Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[C:8]([Cl:15])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1.CCN(CC)CC.O>C1COCC1>[Cl:15][C:8]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:23][CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=1
Reactant: COc1ccc(CN)cc1
Reactant: COC(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(Cl)ccc([N+](=O)[O-])c1NCc1ccc(OC)cc1
Yield: 79.4 %

Procedure:
A solution of methyl 2,6-dichloro-3-nitrobenzoate (11.9 g, 47.4 mmol), p-methoxybenzylamine (8.13 g, 59.3 mmol; additional amounts of 1.63 g, 11.9 mmol added after 5 and 6.5 h), and Et3N (7.20 g, 71.1 mmol; additional amount of 1.20 g, 11.9 mmol added after 6.5 h) in THF (190 mL) was stirred at room temperature for 15 min then was heated to reflux for 10 h. Water (100 mL) was added to the mixture and most of the THF was removed under reduced pressure. The residue was partitioned between aqueous 1 N HCl solution (350 mL) and EtOAc (500 mL). The organic layer was washed with aqueous 1 N HCl solution (100 mL) and brine (100 mL), then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (10-40μ silica gel; hexane:EtOAc 6:1) to give the title compound (13.2 g, 79% yield) as a yellow solid.
Reaction SMILES: [C:1]([CH:11]1[O:17][CH:16]2[CH:13]([C:14](=[O:26])[N:15]2[C:18](=[C:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[NH:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C.[C:34]1([CH2:40][C:41](Cl)=[O:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O>O1CCCC1>[C:1]([CH:11]1[O:17][CH:16]2[C:13]([C:41](=[O:42])[CH2:40][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:14](=[O:26])[N:15]2[C:18](=[C:23]([CH3:24])[CH3:25])[C:19]([O:21][CH3:22])=[O:20])[NH:12]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COC(=O)C(=C(C)C)N1C(=O)C2NC(C(=O)OCc3ccccc3)OC21
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(=C(C)C)N1C(=O)C2(C(=O)Cc3ccccc3)NC(C(=O)OCc3ccccc3)OC12
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
To a solution of 4.90 g of methyl α-(3ξ-carbobenzoxy-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 50 ml of tetrahydrofuran are added 2.4 ml of triethylamine and then 2.5 ml of phenylacetyl chloride under ice-cooling, and the mixture stirred for 30 minutes, poured into water and extracted with ethyl acetate. The extract is washed with water dried on magnesium sulfate and concentrated under reduced pressure. The residue is chromatographed on 150 g of silica gel containing 10% water and eluted with benzene containing 10% ethyl acetate to yield 4.37 g of methyl α-(3ξ-carbobenzoxy-2-phenylacetyl-7-oxo-4-oxa-2,6-diazabicyclo[3.2.0]heptan-6-yl)-α-isopropylideneacetate in 67.2% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:33])[N:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Cl:31])[CH:18]=2)[C:13]1=[O:32])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:34]([CH2:41][CH2:42]O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[O:34]([CH2:41][CH2:42][O:23][C:22]([C:21]1[N:12]([N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[CH3:33])[C:13](=[O:32])[C:14]2[C:19]([C:20]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[CH:18][C:17]([Cl:31])=[CH:16][CH:15]=2)=[O:24])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: OCCOc1ccccc1
Reactant: CN(C(=O)OCc1ccccc1)n1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: CN(C(=O)OCc1ccccc1)n1c(C(=O)OCCOc2ccccc2)c(-c2ccccc2)c2cc(Cl)ccc2c1=O

Procedure:
The present compound was synthesized by a method similar to that in Example 200 using 2-[(benzyloxycarbonyl)(methyl)amino]-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (150 mg) and 2-phenoxyethanol. A colorless powder (78 mg).
Reaction SMILES: [CH2:1]([N:3]1[C:8](=[O:9])[C:7]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=2[F:22])([CH3:10])[C:6](=[O:24])[NH:5][C:4]1=[O:25])[CH3:2].NC1(C)C(=O)N([CH:34]2[CH2:39]CC[CH2:36][CH2:35]2)C(=O)NC1=O>>[CH:1]1([N:3]2[C:8](=[O:9])[C:7]([NH:11][C:12](=[O:23])[C:13]3[CH:18]=[C:17]([F:19])[C:16]([F:20])=[C:15]([F:21])[C:14]=3[F:22])([CH3:10])[C:6](=[O:24])[NH:5][C:4]2=[O:25])[CH2:36][CH2:35][CH2:34][CH2:39][CH2:2]1
Reactant: CCN1C(=O)NC(=O)C(C)(NC(=O)c2cc(F)c(F)c(F)c2F)C1=O
Reactant: CC1(N)C(=O)NC(=O)N(C2CCCCC2)C1=O
Product: CC1(NC(=O)c2cc(F)c(F)c(F)c2F)C(=O)NC(=O)N(C2CCCCC2)C1=O

Procedure:
Compound 20h was prepared by the same method described for 20f using 5-amino-1-cyclohexyl-5-methylbarbituric acid (0.48 g, 2 mmol). The crude 1-cyclohexyl-5-methyl-5-(tetrafluorobenzamido)barbituric acid (20h) was obtained as yellow crystals and did not require further purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C@@H:27]2[C@:44]3([CH3:45])[C@H:30]([C@H:31]4[C@H:41]([CH2:42][CH2:43]3)[C@:39]3([CH3:40])[C:34]([CH2:35][C@@H:36]([O:53][CH:54]5[CH2:59][CH2:58][CH2:57][CH2:56][O:55]5)[CH2:37][C@@H:38]3[O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:33][CH2:32]4)[CH2:29][CH2:28]2)[CH2:14][CH2:15][C@@H:16]([F:26])[C:17]([O:20][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])([CH3:19])[CH3:18])(=O)=O)=CC=1.[I-:60].[Na+].CC(C)=O.O>C(Cl)Cl>[O:48]1[CH2:49][CH2:50][CH2:51][CH2:52][CH:47]1[O:46][C@@H:38]1[C@@:39]2([CH3:40])[C:34](=[CH:33][CH2:32][C@@H:31]3[C@@H:41]2[CH2:42][CH2:43][C@@:44]2([CH3:45])[C@H:30]3[CH2:29][CH2:28][C@@H:27]2[C@H:13]([CH2:12][I:60])[CH2:14][CH2:15][C@@H:16]([F:26])[C:17]([O:20][CH:21]([O:23][CH2:24][CH3:25])[CH3:22])([CH3:19])[CH3:18])[CH2:35][C@@H:36]([O:53][CH:54]2[CH2:59][CH2:58][CH2:57][CH2:56][O:55]2)[CH2:37]1
Reactant: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](COS(=O)(=O)c1ccc(C)cc1)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(C)OC(C)(C)[C@H](F)CC[C@@H](CI)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC5CCCCO5)C[C@H](OC5CCCCO5)[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of 0.223 g. (0.00026 mole) of [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluorocholest-5-en-21-ol 21-(4-methylbenzenesulfonate), and 0.150 g. (0.0010 mole) of sodium iodide in 2 ml. of acetone was heated at 50° for 18 hr and cooled. The mixture was poured into water and the product was isolated with methylene chloride. The organic layers were washed with aqueous sodium sulfite solution, and saturated aqueous sodium bicarbonate solution. The organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to yield [1α,3β,24R]-1,3-bis[(tetrahydro-2H-pyran-2-yl)oxy]-25-(1-ethoxyethoxy)-24-fluoro-21-iodocholest-5-ene.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][C:5](C(OCC)=O)=[CH:4][CH:3]=1.[CH3:13][Mg+].[Br-].CC[O:18][CH2:19][CH3:20]>CCOCC>[CH3:13][C:19]([OH:18])([CH3:20])[C:5]1[CH:11]=[CH:12][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: C[Mg+]
Reactant: CCOCC
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Br-]
Product: CC(C)(O)c1ccc(I)cc1
Reaction time: 2.5 h

Procedure:
To a cooled (ice/H2O) solution of 2.76 g of ethyl 4-iodobenzoate (prepared as described in Step 1) in 10 ml of anhyd. Et2O was added, over a 5 minutes period, 26.5 ml of 1.52M CH3MgBr/Et2O solution. The mixture was stirred at ice bath temperature for 2.5 hours and then quenched by slow addition of 6 ml of H2O. The reaction mixture was filtered and the solid residue rinsed with ether. The combined filtrates were dried over MgSO4 and concentrated under vacuum to provide the title compound as a clear yellowish liquid.
Reaction SMILES: CI.[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:12]=1[CH2:13][NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[OH:26])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:32](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:12]=1[CH2:13][NH:14][C:15]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[O:26][CH3:32])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)c(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)c(OC)c1
Reaction time: 3 h

Procedure:
Methyl iodide (2.7 g) was added to a stirred suspension of ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)amino]-3-hydroxybenzoate (6 g) and potassium carbonate (2.6 g) in N,N-dimethylformamide (50 mL) and stirring was continued for 3 hours. The reaction mixture was poured into water (200 mL) and this was extracted three times with diethyl ether (50 mL each time). The combined diethyl ether extracts were washed three times with water (50 mL each time) and dried (MgSO4). The residue obtained on evaporation of the solvent was triturated with petroleum-ether (bp 60-80° C.) to give ethyl 4-[N-(2-benzyloxy-5-bromobenzyl)amino]-3-methoxybenzoate, yield 5.3 g, mp 78° C.
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:13])[CH2:6][C:7]1[N:11]=[C:10]([NH2:12])[S:9][N:8]=1)[CH:2]=[CH2:3].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[S:23]([N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH2:29][CH2:28][CH2:27]1)(=[O:25])=[O:24]>>[CH2:1]([O:4][C:5](=[O:13])[CH2:6][C:7]1[N:11]=[C:10]([NH:12][C:36]([C:33]2[CH:34]=[C:35]3[C:30]([CH2:29][CH2:28][CH2:27][N:26]3[S:23]([C:17]3[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=3[O:15][CH3:14])(=[O:25])=[O:24])=[CH:31][CH:32]=2)=[O:37])[S:9][N:8]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)Cc1nsc(N)n1
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)O)cc21
Product: C=CCOC(=O)Cc1nsc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCC3)n1

Procedure:
1-(2-Methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid was converted to the title compound in analogy to example 8, steps 3 and 4. Step 3 was performed using (5-amino-[1,2,4]thiadiazol-3-yl)-acetic acid allyl ester and 1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carboxylic acid and yielded (5-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-[1,2,4]thiadiazol-3-yl)-acetic acid allyl ester, which was hydrolyzed to (5-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-[1,2,4]thiadiazol-3-yl)-acetic acid in step 4, MS (ISP): m/e=501.1 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)#[N:2].[OH:21]O.[OH-].[Na+].Cl>C(O)C.O1CCCC1.ClCCl>[S:17]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:3]([CH:4]=1)[C:1]([NH2:2])=[O:21])(=[O:19])(=[O:18])[NH2:20]
Reactant: N#Cc1cc(S(N)(=O)=O)ccc1OCC1CCOCC1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: NC(=O)c1cc(S(N)(=O)=O)ccc1OCC1CCOCC1
Temperature: 35 °C

Procedure:
To a solution of EXAMPLE 38A (0.455 g) in ethanol (3 mL) and tetrahydrofuran (1 mL) was added hydrogen peroxide (30% in water, 2 mL) followed by 1 N aqueous NaOH (1.024 ml) and heated to 35° C. for 3 hours. The reaction was poured into dichloromethane (50 mL) and 1N aqueous HCl (25 mL). The aqueous layer was extracted with dichloromethane (3×50 mL). The precipitate contained in the combined organic layers was collected by filtration to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:12][C:13]([CH3:29])([CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)[C:14]#[N:15]>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:12][C:13]([C:14]#[N:15])([CH3:29])[CH2:16][N:17]1[CH:25]=[C:24]2[C:19]([C:20]([Cl:28])=[C:21]([Cl:27])[CH:22]=[C:23]2[Cl:26])=[N:18]1)=[O:5]
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)c(Cl)c2n1)NC(=O)c1ccc(Cl)cc1Cl

Procedure:
Using a procedure similar to that described in Example 60, except using a solution of 2,4-dichlorobenzoyl chloride (0.16 mmole) in THF and a solution of 2-amino-2-methyl-3-(4,6,7-trichloro-2H-indazol-2-yl)propionitrile (0.075 mmole, described in Example 147) in THF mixed with TEA (3% v./v.), the title compound was isolated as solid residue (4.2 mg). It was dissolved in DMSO for further biological evaluation and analyzed by LCMS. MS (ES): M/Z [M+H]=475, RT=0.74 min.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:24]=[CH:23][S:22][CH:21]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1.Cl[CH2:33][C:34]1[CH:35]=[C:36]([O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51])[C:37]2[C:42]([CH:43]=1)=[C:41]([O:44][CH3:45])[CH:40]=[CH:39][CH:38]=2>>[CH3:45][O:44][C:41]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:42]=1[CH:43]=[C:34]([CH2:33][O:1][CH:2]1[CH:7]([C:8]3[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]4[CH:24]=[CH:23][S:22][CH:21]=4)=[CH:12][CH:13]=3)[CH2:6][CH2:5][N:4]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:3]1)[CH:35]=[C:36]2[O:46][CH2:47][CH2:48][CH2:49][O:50][CH3:51]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccsc3)cc2)C(O)C1
Reactant: COCCCOc1cc(CCl)cc2c(OC)cccc12
Product: COCCCOc1cc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccsc3)cc2)cc2c(OC)cccc12

Procedure:
In an analogous manner to that described in Example 1 (g), by alkylating tert-butyl (3RS,4RS)-3-hydroxy-4-[4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl]-piperidine-1-carboxylate with 3-chloromethyl-5-methoxy-1-(3-methoxy-propoxy)-naphthalene [Example 123 (t)] there was obtained tert-butyl (3RS,4RS)-3-[8-methoxy-4-(3-methoxy-propoxy)-naphthalen-2-ylmethoxy]-4{4-[3-(thiophen-3-ylmethoxy)-propoxy]-phenyl}-piperidine-1-carboxylate as a pale yellow, viscous oil; MS: 723 (M+NH4)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[N:5]1.[C:20]([C:23]1[CH:27]=[C:26]([C:28](O)=[O:29])[NH:25][N:24]=1)(=[O:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>>[C:20]([C:23]1[NH:24][N:25]=[C:26]([C:28]([NH:1][CH2:2][CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=3)=[N:5]2)=[O:29])[CH:27]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: N#Cc1ccc(-c2ccn(CCN)n2)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cc(C(=O)NCCn2ccc(-c3ccc(C#N)c([N+](=O)[O-])c3)n2)n[nH]1
Yield: 73.4 %

Procedure:
The title compound was prepared from 4-(1-(2-aminoethyl)-1H-pyrazol-3-yl)-2-nitrobenzonitrile (0.50 g, 1.94 mmol), 3-acetyl-1H-pyrazole-5-carboxylic acid (0.30 g, 1.94 mmol), HOBt (0.31 g, 2.33 mmol), DIPEA (0.41 ml, 2.33 mmol) and EDCI (0.44 g, 2.33 mmol) using the method of Example 34(d) producing 0.56 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.48 (s, 3H), 3.69-3.73 (m, 2H), 4.39 (t, 2H), 7.05 (d, 1H), 7.30 (s, 1H), 7.88 (d, 1H), 8.18 (d, 1H), 8.32 (d, 1H), 8.66 (d, 1H), 14.16 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([Cl:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.C([O-])(O)=O.[Na+].Cl[C:31]([O:33][C:34]([CH3:36])=[CH2:35])=[O:32]>CCOC(C)=O>[Cl:23][C:5]1[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)=[CH:7][C:2]([NH:1][C:31](=[O:32])[O:33][C:34]([CH3:36])=[CH2:35])=[C:3]([F:24])[CH:4]=1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2Cl)cc2cnc(NC)cc21
Reactant: C=C(C)OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(NC)cc3n(CC)c2=O)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
A suspension of Example A5 (0.154 g, 0.444 mmol) in EtOAc (2.5 mL) was treated with satd. NaHCO3 (2.5 mL) and isopropenyl chloroformate (0.046 mL, 0.422 mmol) and the biphasic mixture stirred vigorously at RT for 3.5 h. Additional isopropenyl chloroformate (20 μL) was added and the mixture was stirred at RT overnight. The mixture was diluted with additional EtOAc and satd. NaHCO3 and the layers separated. The organic layer was washed with brine, dried over MgSO4 and concentrated to dryness. The resulting residue was dissolved in pyridine (1.5 mL), cooled to 0° C., treated with isopropenyl chloroformate (15 μL) and allowed to warm to RT. The mixture was re-cooled to 0° C., treated with additional isopropenyl chloroformate (7 μL) and allowed to warm to RT. The mixture was once again cooled to 0° C., treated with isopropenyl chloroformate (5 μL), allowed to warm to RT and stirred overnight. The mixture was concentrated to dryness, treated with brine and extracted with EtOAc (2×). The combined organics were dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford prop-1-en-2-yl (4-chloro-5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)carbamate (141 mg, 74% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.80 (s, 1H), 8.40 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H), 7.55 (d, J=10.5 Hz, 1H), 7.05 (d, J=5.0 Hz, 1H), 6.23 (s, 1H), 4.73 (m, 2H), 4.13 (q, J=7.1 Hz, 2H), 2.85 (d, J=4.9 Hz, 3H), 1.91 (s, 3H), 1.20 (t, J=7.0 Hz, 3H), MS (ESI) m/z: 431.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:9][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([CH:35]=O)[CH:29]=[CH:28]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:16]2([OH:22])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([CH2:35][C:30]3[CH:29]=[CH:28][C:27]4[C:32](=[CH:33][CH:34]=[C:25]([O:24][CH3:23])[CH:26]=4)[CH:31]=3)[CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(C=O)ccc2c1
Reactant: OC1(C(CN2CCNCC2)c2cccc(Cl)c2)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ccc2cc(CN3CCN(CC(c4cccc(Cl)c4)C4(O)CCCCC4)CC3)ccc2c1
Product: Cl
Reaction time: 16 h
Yield: 165.8 %

Procedure:
A solution of 1-[1-(3-chlorophenyl)-2-piperazin-1-ylethyl]cyclohexanol (see Example 1) (200 mg, 0.62 mmol) and 6-methoxy-2-napthaldehyde (173 mg, 0.93 mmol) in dichloroethane (4 mL) was treated with sodium trisacetoxyborohydride (195 mg, 0.92 mmol). The reaction was placed on a shaker and where it was stirred for 16 h. The reaction was then washed with a 2 N aqueous solution of hydrochloric acid (2×2 mL), and the organic layer was stored at 25° C. for 16 h. The resulting precipitate was collected, washed with diethyl ether and dried in vacuo to yield 194 mg (64%) 1-(1-(3-chlorophenyl)-2-[4-[(6-methoxy-2-naphthyl)methyl]piperazin-1-yl]ethyl)cyclohexanol dihydrochloride as a white solid. MS (ESI) m/z 493/495 ([M+H]+); HRMS: calcd for C30H37ClN2O2.2.00 HCl, 564.2077. found (ESI_FT), 493.2632.
Reaction SMILES: Br[CH2:2][C:3]1[N:7]([CH3:8])[CH:6]=[N:5][C:4]=1[Cl:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][C:17]1[N:22]=[C:21]([SH:23])[N:20]=[C:19]([OH:24])[CH:18]=1>CN(C=O)C>[Cl:9][C:4]1[N:5]=[CH:6][N:7]([CH3:8])[C:3]=1[CH2:2][S:23][C:21]1[N:20]=[C:19]([OH:24])[CH:18]=[C:17]([CH3:16])[N:22]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: Cn1cnc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(Cl)ncn2C)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-(bromomethyl)-4-chloro-1-methyl-1H-imidazole was dissolved in DMF (20 mL). Potassium carbonate (3 g) and 6-methyl-2-sulfanylpyrimidin-4-ol (1.4 g, 10 mmol) were added. The new mixture was stirred at room temperature for 2 hours. DMF was removed under vacuum. The crude compound was purified by column chromatography to provide 2-{[(4-chloro-1-methyl-1H-imidazol-5-yl)methyl]sulfanyl}-6-methylpyrimidin-4-ol as the major product (350 mg, 13% overall yield); 1H NMR (400 MHz, DMSO-d6): δ 2.19 (s, 3H), 3.72 (s, 3H), 4.59 (s, 2H), 6.00 (bs, 1H), 7.59 (s, 1H); M+ 271.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:19])([CH3:18])[CH2:15][CH2:16]O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:27]>C1C=CC=CC=1>[Br:27][CH2:16][CH2:15][C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)([OH:19])[CH3:18]
Reactant: CC(O)(CCO)c1ccc(-c2ccc(F)cc2)cc1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(O)(CCBr)c1ccc(-c2ccc(F)cc2)cc1

Procedure:
A solution of 2.6 g. of 3-(4'-fluoro-4-biphenylyl)-1,3-butanediol in 10 ml. of pyridine is added dropwise, at -5°, while stirring, to a mixture of 1 g. of PBr3, 1 ml. of pyridine and 3 ml. of benzene. The reaction mixture is then stirred for 24 hours at 20° and worked up in the customary manner to give 1-bromo-3-(4'-fluoro-4-biphenylyl)-butan-3-ol, m.p. 72° -74°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][C:25]([NH2:31])=[CH:24]2.CCN(CC)CC>C1COCC1.CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH:27]=[N:26][C:25]([NH:31][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)=[CH:24]2
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: COc1ccc2cnc(N)cc2c1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2cc3cc(OC)ccc3cn2)cc1
Temperature: 25 °C
Reaction time: 0.04 h
Yield: 27.3 %

Procedure:
To a solution of (4-methoxyphenyl)acetic acid (166.2 mg, 0.86 mmol) in 5 ml of anhydrous THF were added oxalyl chloride (126.9 mg, 4.3 mmol) and 100 ul of DMF. A vigorous effervescence occurred. Within 1-4 minutes the effervescence stopped and the mixture was stirred for 30 minutes at room temperature. Then the 6-methoxyisoquinolin-3-amine (150.0 mg, 0.86 mmol) and Et3N (0.86 mmol) were added. The reaction was stirred at the ambient temperature over 16 hours. The reaction was monitored by LC/MS that showed no more start material left. The reaction crude was purified by a silica gel column to give product 75.7 mg (yield 27.3%). 1H NMR (400 MHz, DMSO-d6) ppm 3.68 (s, 2H), 3.72 (s, 3H), 3.89 (s, 3H), 6.89 (d, J=8.81 Hz, 2H), 7.14 (dd, J=8.94, 2.39 Hz, 1H), 7.26 (d, J=2.27 Hz, 1H), 7.30 (d, J=8.81 Hz, 2H), 7.95 (d, J=9.06 Hz, 1H), 8.32 (s, 1H), 8.98 (s, 1H), 10.73 (s, 1H). HRMS: m/z 323.13882 [M+H]+), calc. 323.13902. MS m/z, (APCI); 323.2 ([M+H]+).