Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH2:23][CH2:22]1)[CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:37](OC(=O)C)(=[O:39])[CH3:38]>N1C=CC=CC=1>[C:37]([O:1][C@@H:2]([CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)[CH2:23][CH2:22]1)[CH2:3][O:4][C:5]1[C:13]2[CH:12]=[C:11]([C:14]([N:16]([O:18][CH3:19])[CH3:17])=[O:15])[O:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)OC(C)=O
Reactant: CON(C)C(=O)c1cc2c(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)cccc2o1
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc2c(OC[C@H](CN3CCC(c4ccc5ccccc5c4)CC3)OC(C)=O)cccc2o1
Reaction time: 24 h

Procedure:
(S)-4-(2-Hydroxy-3-(4-(naphthalen-2-yl)piperidino)-propyloxy)-N-methoxy-N-methylbenzo(b)furan-2-carboxamide (0.40 g) obtained in Example 6 was dissolved in pyridine (20 ml) and acetic anhydride (10 ml) was added at room temperature. The mixture was stood for one day. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to give (S)-4-(2-acetoxy-3-(4-(naphthalen-2-yl)piperidino)propyloxy)-N-methoxy-N-methylbenzo(b)furan-2-carboxamide (0.34 g) as a brown oil. This was dissolved in ethanol and maleic acid (0.10 g) was added. The precipitated crystals were collected by filtration and dried to give the title compound (0.25 g) as pale-yellow crystals, melting point 125-127° C.
Reaction SMILES: C(O[C:4]([C:6]1[C:11]([NH:12][C:13]2[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=2)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[N:22]=[C:23]([CH3:26])[S:24][CH:25]=1>>[CH3:26][C:23]1[S:24][CH:25]=[C:21]([NH:20][C:4]([C:6]2[C:11]([NH:12][C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])[N:22]=1
Reactant: Cc1nc(N)cs1
Reactant: CCOC(=O)c1nc(C)ccc1Nc1ccnn1C
Product: Cc1ccc(Nc2ccnn2C)c(C(=O)Nc2csc(C)n2)n1

Procedure:
The title compound, was prepared from 6-Methyl-3-(2-methyl-2H-pyrazol-3-ylamino)-pyridine-2-carboxylic acid ethyl ester in accordance with the general method of example 75, step 2 using 4-Amino-2-methylthiazole instead of 3-Amino-1-methyl-pyrazole to yield the final compound as a light brown solid, MS (ISP): m/e=329.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:22][N:23](/[CH:25]=[N:1]/[C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH3:19])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1)[CH3:24]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2nc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(OC)c(OC)cc2nc1/N=C/N(C)C
Temperature: 25 °C
Yield: 17.8 %

Procedure:
A mixture of methyl 2-amino-6,7-dimethoxy-3-quinolinecarboxylate (3.60 g, 13.04 mmol) and 4.10 g of dimethylformamide dimethylacetal in 60 mL of toluene containing 40 mg of p-toluenesulfonic acid is heated at reflux for 2 hours. Upon cooling to room temperature a solid formed and is collected by filtration to provide 736 mg of methyl 2-{[(E)-(dimethylamino)methylidene]amino}-6,7-dimethoxy-3-quinolinecarboxylate as an off-white solid, mp 166-168° C.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH2:35])=[N:32][CH:33]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]([F:27])=[CH:33][N:32]=4)=[O:24])=[CH:20][CH:19]=3)(=[O:16])=[O:17])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Reactant: NCc1ccc(F)cn1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cn1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Yield: 502.6 %

Procedure:
Stir mixture of 4-(3-Cyclopentyl-indole-1-sulfonyl)-benzoic acid (0.767 g, 0.0.21 m mol), C-(5-fluoro-pyridin-2yl)-methylamine (0.041 g, 0.25 mmol), and EDC (0.063 g, 0.33 mmol) in dry CH2Cl2 (15 mL) under N2 and add DMAP (0.061 g, 0.50 mmol.). Stir the resulting mixture at ambient temperature for 72 h Dilute the reaction mixture to 50 mL with CH2Cl2, wash with H2O, 1N NaOH, and brine sequentially. Dry the organic layer (MgSO4), filter and evaporate to give 0.189 g of crude product. Chromatograph on the ISCO using a 12 g column and eluting with Hexane-EtOAc (0-100%) to gives the title compound 0.60 g as a foam:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N+:7]([C:10]1[CH:15]=[CH:14][C:13](CC(O)=O)=[CH:12][CH:11]=1)([O-:9])=[O:8].CN(C=O)C>ClCCl>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([CH2:1][C:2]([Cl:4])=[O:3])=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
3.75 ml (7.5 mmoles) of a 2M solution of oxalyl chloride in dichloromethane is added at 20° C. to a solution of 0.9 g (5 mmoles) of 4-nitrophenylacetic acid in a mixture composed of 10 ml of dichloromethane and 0.5 ml of DMF. After agitation for 30 minutes, the solution is concentrated under vacuum. The yellow oil obtained is used without additional purification in the following stage.
Reaction SMILES: [CH3:1][CH:2]([CH3:36])[CH2:3][CH:4]([C:26]1[S:27][C:28]([CH2:31][CH2:32][C:33]([OH:35])=O)=[CH:29][N:30]=1)[NH:5][C:6](=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])=[O:16])=[CH:10][CH:9]=1.CN(C=O)C.CCN=C=NCCCN(C)C.Cl.[CH3:54][S:55]([NH2:58])(=[O:57])=[O:56]>CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:54][S:55]([NH:58][C:33](=[O:35])[CH2:32][CH2:31][C:28]1[S:27][C:26]([CH:4]([NH:5][C:6](=[O:25])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH:14][C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH3:24])=[O:16])=[CH:12][CH:13]=2)[CH2:3][CH:2]([CH3:36])[CH3:1])=[N:30][CH:29]=1)(=[O:57])=[O:56]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)O)s2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)NC(CC(C)C)c2ncc(CCC(=O)NS(C)(=O)=O)s2)cc1
Temperature: 25 °C
Yield: 25.6 %

Procedure:
A mixture of 3-[2-(3methyl-1-{2-[4-(3-o-tolyl-ureido)-phenyl]-acetylamino}-butyl)-thiazol-5-yl]-propionic acid (Example 13) (91 mg, 0.2 mmol), DMF (5 ml), EDCl (48 mg, 0.2 mmol) and DMAP (26 mg, 0.2 mmol) was stirred at room temperature. After 10 min. methane sulfonamide (51 mg, 0.5 mmol) was added. After stirring 16 h the solution was diluted with EtOAc and washed with 1N HCl (2×). The organic layer was dried over Na2SO4; filtered; and concentrated under reduced pressure. The resulting solid was purified by Flash 12 chromatography eluting with 10% AcOH in EtOAc to give 30 mg of the title compound as a white amorphous solid. MS [M−1]+ 584.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][OH:12].[H-].[Na+].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](F)[N:21]=1.C(Cl)Cl.CO>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH2:11][O:12][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[N:21]=1
Reactant: OCc1nccn1Cc1cc(Cl)cc(Cl)c1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Fc1cccc(OCc2nccn2Cc2cc(Cl)cc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
[1-(3,5-Dichloro-benzyl)-1H-imidazol-2-yl]-methanol (300 mg, 1.17 mmol) was dissolved in DMF and NaH (46 mg, 1.17 mmol) was added under N2 atmosphere. After 20 minutes, 2,6-di-fluoropyridine (0.11 mL, 1.17 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction was partitioned between EtOAc (50 mL) and water (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×75 mL). The combined organic extracts were washed with water (2×70 mL) and brine, dried over MgSO4, filtered and concentrated to yield a yellow solid. Chromatography (silica, 40:1 CH2Cl2/MeOH) afforded 2-[1-(3,5-dichlorobenzyl)-1H-imidazol-2-ylmethoxy]-6-fluoro-pyridine (270 mg, 66%).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.C(=O)=O.[F:7][C:8]([F:34])([F:33])[S:9]([C:12]1[CH:13]=[CH:14][C:15]2[CH:21]=[CH:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]=3[C:17](=[C:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:16]=2[CH:32]=1)(=[O:11])=[O:10]>CO.C(Cl)(Cl)Cl>[OH:3][CH:1]([N:29]1[CH2:30][CH2:31][C:26](=[C:17]2[C:16]3[CH:32]=[C:12]([S:9]([C:8]([F:34])([F:7])[F:33])(=[O:11])=[O:10])[CH:13]=[CH:14][C:15]=3[CH:21]=[CH:20][C:19]3[CH:22]=[CH:23][CH:24]=[CH:25][C:18]2=3)[CH2:27][CH2:28]1)[CH3:2]
Reactant: C1CO1
Reactant: O=S(=O)(c1ccc2c(c1)C(=C1CCNCC1)c1ccccc1C=C2)C(F)(F)F
Agent: O=C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CC(O)N1CCC(=C2c3ccccc3C=Cc3ccc(S(=O)(=O)C(F)(F)F)cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 0.244 g. of ethylene oxide of 30 ml. of methanol at dry-ice temperature is added to an ice cold solution of 2.55 g. of 4-(3-trifluoromethylsulfonyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine in 15 ml. of chloroform and 75 ml. of methanol. The solution is stirred at ambient temperature overnight. A second quantity (0.25 g.) of ethylene oxide is added as before and the mixture is again stirred overnight. The mixture is concentrated to dryness and the residue is coevaporated in vacuo several times with acetonitrile. The product is recrystallized several times from acetonitrile to give (±)-1-hydroxyethyl-4-(3-trifluoromethylsulfonyl-5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine, m.p. 141°-144° C.
Reaction SMILES: CS(C)=O.C(N(CC)CC)C.[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:18])([CH3:15])([CH3:14])[CH3:13]>ClCCl>[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][CH:22]=[O:23])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCCC=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Dimethyl sulfoxide (321 mL, 4.5 mol) and triethylamine (941 mL, 6.75 mol) were added to a solution of 3-tert-butoxycarbonylamino-1-propanol (262.6 g, 1.5 mol) in dichloromethane (1.2 L) at 0° C. Sulfur trioxide pyridine complex (286.4 g, 1.8 mol) was added in 6 portions. The reaction mixture was then stirred for 30 min at 0° C. and for 30 min at room temperature. The reaction was cooled down to 0° C., quenched with 1N hydrochloric acid, washed with brine (2×500 mL), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 3-(tert-butoxycarbonylamino)propionaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][NH:18][C:17](=O)[CH:16]2[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1.B.CSC.CO.Cl>O1CCCC1.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH:16]2[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:4][CH:3]=1
Reactant: CC(C)CC1C(=O)NCCN1Cc1ccccc1-c1ccc(Cl)cc1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CSC
Product: CC(C)CC1CNCCN1Cc1ccccc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a solution of EXAMPLE 27D in tetrahydrofuran (3.6 mL) was added borane-methyl sulfide complex (10M in tetrahydrofuran) (0.24 mL). The reaction was heated under reflux for 16 hours, then cooled in an ice/water bath. Methanol (5 mL) was added carefully, and the mixture was stirred cold for 75 minutes. Then 4N HCl in dioxane (0.65 mL) was added and the reaction heated under reflux for 60 minutes. After cooling to room temperature, 1NNH4OH (2.6 mL) was added and the reaction was stirred for 15 minutes. Then the reaction was concentrated, redissolved in methanol, concentrated, redissolved in toluene and concentrated. The crude solids were slurried in CHCl3/methanol, the solids were filtered off, and the filtrate concentrated to afford the title compound.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:6][NH2:7].[O:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Br:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:6][NH:7][CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1
Reactant: NCc1ccc(F)c(Br)c1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Fc1ccc(CNC2CCOCC2)cc1Br
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
Triethylamine (2.52 g) was added to a suspension of 3-bromo-4-fluorobenzylamine hydrochloride (2.79 g) in chloroform (50 mL), and the mixture was stirred at room temperature for 10 min. Tetrahydro-4H-pyran-4-one (2.29 g) was added thereto and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (4.85 g) was added thereto, followed by further stirring for 1 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was then stirred for a while and extracted with chloroform. The organic phase was separated out and the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=100:0-90:10) to afford the title compound (2.70 g).
Reaction SMILES: N12CCCN=C1CCCCC2.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27](Cl)=[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:25][C:24]=2[CH:34]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:35]1([SH:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27]([S:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[S:25][C:24]=2[CH:34]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Sc1ccccc1
Reactant: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1sc2cc(OCc3ccccc3)ccc2c1Sc1ccccc1
Temperature: 60 °C
Yield: 83.7 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--0.39 ml, 2.5 mmol) was added to a mixture of ethyl 6-(benzyloxy)-3-chlorobenzo[b]thiophene-2-carboxylate (Preparation 8, 800 mg, 2.3 mmol) and thiophenol (0.47 ml, 4.6 mmol) in dimethylformamide (4 ml) under a nitrogen atmosphere. The solution was heated to 60° C. for 6 hours and then partitioned between diethyl ether and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using a mixture of 20% dichloromethane and 80% hexane, then 50% dichloromethane and 50% hexane as eluant. The isolated product was crystallised from diisopropyl ether and hexane to give the title compound as a colourless solid (810 mg).
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)([CH3:11])[CH3:10]>N1C=CC=CC=1>[C:1]1([N:7]([C:16](=[O:17])[C:15]2[CH:19]=[CH:20][C:12]([CH:9]([CH3:10])[CH3:11])=[CH:13][CH:14]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Reactant: NNc1ccccc1
Solvent: c1ccncc1
Product: CC(C)c1ccc(C(=O)N(N)c2ccccc2)cc1
Reaction time: 37 h
Yield: 84.8 %

Procedure:
To a solution of 35.0 g. (0.323 mole) phenylhydrazine in 300 ml. pyridine, cooled to about 5° to 8° C., was added 54.8 g. (0.30 mole) p-isopropylbenzoyl chloride. This reaction mixture was set aside for 37 hrs. at about 25° C. The mixture was then poured into 1500ml. ice-water and the solids that separated were collected on a filter and washed with water. After recrystallization from 850 ml. ethanol, there was obtained 64.7 g. (84.8% yield) of p-isopropylbenzoic acid phenylhydrazide melting at 198° to 201° C. An analytical sample melting at 200.5° to 202.5° C. was obtained after two recrystallizations from ethanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27]Br)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:29][C:30]1[CH:31]=[N:32][NH:33][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:32]4[CH:31]=[C:30]([Br:29])[CH:34]=[N:33]4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: Brc1cn[nH]c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CBr)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Cn4cc(Br)cn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using 1-[4′-(4-bromomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 4-Bromo-1H-pyrazole.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[Cl:29][C:30]1[N:35]=[N:34][C:33]([NH2:36])=[C:32]([CH3:37])[C:31]=1[CH3:38].C(N(CC)C(C)C)(C)C>C(#N)CCC>[Cl:29][C:30]1[C:31]([CH3:38])=[C:32]([CH3:37])[C:33]2[N:34]([C:2]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([C:11]4([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]4)=[CH:7][CH:6]=3)[N:36]=2)[N:35]=1
Reactant: Cc1c(N)nnc(Cl)c1C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCC#N
Product: Cc1c(Cl)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc2c1C
Temperature: 125 °C
Yield: 78 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate [that was prepared in a manner analgous to that described for Intermediate Example Int-1-A] (237 mg, ˜80% purity, 0.430 mmol, 1.0 eq), 6-chloro-4,5-dimethylpyridazin-3-amine (CAS-Nr. 76593-36-7, 67.2 mg, 0.430 mmol, 1.0 eq) and N,N-diisopropylethylamine (70 μL, 0.430 mmol, 1.0 eq) in butyronitrile (2.6 mL) was heated for 17 hours at 125° C. On cooling the mixture was partitioned between DCM and water, stirred vigorously and filtered through a silicone coated filter paper. The filtrate was concentrated in vacuo. The crude mixture was purified via MPLC (Biotage Isolera; 25 g SNAP cartridge: hexane/EtOAc 9/1→hexane/EtOAc 3/2) to give 185 mg (78% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:14])[C:4]([N:6]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][C:7]1=[O:13])=[O:5].C[Si](C)(C)N[Si](C)(C)C.[Li].[C:25]([C:29]1[CH:30]=[C:31]([CH:34]=[C:35]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:36]=1[O:37][Si](C)(C)C)[CH:32]=O)([CH3:28])([CH3:27])[CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+]>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][O:2][N:3]([CH3:14])[C:4]([N:6]1[C:10]([CH3:12])([CH3:11])[CH2:9][C:8](=[CH:32][C:31]2[CH:30]=[C:29]([C:25]([CH3:26])([CH3:28])[CH3:27])[C:36]([OH:37])=[C:35]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:34]=2)[C:7]1=[O:13])=[O:5]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O[Si](C)(C)C
Reactant: CON(C)C(=O)N1C(=O)CCC1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CON(C)C(=O)N1C(=O)C(=Cc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC1(C)C
Temperature: 25 °C
Yield: 29 %

Procedure:
To a chilled solution (-70° C.) of 453 mg (2.26 mmol) of the thus obtained 1-(N-methoxy-N-methylcarbamoyl)-5,5-dimethylpyrrolidin-2-one in THF (12 ml) was added 2.26 ml (2.26 mmol) of a THF solution of 1.0M lithium hexamethyldisilazane while being stirred under a nitrogen atmosphere. Five minutes later, 693 mg (2.26 mmol) of 3,5-di-tert-butyl-4-trimethylsiloxybenzaldehyde was added thereto and the mixture was warmed to room temperature and stirred for 2 hours. The reaction mixture was then poured into ice-water and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over magnesium sulfate and evaporated to give a residue, which was then dissolved in 23 ml of toluene. To the mixture was added 145 mg of p-toluenesulfonic acid, which was refluxed for 1.5 hours. The solvent was removed under reduced pressure to give a residue, which was dissolved in 13 ml of THF and stirred under ice-cooling. To the reaction mixture was added 1 ml of a THF solution of 2.0M tetra-n-butylammonium fluoride, which was stirred for 10 minutes. The reaction mixture was poured into ice-water containing sodium bicarbonate and extracted with dichloromethane. The dichloromethane layer was washed with an aq. sodium bicarbonate and water, dried over magnesium sulfate and evaporated to give a residue, which was then chromatographed on silica gel (toluene/ethyl acetate=9/1) and lyophilized from benzene to give 270 mg of the objective compound (Id-3) in 29% yield.
Reaction SMILES: [Si](C=[N+]=[N-])(C)(C)[CH3:2].[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:38])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:37])[CH:17]=1.CO>C1(C)C=CC=CC=1>[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:38])[C:14]=1[NH:15][C:16]1[C:25]2[C:20](=[C:21]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:2])=[O:35])[C:22]([O:26][CH3:27])=[CH:23][CH:24]=2)[O:19][C:18](=[O:37])[CH:17]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCC(=O)O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CCCCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12
Reaction time: 0.17 h

Procedure:
A solution of TMSCHN2 (0.75 mL, 2M Et2O, 1.5 mmol) was added to a solution of 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoic acid (115 mg, 0.25 mmol, Example 44), methanol (1 mL), and toluene (8 mL). After 10 min, the reaction was concentrated and purified by silica gel chromatography (4:1→1:4; hexanes:ethyl acetate) to give methyl 6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)hexanoate: 1H NMR (400 MHz, DMSO-d6): δ 9.50 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.63 (s, 1H), 3.97 (t, 2H), 3.91 (s, 3H), 3.56 (s, 3H), 2.31 (t, 2H), 1.67 (m, 2H), 1.57 (m, 2H), 1.46 (m, 2H); MS (ESI): 480.9.
Reaction SMILES: [CH:1]1([C:4]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[O:5])[CH2:3][CH2:2]1.[BH4-].[Na+].C(Cl)Cl.O>C(O)C>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][CH:4]([CH:1]2[CH2:3][CH2:2]2)[OH:5])=[CH:9][CH:10]=1)#[N:15]
Reactant: N#Cc1ccc(CCC(=O)C2CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1ccc(CCC(O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.3 %

Procedure:
To a solution of 30.9 g of 4-cyanophenylethyl cyclopropyl ketone in 90 ml of absolute ethanol was added 1.48 g of sodium borohydride, and the mixture was stirred at room temperature for three hours. The product isolated from the reaction still contained unreacted starting material, so the material was redissolved in 90 ml of ethanol and treated with 0.7 g additional sodium borohydride for three hours. The product obtained by evaporation of the solvent, trituration of the residue with methylene dichloride and water, and isolation of the product from the organic phase, gave 31.0 g of 4-cyanophenylethyl cyclopropyl carbinol as an oil which crystallized to a colorless solid, m.p. 70°-71° C.