Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH:16]([C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[C:17]([O-:19])=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[Si:27](Cl)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].N1C=CN=[CH:36]1>CN(C=O)C.CCOCC>[CH3:36][O:18][C:17](=[O:19])[CH:16]([C:20]1[CH:21]=[CH:22][C:23]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:24][CH:25]=1)[NH:15][S:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:7][CH:8]=1)(=[O:14])=[O:13]
Reactant: c1c[nH]cn1
Reactant: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)[O-])c2ccc(O)cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)NC(C(=O)OC)c2ccc(O[Si](C)(C)C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82451.5 %

Procedure:
To a solution of 6.62 g (0.017 mmol) of [{[4-(2-butynyloxy)phenyl]-sulfonyl}amino](4-hydroxyphenyl)acetate from Example 178 in 50 mL of DMF was added 3.08 g (0.020 mmol) of tert-butyldimethylsilyl chloride followed by 2.89 g (0.043 mmol) of imidazole. The reaction was stirred at room temperature for 5 h and then diluted with ether. The resulting mixture was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo to give 7.06 g of [4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-(4-but-2-ynyloxy-benzenesulfonylamino)-acetic acid methyl ester as a white solid. Electrospray Mass Spec 504.4 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8][OH:9])([O-:3])=[O:2].ClN1C(=O)CCC1=O.[Cl:21][C:22]1[CH:23]=[C:24]([C:29]([C:31]([F:34])([F:33])[F:32])=[CH2:30])[CH:25]=[C:26]([Cl:28])[CH:27]=1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:21][C:22]1[CH:23]=[C:24]([C:29]2([C:31]([F:34])([F:32])[F:33])[O:9][N:8]=[C:7]([C:6]3[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=[CH:11][CH:10]=3)[CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: O=[N+]([O-])c1cccc(C=NO)c1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
In N,N-dimethylformamide (15 ml), 3-nitrobenzaldoxime (249 mg) was dissolved, and thereto was added N-chlorosuccinimide (201 mg) at room temperature. The mixture was stirred at 60° C. for 1 hour, and then cooled to room temperature. To the reaction solution were added 2-(3,5-dichlorophenyl)-3,3,3-trifluoro-1-propene (362 mg), followed by triethylamine (152 mg), and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 3-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]nitrobenzene (232 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([O:16]CC)=O)=[C:5]2[OH:19].[C:20]([NH:33][NH2:34])(=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[C:6]([C:14]([NH:34][NH:33][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:16])=[C:5]2[OH:19]
Reactant: CCCCCCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2cc(Br)ccc2n(C)c1=O
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Br)ccc2n(C)c1=O

Procedure:
Reagents: Comp 35 (0.36 mmols, 0.12 g); dodecanoyl hydrazine (0.4 mmols, 0.08 g). Yield: 0.1 g (55%), white solid, m.p.=160° C.-161° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:4]([O:21][CH3:22])[CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([CH3:32])[CH:31]=1)CCl>>[ClH:8].[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9](=[O:20])[CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[C:4]([O:21][CH2:22][C:26]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:24]([CH3:23])[CH:25]=2)[CH:3]=1
Reactant: Cc1cc(C)cc(CCl)c1
Reactant: COc1cc(N)c(Cl)cc1C(=O)CCCCN1CCCCC1
Product: Cc1cc(C)cc(COc2cc(N)c(Cl)cc2C(=O)CCCCN2CCCCC2)c1
Product: Cl

Procedure:
Proceeding as in Example 12, Step (a), but replacing 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{1-[2-(methylsulfonyl)aminoethyl]piperidin-4-ylpropan-1-one with 1-[4-amino-5-chloro-2-methoxyphenyl]-5-(piperidin-1-yl)pentan-1-one, and then as in Example 12, Step (b), but replacing 3,5-dimethoxybenzyl chloride with 3,5-dimethylbenzyl chloride, gave 1-[4-amino-5-chloro-2-(3,5-dimethylbenzyloxy)-phenyl]-5-(piperidin-1-yl)pentan-1-one hydrochloride, m.p. 218°-233° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH:16]1([CH2:22][NH2:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>CCO>[CH:16]1([CH2:22][NH:23][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[O:10][CH3:11])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NCC1CCCCC1
Reactant: COC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: COC(=O)Nc1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1

Procedure:
Methyl (4-fluoro-3-nitrophenyl)carbamate (1.00 g, 4.67 mmol) and cyclohexylmethyl amine (0.730 mL, 5.60 mmol) were stirred in EtOH (20 mL) containing TEA (1.0 mL, 7.00 mmol) at 75° C. for 24 h. The solvent was concentrated. The residue was dissolved in EtOAc and washed with 5% KHSO4 solution, saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 4:1/hex:EtOAc on silica gel. Yield: 1.05 g (73%); 1H NMR (400 MHz, CHLOROFORM-D) δ 1.04 (ddd, J=24.02, 12.11, 2.93 Hz, 2H), 1.25 (m, 3H), 1.69 (m, 2H), 1.76 (m, 1H), 1.79 (m, 1H), 1.83 (m, 1H), 1.86 (m, 1H), 3.14 (dd, J=6.44, 5.66 Hz, 2H), 3.78 (s, 3H), 6.46 (m, 1H), 6.84 (d, J=9.37 Hz, 1H), 7.63 (m, 1H), 8.05 (d, J=2.54 Hz, 1H), 8.09 (m, 1H).
Reaction SMILES: [O:1]=[C:2]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N+:18]([O-])=O)[NH:9][N:8]=1)=[O:6].CO>[Pd].C1COCC1>[O:1]=[C:2]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:37])[F:36])[CH2:25][CH2:26]1)[CH2:3][NH:4][C:5]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])[NH:9][N:8]=1)=[O:6]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2[N+](=O)[O-])[nH]n1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccccc1-c1cc(C(=O)NCC(=O)N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)n[nH]1
Yield: 26.8 %

Procedure:
10% Pd/c (30 mg) was added to a stirred solution of 5-(2-Nitro-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide (160 mg, 0.3 mmol) in mixture of MeOH (60 mL) and THF (10 mL) and stirred under hydrogen atmosphere. The reaction mixture was then stirred for 1.5 hrs at room temperature. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated under reduced pressure. The crude was washed with ethyl acetate, filtered and dried to afford 40.3 mg (27% yield) of 5-(2-Amino-phenyl)-1H-pyrazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-amide. LCMS Purity: 97.73%. 1H NMR (DMSO-d6): δ 13.6 (s, 1H), 8.6 (m, 1H), 7.6 (m, 4H), 7.5 (m, 1H), 7.4 (d, 1H), 7.3 (s, 1H), 7.0 (s, 1H), 6.5 (m, 4H), 6.2 (m, 2H), 5.1 (m, 1H), 4.2 (m, 3H), 3.6 (m, 4H), 3.4 (m, 2H), 3.2 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][C:23]#[CH:24])[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3[N:15]=[N:16][N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2].C(OCCNC(=O)OC(C)(C)C)C#C.Br[C:40]1[CH:41]=[N:42][CH:43]=[N:44][CH:45]=1.BrC1C=NC=CC=1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][C:23]#[C:24][C:40]2[CH:41]=[N:42][CH:43]=[N:44][CH:45]=2)[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]3[N:15]=[N:16][N:17]=[C:9]3[C:8]=2[N:18]=1)[CH3:2]
Reactant: Brc1cncnc1
Reactant: C#CCOCCn1c(COCC)nc2c1c(C)c(C)n1nnnc21
Agent: C#CCOCCNC(=O)OC(C)(C)C
Solvent: Brc1cccnc1
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1CCOCC#Cc1cncnc1

Procedure:
The method described in Part B of Example 81 was followed. 8-Ethoxymethyl-5,6-dimethyl-7-(2-prop-2-ynyloxyethyl)-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine (5.5 g, 17 mmol) was used as the starting material in lieu of tert-butyl 2-(prop-2-ynyloxy)ethylcarbamate, and 5-bromopyrimidine was used in lieu of 3-bromopyridine. The crude product was purified by column chromatography on silica gel (620 g, eluting with 98:2 dichloromethane:methanol), and the resulting solid was mixed with 2-propanol (150 mL). Insoluble impurities were removed by filtration, and the solution was concentrated to a volume of 20 mL. The product crystallized and was isolated by filtration and washed with 2-propanol and diethyl ether to provide 6.10 g of 8-ethoxymethyl-5,6-dimethyl-7-[2-(3-pyrimidin-5-ylprop-2-ynyloxy)ethyl]-7H-imidazo[4,5-c]tetrazolo[1,5-a]pyridine as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:10])=O)=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[N:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1>S(Cl)(Cl)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[C:21]([N:27]3[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]3)[CH:22]=2)=[O:10])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2ccc(Br)nc2)cc1N1CCN(C)CC1
Reaction time: 18 h

Procedure:
2-Bromo-5-pyridinecarboxylic acid (0.34 g; 1.68 mmol) was heated at reflux in thionyl chloride (8 ml) for 1 hour, cooled, evaporated in vacuo and the residue azeotroped with toluene. The orange residue was redissolved in CH2Cl2 (6 ml) and treated with dry triethylamine (0.24 ml;1.68 mmol) and 4-methoxy-3-(4-methyl-1-piperazinyl)benzenamine (0.372 g;1.68 mmol). The solution was stirred under Ar (18 hours), evaporated in vacuo and partitioned satd. K2CO3 (aq)/EtOAc. The organic phases were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 3%MeOH/CHCl3 to yield the title compound as brown crystals after trituration with acetone/Et2O (0.13 g;19%).
Reaction SMILES: [C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH:21]([O:30][C:31](=[O:33])[CH3:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][OH:10])(=[O:3])[CH3:2].CCCCCC.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:4][CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13](/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[CH:21]([O:30][C:31](=[O:33])[CH3:32])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH:12]=1)[CH2:6][CH2:7][CH2:8][CH:9]=[O:10])(=[O:3])[CH3:2]
Reactant: CCCCCCCCC(/C=C/C=C/c1cccc(C(CCCCO)OC(C)=O)c1)OC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCC(/C=C/C=C/c1cccc(C(CCCC=O)OC(C)=O)c1)OC(C)=O
Yield: 78.1 %

Procedure:
A solution of 193 mg of the above-produced alcohol in 5 ml of methylene chloride is instilled in a mixture of 1.25 g of Collins reagent (chromic acid-pyridine complex) in 20 ml of methylene chloride at 0° C. with stirring, and it is stirred for 1 hour at 0° C. Then, enough Celite is added until a thick paste results, the latter is suspended with hexane/ethyl acetate (1:1), filtered off, washed well with hexane/ethyl acetate (1:1) and the filtrate is concentrated by evaporation in a vacuum. 150 mg of (5RS)-5-acetoxy-5-{3-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-phenyl)-pentanal is obtained as colorless oil.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](C=O)=[CH:3][CH:2]=1.C1C[O:16][CH2:15]C1.[BH4-].[Na+].N1C2C(=CC=CC=2)C(CO)=CC=1>CCO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:15][OH:16])[CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: C1CCOC1
Agent: OCc1ccnc2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of 4-quinolinecarboxaldehyde (0.47 g, 3.00 mmol) in a mixture of EtOH:THF=1:1 (40 mL) at 0° C. in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added NaBH4 (0.11 g, 3.01 mmol) and the mixture was stirred overnight at RT. The solution was then cooled down to 0° C. before quenching a 6 N aq. HCl solution (2 mL). The reaction mixture was stirred at RT for 15 min then basified with a 2 N aq. NaOH solution (6 mL). EtOH was removed at 40° C. under vacuum and the residue was extracted with CH2Cl2 (2×50 mL). The organic phase was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 0:100) gave, after evaporation and drying, quinolin-4-ylmethanol MDE 32014 as an off-white solid (311 mg, 65% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([S:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)[CH3:2].[CH2:26](O)[C:27]#[C:28][CH3:29]>>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([S:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:26][C:27]#[C:28][CH3:29])=[CH:22][CH:23]=1)[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: CCOC(=O)C(Sc1ccc(O)cc1)c1ccc(-c2cccs2)cc1
Reactant: CC#CCO
Product: CC#CCOc1ccc(SC(C(=O)OCC)c2ccc(-c3cccs3)cc2)cc1
Yield: 74 %

Procedure:
Ethyl{[4-(2-butynyloxy)phenyl]sulfanyl}[4-(2-thienyl)phenyl]acetate was prepared according to the general method as outlined in example 83 (step 2), starting from ethyl[(4-hydroxyphenyl)sulfanyl][4-(2-thienyl)phenyl]acetate (1.6 g, 4.3 mmol) and 2-butyn-1-ol (0.33 ml, 4.32 mmol); 1.34 g yellow oil. Yield 74%; MS(EI): 421.71 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:20]=[C:19]([S:27][CH3:28])[N:18]=2)[CH2:13]1)(=[O:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:35][O:36][CH2:37][CH2:38][OH:39]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:39][CH2:38][CH2:37][O:36][CH3:35])[CH:5]=[CH:4][C:3]=1[S:9]([C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[N:20]=[C:19]([S:27][CH3:28])[N:18]=2)[CH2:13]1)(=[O:11])=[O:10]
Reactant: COCCO
Reactant: CSc1nc(N2CC[C@H](S(=O)(=O)c3ccc(F)cc3Cl)C2)cc(C(F)(F)F)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc(S(=O)(=O)[C@H]2CCN(c3cc(C(F)(F)F)nc(SC)n3)C2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-[(S)-3-(2-Chloro-4-fluoro-benzenesulfonyl)-pyrrolidin-1-yl]-2-methylsulfanyl-6-trifluoromethyl-pyrimidine (Intermediate of example 42; 300 mg) was dissolved in DMF (5.0 mL). Cs2CO3 (429 mg) and 2-methoxy-ethanol (0.10 mL) were added. The reaction mixture was stirred for 24 h at 25° C. After that, the reaction mixture was diluted with ethyl acetate (20 mL) and extracted with water (10 mL). The organic layers were dried over Na2SO4, filtrated and evaporated to dryness. The crude material was purified by flash chromatography (50 g silica gel; ethyl acetate/n-heptane) to yield a colorless waxy solid (170 mg; 50%) MS: m/z=512.2 [M+H]+.
Reaction SMILES: Cl[Mg][CH2:3][C:4]([CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:5].[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH2:24][C@@:23]([OH:27])([CH2:3][C:4](=[CH2:5])[CH2:6][O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C@@H:22]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1c1ccccc1
Reactant: C=C(COc1ccccc1)C[Mg]Cl
Solvent: C1CCOC1
Product: C=C(COc1ccccc1)C[C@]1(O)CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A tetrahydrofluran solution of 3-(chloromagnesio)-2-(phenoxymethyl)-1-propene (0.91M, 3 ml) (Louw et. al. Tetrahedron 48:6087-6104, (1992), prepared from 2.74 mmol of 3-chloro-2-(phenoxymethyl)-1-propene) was slowly added to a solution of (±)1-tert-butoxycarbonyl-2-phenylpiperidin-3-one (Desc. 1) in tetrahydrofuran (3 ml). The solution was stirred at room temperature for 1 hour, quenched by addition of saturated ammonium chloride solution (20 ml) and extracted with ethyl acetate (20 ml). The organic phase was washed (saturated brine), dried (MgSO4), evaporated to a small volume and purified by chromatography on a column containing silica gel (eluting with hexane containing increasing proportions of ethyl acetate between 0% to 20%). Evaporation of the fractions gave the title compound. m/z (CI+)424 (M+H), 324 (M+2H--t-BuOCO--), 368 (M+2H--t-Bu).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([OH:29])=[O:28])=[N:23][N:22]4[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:37](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:14]=[CH:15][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:37])=[O:28])=[N:23][N:22]4[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:17][CH:18]=2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(=O)O)nn4c3-c3ccccc3)cc2)CCC1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Temperature: 50 °C
Yield: 113 %

Procedure:
A mixture of 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylic acid that was prepared in a manner analgous to that described for Intermediate Example Int-27 (0.075 g, 0.16 mmol), cesium carbonate (0.15 g, 0.46 mmol, 3.0 equiv) and methyl iodide (0.020 mL, 0.31 mmol, 2.0 equiv) in DMF (2 mL) was stirred at room temperature for 2 days, after which additional methyl iodide (0.020 mL, 0.31 mmol, 2.0 equiv) was added and the mixture was heated at 50° C. for 3 h. The resulting mixture was treated with water (25 mL). The aqueous mixture was extracted with EtOAc (3×10 mL). The combined organics were dried (Na2SO4 anh) and concentrated under reduced pressure to give methyl 2-(4-{1-[(tert-butoxycarbonyl)amino]cyclobutyl}phenyl)-3-phenylimidazo[1,2-b]pyridazine-6-carboxylate (0.087 g, 113%) which was used without further purification:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[CH:29]=[N:28][NH:27][C:14]3=[N:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[C:30]1([C@@H:36]([NH2:38])[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:30]1([C@@H:36]([NH:38][C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[C:13]4[CH:29]=[N:28][NH:27][C:14]4=[N:15][C:16]=3[C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)[CH:8]=[CH:7][N:6]=2)[CH3:37])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)c1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](Nc1nccc(-c2cc3cn[nH]c3nc2-c2cccc(C(F)(F)F)c2)n1)c1ccccc1
Temperature: 100 °C
Yield: 16.7 %

Procedure:
A mixture of 5-[2-(methylsulfonyl)pyrimidin-4-yl]-6-[3-(trifluoromethyl)phenyl]-1H-pyrazolo[3,4-b]pyridine (0.55 g, 0.13 mmol, obtained in example 127) and (1S)-1-phenylethylamine (0.16 g, 1.3 mmol) was heated to 100° C. for 1 h. It was allowed to cool and the crude product obtained was purified by chromatography on silica gel using increasing polarity mixtures of EtOAc-hexane as eluent, to afford 10 mg of the title compound (yield: 16%).
Reaction SMILES: [C:1]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:17])[S:8][C:7]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23]Cl)=[O:20])([O:3][CH2:4][CH3:5])=[O:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(N(C(C)C)CC)(C)C>C(#N)C>[C:1]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([CH3:17])[S:8][C:7]=1[NH:18][C:19]([NH:21][CH2:22][CH2:23][N:36]1[CH2:35][CH2:34][N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])[CH2:38][CH2:37]1)=[O:20])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)c1c(NC(=O)NCCCl)sc(C)c1-c1ccccc1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1c(NC(=O)NCCN2CCN(c3ccccc3OC)CC2)sc(C)c1-c1ccccc1
Yield: 63.4 %

Procedure:
A solution of Example 2A (0.60 g, 1.6 mmol), 1-(2-methoxyphenyl)piperazine (0.84 g, 6.5 mmol) and diisopropylethylamine (0.35 mL) in acetonitrile (25 mL) was processed as in Example 1B. Purification of the crude product on silica gel with 2% triethylamine 50% ethyl acetate/hexane provided 0.53 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O>CN(C)C=O>[CH2:24]([O:23][C:21]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
To a suspension of 1-(4-hydroxyphenyl)piperazine (50 g) and potassium carbonate (46.5 g) in N,N-dimethylformamide (100 ml) was added dropwise benzyl chloroformate (47.86 g) at 0 to 10° C., and stirred for 4 hours at ambient temperature. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methyl alcohol (30:1) to give 4-(4-hydroxyphenyl)piperazine-1-carboxylic acid benzyl ester (60.8 g).