Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([NH2:16])[CH:3]=1.[C:17](O)(=[O:21])[C:18](O)=[O:19]>Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[N:8]1[CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]1)[NH:15][C:18](=[O:19])[C:17](=[O:21])[NH:16]2
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(Cl)c(-n2ccc(=O)cc2)cc1N
Agent: Cl
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2Cl)cc1
Yield: 12.6 %

Procedure:
First, a mixture containing 1.93 g of 4-chloro-5-(4-oxo-4H-pyridin-1-yl)-1,2-phenylenediamine, 2.21 g of oxalic acid, and 40 ml of 2N hydrochloric acid was refluxed by heating in an oil bath for 2 hours. The mixture was cooled and precipitated crystals were filtered to give 2.1 g of crude crystals of 6-chloro-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione (melting point: >400° C.). Then, 500 mg of the crude crystals were recrystallized with dimethylformaldehyde and water to give 299 mg of 6-chloro-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([CH3:15])=[N:5][O:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1.[C:16]1([CH2:22][CH2:23][SH:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[O:6][N:5]=[C:4]([CH3:15])[C:3]=2[CH2:2][S:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1CBr
Reactant: SCCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1CSCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 51, Step 1, using 4-bromomethyl-5-(4-bromo-phenyl)-3-methyl-isoxazole and 2-phenylethanethiol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[Cl:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.ClC(Cl)C>ClCCl>[Cl:12][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:19]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:20]
Reactant: Nc1cnc2ccccc2c1Cl
Reactant: O=C(Cl)C1CCCCC1
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1cnc2ccccc2c1Cl)C1CCCCC1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere, a mixture of 3-amino-4-chloroquinoline (8.00 g, 1 eq), cyclohexanecarbonyl chloride (18.2 mL, 3 eq) and anhydrous dichloroethane (150 mL) was heated at 90° C. for 23 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with saturated aqueous potassium carbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was triturated with hexanes to provide a solid. The solid was combined with hexanes, stirred for 30 minutes, isolated by filtration, rinsed with hexanes, and then dried to provide 11.9 g of N-(4-chloroquinolin-3-yl)cyclohexanecarboxamide.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7].S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Cl:1][CH2:2][CH2:3][N:4]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([Cl:19])=[O:13])=[CH:10][CH:9]=1)[CH2:5][CH2:6][Cl:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(N(CCCl)CCCl)cc1
Solvent: c1ccccc1
Product: O=C(Cl)c1ccc(N(CCCl)CCCl)cc1

Procedure:
A solution of N-(N',N'-dimethylaminoethyl) 1-methyl-4-{1-methyl-4[1-methyl-4-nitroimidazole-2-carboxamido]imidazole-2-carboxamido}imidazole-2-carboxamide (248 mg, 0.510 mmol) in methanol (35 mL) was hydrogenated over 5% Pd on carbon (118 mg) at room temperature and atmospheric pressure until TLC analysis indicated complete reduction of the starting material (5 h). The catalyst was removed by filtration. Concentration of the filtrate gave a residue which was coevaporated with dry THF (20 mL, twice) to give N-(N',N'-dimethylaminoethyl)-2-methyl-4-{1-methyl-4[1-methyl-4-aminoimidazole-2-carboxamido]imidazole-2-carboxamido}imidazole-2-carboxamide as an off-white powder. p-N,N-Bis(2-chloroethyl)aminobenzoyl chloride was prepared by dissolving p-N,N-Bis(2-chloroethyl)aminobenzoic acid (13.4 mg, 0.510 mmol) in benzene (2 mL) and thionyl chloride (2 mL) and heating to reflux under a drying tube for 1.25 h. (The solution turned from purple to green upon addition of thionyl chloride). The excess thionyl chloride and solvent were then removed under reduced pressure and the residue coevaporated with dry CH2Cl2 (10 mL, once).
Reaction SMILES: [CH2:1]([NH:4][C:5](=S)[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2C(=O)C3=CC=CC=C3C2=O)[N:8]=1)[CH2:2][CH3:3].[NH3:30]>CN(C=O)C>[CH2:1]([N:4]=[C:5]([NH2:30])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])[N:8]=1)[CH2:2][CH3:3]
Reactant: CCCNC(=S)Nc1ccnc(CCCCCN2C(=O)c3ccccc3C2=O)n1
Reactant: N
Solvent: CN(C)C=O
Product: CCCN=C(N)Nc1ccnc(CCCCCN)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(3-propylthioureido)-2-(5-phthalimidopentyl)pyrimidine (1.7 g.), DMF (25 ml.) saturated ethanolic ammonia (10 ml.) and yellow mercuric oxide (1.1 g.) was stirred at room temperature for 2 hours. The mixture was evaporated to dryness and the residue was redissolved in ethanol, filtered and the filtrate evaporated to dryness. A solution of this residue in EtOH (20 ml.) was treated with hydrazine (5 ml.) and stirred at room temperature for 16 hours. The mixture was evaporated to dryness and the residue was dissolved in water, acidified with 2N aqueous HCl and filtered. The filtrate was basified with 10N aqueous NaOH and the mixture was extracted twice with EtOAc. The extract was dried (MgSO4) and evaporated to give 4-[2-propylguanidino]-2-(5-aminopentyl)pyrimidine as a gum (0.4 g.) which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:16][C:17]([C:19]1[N:20]=[C:21]([CH2:24]Br)[S:22][CH:23]=1)=[O:18])C>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:24][C:21]2[S:22][CH:23]=[C:19]([C:17]([OH:18])=[O:16])[N:20]=2)[CH:8]=1
Reactant: CCOC(=O)c1csc(CBr)n1
Reactant: Oc1cccc(-c2ccccc2)c1
Product: O=C(O)c1csc(COc2cccc(-c3ccccc3)c2)n1

Procedure:
2-(Biphenyl-3-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure B from 3-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (Intermediate 3). Yield: 65 mg. Mass spectrum (ES) MH+=312.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=3)[NH:10][C:9]2=O)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O.C(N(CC)C(C)C)(C)C>>[Cl:26][C:9]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:15]=2)[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(=O)[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(=O)n(-c3ccc(Cl)cc3)c(Cl)nc2c1
Temperature: 120 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
Into a round bottom flask was added methyl 3-(4-chlorophenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-7-carboxylate (0.28 g, 0.76 mmol) dissolved in phosphoryl chloride (3.2 mL, 34.5 mmol) and N,N-diisopropylethylamine (0.29 mL, 1.7 mmol). The reaction mixture was heated to 120° C. and stirred for 5 h. The mixture was then cooled to rt and concentrated. The residue was poured over ice and the resulting solid was filtered and washed with water to afford methyl 2-chloro-3-(4-chlorophenyl)-4-oxo-3,4-dihydroquinazoline-7-carboxylate (0.26 g, 98%). LC-MS: (FA) ES+ 350.
Reaction SMILES: [N:1]1([C:6]2[CH:18]=[CH:17][C:9]3[O:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][O:16][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:19]1([CH2:25][CH:26]=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[BH3-]C#N.[Na+]>>[CH:19]1([CH2:25][CH2:26][N:13]2[CH2:12][CH2:11][O:10][C:9]3[CH:17]=[CH:18][C:6]([N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)=[CH:7][C:8]=3[O:16][CH2:15][CH2:14]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: c1cn(-c2ccc3c(c2)OCCNCCO3)cn1
Reactant: O=CCC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: c1cn(-c2ccc3c(c2)OCCN(CCC2CCCCC2)CCO3)cn1

Procedure:
In a manner similar to example 4, react 9-(1H-imidazol-1-yl)-3,4,5,6-tetrahydro-2H-1,7,4-benzodioxazonine with cyclohexaneacetaldehyde and NaBH3CN to obtain the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30]([OH:32])=O)[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][O:64][C:65]([C:67]1[S:71][C:70]2[CH:72]=[CH:73][C:74]([NH2:76])=[CH:75][C:69]=2[CH:68]=1)=[O:66]>>[CH3:63][O:64][C:65]([C:67]1[S:71][C:70]2[CH:72]=[CH:73][C:74]([NH:76][C:30]([C@@H:20]3[NH:19][C@@H:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C@:17]4([C:12]5[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=5)[NH:15][C:16]4=[O:38])[C@H:21]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])=[O:32])=[CH:75][C:69]=2[CH:68]=1)=[O:66]
Reactant: COC(=O)c1cc2cc(N)ccc2s1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc2cc(NC(=O)[C@@H]3N[C@@H](CC(C)(C)C)[C@@]4(C(=O)Nc5cc(Cl)ccc54)[C@H]3c3cccc(Cl)c3F)ccc2s1
Yield: 43.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (100 mg, 0.173 mmol), was reacted with diisopropylethylamine (111 mg, 0.86 mmol), diphenylphosphinic chloride (106 mg, 0.446 mmol), then reacted with 5-Amino-benzo[b]thiophene-2-carboxylic acid methyl ester (Maybridge, 41 mg, 0.190 mmol) to give rac-5-{[(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-benzo[b]thiophene-2-carboxylic acid methyl ester (49 mg, 43%). MS (ES+) m/z [(M+H)+]: 654
Reaction SMILES: [Na].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.Cl[CH:12](Cl)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C.C(OCC)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:12]([O:10][C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: COc1ccc(O)cc1
Reactant: CCOC(=O)C(Cl)Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(Oc1ccc(OC)cc1)Oc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
Sodium (5.4 g) is dissolved in absolute ethanol (160 cc). 4-Methoxyphenol (29.2 g) dissolved in absolute ethanol (20 cc) is added. The mixture is stirred for 1 hour at ambient temperature. Ethyl 2,2-dichloro-acetate (20 g) dissolved in absolute ethanol (20 cc) is then added and the mixture is heated under reflux for 20 hours. The ethanol is driven off under reduced pressure (20 mmHg) at 40° C. and the residue is taken up in diethyl ether (100 cc). The organic phase is washed with 0.1 N sodium hydroxide solution (100 cc) and with water (2×100 cc) and is then dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (20 mmHg) at 40° C. Ethyl 2,2-bis(4-methoxyphenoxy)-acetate (30 g) is thus obtained in the form of an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=2)[N:6]=1.[C:17]1([C:23]2[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:23]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[S:3][CH:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])=[CH:11][CH:12]=3)[N:6]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: CC(=O)Nc1ccc(-c2csc(N)n2)cc1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: CC(=O)Nc1ccc(-c2csc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)n2)cc1

Procedure:
The title compound was prepared N-[4-(2-amino-1,3 -thiazol-4-yl)phenyl]acetamide and 4-phenylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white-yellow solid (8.6 mg) with purity >80%. MS (pos) m/z 450.3.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C@H:27]2[CH2:44][C@@:42]3([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]3[OH:45])[C@H:37]3[C@H:28]2[C:29]2[CH:30]=[CH:31][C:32]([OH:46])=[CH:33][C:34]=2[CH2:35][CH2:36]3)=[CH:23][CH:22]=1.I([O-])(=O)(=O)=[O:48]>O.CO>[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][S:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C@H:27]2[CH2:44][C@@:42]3([CH3:43])[C@@H:38]([CH2:39][CH2:40][C@@H:41]3[OH:45])[C@H:37]3[C@H:28]2[C:29]2[CH:30]=[CH:31][C:32]([OH:46])=[CH:33][C:34]=2[CH2:35][CH2:36]3)=[CH:25][CH:26]=1)=[O:48]
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCSCc4ccccn4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)Cc4ccccn4)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 0.5 h

Procedure:
3.7 cm3 of a 0.1M solution of sodium metaperiodate in water is added to a solution of 172 mg of the product obtained in Example 4 in 12 cm3 of methanol. The reaction medium is agitated for 1 hour 30 minutes and 3.4 cm3 of methanol and 0.6 cm3 of the metaperiodate solution are added, after 3 hours 30 minutes of agitation the reaction medium is poured into water, extracted with ethyl acetate, washed with salt water and evaporated to dryness under reduced pressure. 176 mg of residue is obtained which is chromatographed on silica twice (eluant methylene chloride-methanol (92.5-7.5)). 107 mg of desired product is collected.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]([C:11]([O:13]C)=[O:12])=[C:9]([N+:15]([O-:17])=[O:16])[C:8]([C:18]([O:20][CH3:21])=[O:19])=[N:7]1)[CH3:2].[OH-].[K+]>CO>[CH3:21][O:20][C:18]([C:8]1[C:9]([N+:15]([O-:17])=[O:16])=[C:10]([C:11]([OH:13])=[O:12])[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[N:7]=1)=[O:19]
Reactant: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOCCn1nc(C(=O)OC)c([N+](=O)[O-])c1C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The ester of step 1 (1.63 g, 5.4 mmol) was added to a solution of potassium hydroxide (330 mg, 5.9 mmol) in methanol (20 mL) and the reaction mixture stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the crude product dissolved in water and washed with ether. The aqueous phase was acidified with 2M hydrochloric acid and extracted into dichloromethane (3×100 mL). The organics were combined, dried over magnesium sulphate and concentrated in vacuo to yield the nitro product.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](O)=[O:9])=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:25][NH2:26]>C1COCC1>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:25][NH2:26])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)COc1ccc(Br)cc1
Reactant: NN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: NNC(=O)COc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a solution of (4-bromophenoxy)acetic acid (1.0 g, 4.3 mmol) in THF (15 mL) was added N,N-Carbonyldiimidazole (0.84 g, 5.2 mmol). After refluxing for 2 hours, hydrazine (0.6 g, 20 mmol) was added to the reaction mixture slowly with a syringe at 0° C. The reaction mixture was allowed to warm to room temperature slowly and then concentrated to yield the desired product as a white solid. LCMS calculated for C8H10BrN2O2 (M+H): 245.0. found: 244.9, 246.9.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22]>>[F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH:20]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=1)[C:21]([OH:23])=[O:22])=[O:6]
Reactant: NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O
Reactant: O=C(O)c1ccc(OCCC(F)(F)F)cc1F
Agent: Cl
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1F
Yield: 93.7 %

Procedure:
A reaction similar to that described in Example 70 (70a) was conducted using 2-fluoro-4-(3,3,3-trifluoropropoxy)benzoic acid (177 mg) prepared in Example 84 (84a) and 2-amino-3-[4-(trifluoromethoxy)phenyl]propanoic acid hydrochloride (200 mg) prepared in Reference Example 2 to give 317 mg of the title compound (white powder).
Reaction SMILES: [CH3:1][O:2]/[CH:3]=[CH:4]/[C:5]#[CH:6].[CH2:7]([SnH:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:16]([Sn:11]([CH2:7][CH2:8][CH2:9][CH3:10])([CH2:12][CH2:13][CH2:14][CH3:15])/[CH:6]=[CH:5]/[CH:4]=[CH:3]/[O:2][CH3:1])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#C/C=C/OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: CCCC[Sn](/C=C/C=C/OC)(CCCC)CCCC

Procedure:
Scheme D shows a method of preparing an aldehyde which may be used in Scheme A. 1-Methoxy-1E-buten-3-yne is reacted with tributylstannane in the presence of catylytic 2,2'-azobisisobutyronitrile (AIBN) to give tributyl(4-methoxy-1E,3E-butadienyl)stannane which is then reacted with butyllithium followed by coupling with an appropriate aldehyde (XVIII). The alcohol-formed is reacted with toluene sulfonic acid (TSOH) to give the desired aldehyde (V).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH3:19])[C:9]([F:18])([F:17])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>ClCCl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[F:17][C:9]([F:18])([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:8]([NH2:7])[CH3:19]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(F)(F)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](N)C(F)(F)Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a round-bottomed flask, ((R)-2,2-difluoro-1-methyl-3-phenyl-propyl)-carbamic acid tert-butyl ester (92 mg, 0.32 mmol) was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (0.75 ml, 9.73 mmol) was slowly added. The reaction was stirred at room temperature for 2 h then concentrated to give (R)-2,2-difluoro-1-methyl-3-phenyl-propylamine trifluoroacetate as a light brown oil which was used without further purification
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[C:5](=[O:12])[O:4][CH2:3][CH2:2]1.Cl.[CH3:14][NH:15][CH3:16]>>[OH:4][CH2:3][CH2:2][O:1][C:6]1([C:5]([N:15]([CH3:16])[CH3:14])=[O:12])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: CNC
Reactant: O=C1OCCOC12CCOCC2
Agent: Cl
Product: CN(C)C(=O)C1(OCCO)CCOCC1
Yield: 99 %

Procedure:
Using 1,4,9-trioxaspiro[5.5]undecane-5-one produced in Reference Example 15 (15a) and dimethylamine hydrochloride (659 mg, 8.14 mmol), the desired title compound (630 mg, yield 99%) was obtained by the same method as in Example 5.
Reaction SMILES: [CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClCCl>[CH:1]1([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(=O)C2CCCC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(c1ccc(O)cc1)C1CCCC1

Procedure:
The title compound is prepared in analogy to the procedure of Example II from 30 g (0.147 mol) of the compound from Example VI and 290 ml of a 1M solution of boron tribromide (0.29 mmol) in dichloromethane,
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2)=[N+]=[N-].O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[NH2:1][CH2:4][C:5]1[CH:6]=[N:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: [N-]=[N+]=NCc1cncc2cccnc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1cncc2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.1 g (5.9 mmol) 8-azidomethyl-1,6-napthyridine in 20 mL THF was added 2 mL H2O and 3 g PPh3. The resulting solution was alloed to stir overnight at room temperature, then concentrated in vacuo. Purification by flash chromatography (50×140 mm silica gel, linear gradient 5-20% (10% NH4H in MeOH):CH2Cl2) yielded 8-aminomethyl-1,6-napthyridine. 1H NMR (CDCl3, 400 MHz) δ 9.22 (s, 1H); 9.13 (dd, 1H, J=4.3 and 1.8 Hz); 8.70 (s, 1H); 8.32 (dd, 1H, J=8.24 and 1.83 Hz); 7.61 (dd, 1H, J=8.24 and 4.3 Hz); 4.40 (s, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][N:6]=1)([CH3:3])[CH3:2]>CO.[Pd]>[CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]([NH2:11])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CC(C)Oc1ccc(N)cn1
Reaction time: 4 h

Procedure:
To a solution of 2-isopropoxy-5-nitro-pyridine, as prepared in the previous step, in MeOH (5 mL) was added 20 mg of 10% Pd/C. The mixture was degassed several times and stirred under hydrogen atmosphere for 4 h. It was filtered through a pad of celite and the filtrate was evaporated. The residue was purified by flash column chromatography on silica gel (EtOAc as eluent). 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J=2.96 Hz, 1H), 7.02 (dd, J=8.71 and 2.99 Hz, 1H), 6.54 (d, J=8.67 Hz, 1H), 5.14 (m, 1H), 1.31 (d, J=6.17 Hz, 6H). LC-MS (ESI) calcd mass 152.1, found 153.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC(C)C(N1CCCC1C(=O)[NH:33][CH:34]1[CH2:38][C:37](=[O:39])[O:36][CH:35]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14](=[O:16])[NH:33][CH:34]1[CH2:38][C:37](=[O:39])[O:36][CH:35]1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)O
Product: CC(C)(C)OC(=O)N1CCCCC1C(=O)NC1CC(=O)OC1OCc1ccccc1
Yield: 57 %

Procedure:
Prepared from piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 99 and 40 following the method used in the preparation of 75 to give the title compound as a yellow solid (2.63 g, 57% yield). 1H-NMR (500 MHz, CDCl3) δ 1.15-1.79 (m, 15H), 2.12-2.50 (m, 2H), 2.56-2.83 (m, 1H), 2.89 (dd, 0.5H), 3.05 (dd, 0.5H), 3.81-4.15 (br s, 1H), 4.36-4.97 (m, 3H), 5.37-5.61 (m, 1H), 6.42-6.89 (br s, 1H), 7.17-7.51 (m, 5H). LC-MS (ES+) m/e=419.4 (MH+).
Reaction SMILES: Cl.[S:2]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)([CH3:5])(=[O:4])=[O:3].Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[S:2]([N:6]1[CH2:11][CH2:10][N:9]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=2)[CH2:8][CH2:7]1)([CH3:5])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(N2CCN(S(C)(=O)=O)CC2)nc1
Temperature: 120 °C
Yield: 69.1 %

Procedure:
1-Mesylpiperazine hydrochloride (4.24 g) was added to a solution of methyl 6-chloronicotinate (1.7 g) and N,N-diisopropylethylamine (6.3 ml) in dimethylacetamide (20 ml) and the mixture was heated at 120° C. for 2 hours. The mixture was allowed to cool to ambient temperature and poured onto crushed ice/water (50 ml) to precipitate a tan solid. The solid was collected by filtration and dried at 80° C. for 18 hours in a vacuum oven, to give 1-mesyl-4-(5-methoxycarbonyl-2-pyridyl)piperazine (2.05 g),