Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[S:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]=1.[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([N:28](C(OCC(Cl)(Cl)Cl)=O)[C:29](OCC(Cl)(Cl)Cl)=[O:30])=[N:20]1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:28][C:29]([N:6]2[CH2:5][CH2:4][N:3]([C:8]3[S:12][N:11]=[C:10]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:9]=3)[CH:2]([CH3:1])[CH2:7]2)=[O:30])=[N:20]1
Reactant: CC1CNCCN1c1nc(-c2ccccc2)ns1
Reactant: O=C(OCC(Cl)(Cl)Cl)N(C(=O)OCC(Cl)(Cl)Cl)c1noc2ccccc12
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC1CN(C(=O)Nc2noc3ccccc23)CCN1c1nc(-c2ccccc2)ns1

Procedure:
A solution of 2-methyl-1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (390 mg, 1.50 mmol), bis(2,2,2-trichloroethyl) 1,2-benzisoxazol-3-ylimidodicarbonate (363 mg, 0.750 mmol), diisopropylethylamine (0.131 ml, 0.750 mmol) and dimethylsulfoxide (10 ml) was stirred at 70° C. for 2 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (220 mg, 69.8%) as a solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([NH2:12])=[O:11])[CH:5]=[N:4][C:3]=1[C:20]#[N:21].[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:20]([C:3]1[N:4]=[CH:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[CH:26]2)#[N:21]
Reactant: Nc1ccc2ncccc2c1
Reactant: N#Cc1ncc(N[C@H](Cc2ccccc2)C(N)=O)nc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: N#Cc1ncc(N[C@H](Cc2ccccc2)C(N)=O)nc1Nc1ccc2ncccc2c1
Reaction time: 20 h
Yield: 12.1 %

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-phenylpropanamide (128 mg, 0.424 mmol), 6-aminoquinoline (80 mg, 0.555 mmol), K2CO3 (100 mg, 0.724 mmol), BINAP (30 mg, 0.048 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (3 mL) was degassed with Ar, then was stirred at 110 C for 20 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-phenylpropanamide (21 mg).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([N:15]=[C:16]=[S:17])[CH:8]=[C:9]([S:11]([OH:14])(=[O:13])=[O:12])[CH:10]=1)([OH:4])(=[O:3])=[O:2].[Na:18].[N:19]1C=CC=CC=1.O>>[S:1]([C:5]1[CH:6]=[C:7]([NH:15][C:16]([NH2:19])=[S:17])[CH:8]=[C:9]([S:11]([OH:14])(=[O:12])=[O:13])[CH:10]=1)([OH:4])(=[O:3])=[O:2].[Na:18]
Reactant: c1ccncc1
Reactant: O=S(=O)(O)c1cc(N=C=S)cc(S(=O)(=O)O)c1
Agent: [Na]
Solvent: O
Product: NC(=S)Nc1cc(S(=O)(=O)O)cc(S(=O)(=O)O)c1
Temperature: 53 °C

Procedure:
Trifluoroacetic acid (3 ml) was added to a stirred suspension of BHAlyslys2lys4lys8lys16DBL32 (300 mg; 0.02 mmol) in dry dichloromethane (3 ml) and the resulting solution stirred at room temperature under nitrogen for two hours and then concentrated. The residue was dissolved in water and the solution passed through a column of Amberlite IRA 401 (OH) and the filtrate concentrated to give a viscous oil (187 mg). The oil was dissolved in a 1:1 mixture of pyridine/water (8 ml) and solid sodium 3,5-disulfophenyl isothiocyanate (680 mg; 2 mmol) added. The resulting solution was heated at 53° C. for three hours under nitrogen. The solution was then concentrated to give a white solid residue. The crude product was purified by gel filtration (Sephadex LH20; water) to give BHAlyslys2lys4lys8lys16lys32 with 64 sodium 3,6-disulfophenylurea groups as a white fluffy solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([CH3:20])[C:8]=1[C:9]([OH:11])=O.C1(C)C=CC=CC=1.[Cu][C:29]#[N:30]>C(#N)C>[CH3:5][O:6][C:7]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([CH3:20])[C:8]=1[C:9]([C:29]#[N:30])=[O:11]
Reactant: N#C[Cu]
Reactant: COc1cc(C)c(C(=O)O)c(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: COc1cc(C)c(C(=O)C#N)c(OC)c1OC
Temperature: 25 °C
Yield: 44.7 %

Procedure:
10 ml of thionyl chloride was added to 6.0 g (26.6 mmol) of 2,3,4-trimethoxy-6-methylbenzoic acid, followed by stirring under reflux with heating for 4 hours, and the surplus thionyl chloride was distilled off under reduced pressure. 20 ml of toluene, 8 ml of acetonitrile and 3.1 g (34.5 mmol) of copper(I) cyanide were added, followed by stirring under reflux with heating for 16 hours. After cooling to room temperature, the reaction solution was subjected to filtration on the pad of celite, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 2.8 g (yield: 45%) of 2,3,4-trimethoxy-6-methylbenzoyl cyanide.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([S:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Cl)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][S:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: ClCCCCCSCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCSCc2ccccc2)CC1
Yield: 28.7 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.5 g) as starting compound, potassium carbonate (2.2 g) and 5-benzylthiopentyl chloride (1.4 g) were reacted and treated in the same manner as in Example 168 to give 0.57 g of 4-amino-N-((1-(5-benzylthiopentyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: C([C:3]1[C:4](=[O:28])[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)O[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)C.CO.[CH3:31][NH2:32]>O.C(O)(=O)C>[CH3:31][N:32]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:3][C:4](=[O:28])[C:5]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:6]1[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccc(Cl)cc2)oc(-c2ccc(Cl)cc2)c(CC)c1=O
Reactant: CN
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCOC(=O)c1c(-c2ccc(Cl)cc2)n(C)c(-c2ccc(Cl)cc2)cc1=O
Reaction time: 3 h

Procedure:
5.0 gms of ethyl 2,6-di(4'-chlorophenyl) 3-ethoxycarbonyl-pyr-4-one, 100 mls of methanol, 19 mls of 40% aqueous methylamine, 19 mls of water and 2.9 mls of glacial acetic acid were mixed and allowed to stand at room temperature for 3 hours. The mixture was poured into water and extracted with methylene chloride to provide 5 gms of crude ethyl 1-methyl-2,6-di(4-chlorophenyl)-4-oxonicotinate as a yellowish semi-solid.
Reaction SMILES: O1CCOC1[C:6]1[CH:7]=[C:8]([N:14]2[CH:18]=[N:17]N=N2)C=[CH:10][C:11]=1[O:12][CH3:13].C([Li])CCC.C(=O)(O)[O-].[Na+].[C:29]([O:32][CH2:33][CH3:34])(=[O:31])[CH3:30]>O1CCCC1.CCCCCC>[O:32]1[CH2:33][CH2:34][O:31][CH:29]1[C:30]1[CH:10]=[C:11]([O:12][CH3:13])[CH:6]=[CH:7][C:8]=1[NH:14][C:18]#[N:17]
Reactant: COc1ccc(-n2cnnn2)cc1C1OCCO1
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(NC#N)c(C2OCCO2)c1
Reaction time: 0.08 h

Procedure:
To a solution of 1-(3-[1,3]dioxolan-2-yl-4-methoxy-phenyl)-1H-tetrazole (9.09 g) in dry tetrahydrofuran (200 ml) at -78° under nitrogen, n-butyl lithium solution in hexane (30 ml of 1.6 mol dm-3) was added. Nitrogen gas was evolved. After stirring under nitrogen for 5 min the mixture was allowed to warm to 0° over 10 min and 8% aqueous sodium bicarbonate (200 ml) was then added. After stirring for 10 min ethyl acetate (150 ml) was added and the layers separated. The aqueous layer was then extracted with dichloromethene (2×200 ml) and the organic layers combined, dried (Na2SO4) and evaporated in vacuo to yield the title compound as an oil (8.0 g). T.l.c. (5% Methanol/methyl tert-butyl ether), Rf 0.7.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[NH2:20][C:21]1[S:25][N:24]=[C:23]([CH3:26])[CH:22]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([NH:10][C@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([NH2:14])=[O:13])=[CH:3][C:2]=1[NH:20][C:21]1[S:25][N:24]=[C:23]([CH3:26])[CH:22]=1)#[N:9]
Reactant: CC(C)C[C@@H](Nc1ccc(C#N)c(Br)c1)C(N)=O
Reactant: Cc1cc(N)sn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)ccc2C#N)sn1
Reaction time: 18 h
Yield: 49.3 %

Procedure:
A mixture of (R)-2-(3-bromo-4-cyanophenylamino)-4-methylpentanamide (187 mg, 0.603 mmol), 5-amino-3-methylisothiazole hydrochloride (115 mg, 0.763 mmol), BINAP (40 mg, 0.064 mmol), Pd(OAc)2 (30 mg, 0.13 mmol) and K2CO3 (300 mg, 2.17 mmol) in dioxane (4 mL) was degassed with Ar, then was stirred at 120 C for 18 h. The mixture was concentrated in vacuo. The residue was purified by HPLC to give (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-4-methylpentanamide (102 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:3]=1.[NH:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1>N1C=CC=CC=1>[CH3:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:3]=[C:2]2[N:19]1[CH2:27][CH2:26][CH:22]([C:23]([NH2:25])=[O:24])[CH2:21][CH2:20]1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1ccc2nc(-c3ccccc3)cc(Cl)c2c1
Solvent: c1ccncc1
Product: Cc1ccc2nc(-c3ccccc3)cc(N3CCC(C(N)=O)CC3)c2c1

Procedure:
The named compound was made in a manner analogous to that of Example 4(c) using 4-chloro-6-methyl-2-phenylquinoline and isonipecotamide as starting materials. It was obtained as white solid, mp 245°-247° dec on recrystallization from pyridine.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH:17]=[CH:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=O)[NH:10][C:4]=2[CH:3]=1.COC1C=CC(P2(=S)SP(=S)[S:29]2)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]3[CH:17]=[CH:16][C:15]4[C:7]3=[C:8]([CH:12]=[CH:13][CH:14]=4)[C:9](=[S:29])[NH:10][C:4]=2[CH:3]=1
Reactant: COc1ccc(P2(=S)S[PH](=S)S2)cc1
Reactant: O=C1Nc2cc(Br)ccc2-n2ccc3cccc1c32
Solvent: Cc1ccccc1
Product: S=C1Nc2cc(Br)ccc2-n2ccc3cccc1c32
Reaction time: 8 h
Yield: 71.5 %

Procedure:
A mixture of 9-bromobenzo[b]pyrrolo[3,2,1-jk][1,4]benzodiazepin-6(7H)-one (12.8 g), 2,4-bis(4-methoxyphenyl-1,3-dithia-2,4-diphosphetane-2,4-disulfide (8.3 g), and toluene (500 ml) was refluxed for 2 hrs. The reaction mixture was allowed to stand overnight at room temperature. The precipitate was collected, washed with hexane, and dried overnight under vacuum at 40° C. to provide 9.6 g, (71.5%) of product. Recrystallization from chloroform gave the analytical sample, mp 214°-215° C.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([C:24]1[CH:42]=[CH:41][C:27]([O:28][CH2:29][C:30]([O:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=2[CH3:40])=[O:31])=[CH:26][CH:25]=1)[C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[N:19][CH:18]=[CH:17]2)=[O:12])=O)(C)(C)C.[ClH:43]>C(Cl)Cl>[ClH:43].[ClH:43].[NH2:8][CH2:9][CH:10]([C:24]1[CH:25]=[CH:26][C:27]([O:28][CH2:29][C:30]([O:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=2[CH3:40])=[O:31])=[CH:41][CH:42]=1)[C:11]([NH:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[N:19][CH:18]=[CH:17]2)=[O:12]
Reactant: Cc1ccc(OC(=O)COc2ccc(C(CNC(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccc(OC(=O)COc2ccc(C(CN)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Reaction time: 8 h

Procedure:
To 2,4-dimethylphenyl 2-(4-(3-(tert-butoxycarbonylamino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)phenoxy)acetate (E252) in CH2Cl2 was added HCl (4 N, dioxane) and the solution was stirred overnight. The solvents were evaporated to give 2,4-dimethylphenyl 2-(4-(3-amino-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)phenoxy)acetate dihydrochloride (E253).
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH:8]([CH2:11][OH:12])[CH2:7][C:6]=2[CH:5]=[C:4]([C:13]#[N:14])[CH:3]=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:12][CH2:11][CH:8]2[CH2:7][C:6]3[CH:5]=[C:4]([C:13]#[N:14])[CH:3]=[C:2]([Br:1])[C:10]=3[O:9]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: N#Cc1cc(Br)c2c(c1)CC(CO)O2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C#N)cc(Br)c3O2)cc1
Yield: 73.5 %

Procedure:
Treatment of 3-bromo-4-hydroxybenzonitrile (10.0 g, 50.0 mmol) with potassium carbonate (27.9 g, 200 mmol) and allyl bromide (7.96 g, 66.0 mmol), followed by refluxing the resultant allyl ether in mesitylene generally according to the procedure described for Intermediate 8 provided 3-allyl-5-bromo-4-hydroxybenzonitrile. Treatment of 3-allyl-5-bromo-4-hydroxybenzonitrile (4.63 g, 19.0 mmol) with 3-chloroperoxybenzoic acid (6.2 g, 35.93 mmol, 77%) followed by potassium carbonate (6.56 g, 47.5 mmol) generally according to the procedure described for Intermediate 9 afforded 1.30 g (426) of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of (±)-7-bromo-2-(hydroxymethyl)-2,3-dihydro-1-benzofuran-5-carbonitrile (1.3 g, 5.0 mmol) with p-toluenesulfonyl chloride (1.02 g, 5.4 mol) generally according to the procedure described for Intermediate 10 gave 1.5 g (72%) of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Treatment of (±)-(7-bromo-5-cyano-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.73 mmol) and 2-methylphenylboronic acid (0.3 g, 2.20 mmol) generally according to the procedure described for Intermediate 35 afforded 0.33 g, (99%) of (±)-[5-cyano-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (0.26 g, 4.0 mmol) generally according to the procedure described for Intermediate 98 afforded 0.17 g (74%) of (±)-2-(azidomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile. Treatment of the azide with polymer-supported triphenylphosphine (0.24 g, 0.67 mmol) according to the procedure described in Example 154 afforded 0.118 g (53%) of (±)-2-(aminomethyl)-7-(2-methylphenyl)-2,3-dihydro-1-benzofuran-5-carbonitrile as a white solid, hydrochloride salt. mp 127-129° C.
Reaction SMILES: C([O:3][C:4](=[O:27])[C:5]([NH:23]C(=O)C)([CH:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:12])C(OCC)=O)C.Cl>C(O)(=O)C>[NH2:23][CH:5]([CH:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[CH3:12])[C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)C(NC(C)=O)(C(=O)OCC)C(C)c1cccc2ccccc12
Agent: Cl
Solvent: CC(=O)O
Product: CC(c1cccc2ccccc12)C(N)C(=O)O
Yield: 73.2 %

Procedure:
A solution of 2-acetylamino-2-[1-(1-naphthyl)ethyl]propanedioic acid diethyl ester (21.59 g) in a mixture of concentrated hydrochloric acid (100 ml) and acetic acid (70 ml) was refluxed for 13 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in water (100 ml). The solution was neutralized to pH 5 with 30% sodium hydroxide. The precipitated crystalline solid was collected by filtration to give 2-amino-3-(1-naphthyl)butyric acid (9.76 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.[NH2:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[CH:25][CH:26]=[N:27]2)=[CH:22][CH:21]=1>CCOC(C)=O.[Cl-].[Cl-].[Zn+2]>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:19][C:20]2[CH:29]=[C:28]3[C:23]([CH:24]=[CH:25][CH:26]=[N:27]3)=[CH:22][CH:21]=2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)nnc2Cl)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(-c2cc(Nc3ccc4cccnc4c3)nnc2Cl)cc1
Temperature: 220 °C
Reaction time: 0.33 h

Procedure:
(Analogous to the procedure of WO 178270). A mixture of 3,6-dichloro-4-(4-trifluoromethylphenyl)pyridazine, Example 81(d), (2.0 g, 6.8 mmol), 7-amino-quinoline (984 mg, 6.8 mmol) and ZnCl2 (980 mg, 3.4 mmol) was heated in a microwave with stirring at 220° C. for 20 min. The reaction mixture was cooled to room temperature, a second portion of 3,6-dichloro-4-(4-trifluoromethylphenyl)-pyridazine (2.0 g, 6.8 mmol), was added and the mixture was heated again in microwave at 220° C. for 40 min. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL) and washed with H2O (3×). The organic layer was dried over Na2SO4, filtered and the solvent evaporated in vacuo. The residue was purified by preparative thin layer chromatography, eluting with MeOH:CH2Cl2 (1:39), to give the title compound as a light-yellow powder. MS (ESI, pos. ion) m/z: 401 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10](I)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1I.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1>>[NH2:1][C:2]1[C:10]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:14]([F:25])([F:24])[F:13])[CH:20]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1c(I)cc(C(=O)O)cc1I
Product: Nc1c(-c2cccc(C(F)(F)F)c2)cc(C(=O)O)cc1-c1cccc(C(F)(F)F)c1

Procedure:
2′-Amino-3,3″-bis-trifluoromethyl-[1,1′:3′1″]terphenyl-5′-carboxylic acid was prepared as an off white solid (0.992 g, 94%) from 4-amino-3,5-diiodobenzoic acid and 3-trifluoromethylphenyl boronic acid using a procedure similar to step 1 of Example 175. 1H NMR (CDCl3) δ 7.90 (s, 2H); 7.78 (m, 2H); 7.74-7.60 (m, 6H); 4.24 (bs, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C:7](=[N:12]O)[CH2:6][CH2:5]2.[ClH:14]>[Pd].CO>[ClH:14].[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([NH2:12])[CH2:6][CH2:5]2
Reactant: ON=C1CCc2cc(F)ccc2C1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NC1CCc2cc(F)ccc2C1
Reaction time: 18 h
Yield: 83 %

Procedure:
A mixture of 6-fluoro-3,4-dihydronaphthalen-2(1H)-one oxime (1.58 g, 8.81 mmol), methanol (25 mL), conentrated hydrochloric acid (2 mL) and 10% palladium on charcoal (316 mg) was shaken in a pressure bottle under a hydrogen atmosphere (55 psig). After 18 hours, the mixture was filtered and the solid washed with methanol. The filtrate was concentrated under vacuum, and the residue was washed with ether, dried by concentration from benzene, and dried further under vacuum to provide a white solid (1.48 g, 83%).
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(O[C:14]([N:16]1[CH2:21][CH2:20][C:19]2(CCNCC2)C[CH2:17]1)=O)(C)(C)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:21]1([N:16]2[CH2:14][CH2:3][C:8]3([CH2:4][CH2:5][NH:6][CH2:7]3)[CH2:17]2)[CH2:19][CH2:20]1
Reactant: Brc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)CC1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C1CC2(CCN(C3CC3)C2)CN1
Temperature: 90 °C
Yield: 45 %

Procedure:
Sodium tert-butylate (4 mmol) was added to a solution of 4-bromopyridine hydrochloride (1.9 mmol) in dry toluene (10 ml) under argon, followed by 3,9-diazaspiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1.6 mmol) in toluene (5 ml). Argon was added to the mixture for 15 min, then (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.123 mmol) and tris(dibenzylidene acetone)dipalladium (0.041 mmol) were added. The mixture was heated at 90° C. for 4 h and the reaction progress was monitored by thin-layer chromatography. On completion of the reaction the mixture was diluted with ethyl acetate (100 ml) and extracted with water and saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to small volume. The crude product was purified by column chromatography (3% methanol in DCM). Yield: 45% 2. TFA (13 eq.) was added to a DCM solution (10 ml/mmol) of tert-butyl 9-(pyridin-4-yl)-3,9-diazaspiro[5.5]undecane-3-carboxylate (1 eq.) at 0° C. and the mixture was stirred for 2 h at RT. The solvent was removed and the product was dried under vacuum. The crude product was used in the following stage with no further purification. Yield: quantitative
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.ClCCl.[OH-].[Na+].[CH3:14][C:15]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:16]=1[CH2:17]Br>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[NH2:1][C:2]1[C:7]([O:8][CH2:17][C:16]2[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[CH:22][C:15]=2[CH3:14])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(C)c(CBr)c(C)c1
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)c(COc2cccnc2N)c(C)c1
Reaction time: 0.08 h

Procedure:
A mixture of 2-amino-3-hydroxy pyridine (29.6 g, 0.269 mol), dichloromethane (200 ml) and 40% aqueous sodium hydroxide solution (200 ml) was stirred for five minutes, then 2,4,6-trimethylbenzyl bromide (50 g, 0.296 mol) and Adogen 464 (5 ml) were added and stirring continued for 16 hours. The mixture was diluted with water and extracted with dichloromethane. Drying and evaporation of the organic extracts, and trituration with ether gave the desired product. Yield 29.6 g (41%), m.p. 160°-166 ° C.
Reaction SMILES: [NH2:1][C:2]([C:5]1[N:6]([CH3:24])[C:7](=[O:23])[C:8]([OH:22])=[C:9]([C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[O:12])[N:10]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35]>C(Cl)(Cl)Cl>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][NH:13][C:11]([C:9]2[N:10]=[C:5]([C:2]([NH:1][C:33](=[O:38])[C:34]([O:36][CH3:37])=[O:35])([CH3:4])[CH3:3])[N:6]([CH3:24])[C:7](=[O:23])[C:8]=2[OH:22])=[O:12])=[CH:20][CH:19]=1
Reactant: COC(=O)C(=O)Cl
Reactant: Cn1c(C(C)(C)N)nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)C(=O)NC(C)(C)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c(=O)n1C
Temperature: 25 °C

Procedure:
To a stirred mixture of 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxamide (4) and triethyl amine (3 eq) in chloroform, methyl chlorooxoacetate (1.5 eq) was added with an external cooling. Finished the addition, the ice bath was removed and the mixture was stirred at room temperature for 3 H. Reaction mixture was then partitioned between chloroform and 1N HCl. Organic layer was separated, washed with brine, dried (Na2SO4), filtered and concentrated to obtain title product.