:12]=[N:11]1
Reactant: CNCC(O)c1ccc(NS(C)(=O)=O)cc1
Reactant: O=c1cc(-c2ccccc2)cnn1CCBr
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(CCn1ncc(-c2ccccc2)cc1=O)CC(O)c1ccc(NS(C)(=O)=O)cc1

Procedure:
2-[5-Phenyl-2H-pyridazin-3-on-2-yl]ethyl bromide (0.28 g), 2-hydroxy-N-methyl-2-(4-methanesulphonamidophenyl)ethylamine (0.24 g) and triethylamine (0.22 g) were refluxed in ethanol (30 ml) for 4 hours. The solvent was removed and the residue taken up in methylene chloride, washed with water, evaporated and the residue chromatographed on silica [Merck `Kieselgel 60` (Trade Mark)], eluting with ethyl acetate. Collection and evaporation of appropriate fractions gave the title compound as a solid which was recrystallised from diisopropyl ether, yield 0.1 g, m.p. 108°.