Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([O:34]CC)=[O:33].[OH-].[Na+].C(O)C>C1COCC1.C(OCC)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:31])[NH:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)=[CH:17][CH:18]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:32]([OH:34])=[O:33]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCCc4ccc(Cl)cc4)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCCCc1ccc(Cl)cc1)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
Ethyl 6-chloro-7-(4-(3-(4-chlorophenyl) propylcarbamoyl)phenoxy)chroman-4-carboxylate (80 mg, 0.15 mmol) was diluted with THF (1 mL) followed by the addition of NaOH (757 μl, 0.76 mmol) and ethanol (500 μL). After stirring for 2 hours, the reaction was diluted with ethyl acetate and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 6-chloro-7-(4-(3-(4-chlorophenyl)propylcarbamoyl)phenoxy)chroman-4-carboxylic acid (76 mg, 0.15 mmol, 100% yield).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH:13]1([CH2:16]Br)[CH2:15][CH2:14]1.[H-].[Na+]>>[CH:13]1([CH2:16][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[Cl:1])[CH2:15][CH2:14]1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1c(Cl)n(CC2CC2)c2ccccc12
Yield: 98.2 %

Procedure:
Prepared from (1) (18 g), cyclopropylmethyl bromide (16.2 g) and NaH (2.8 g) yielding (4) (23 g), m.p. 108°-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].[CH3:24][N:25]([CH3:38])[CH2:26][CH2:27][NH:28][S:29]([C:32]1[S:33][C:34](Br)=[CH:35][CH:36]=1)(=[O:31])=[O:30]>>[CH3:24][N:25]([CH3:38])[CH2:26][CH2:27][NH:28][S:29]([C:32]1[S:33][C:34]([C:22]#[C:21][C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:15])([F:17])[F:16])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:23])[CH:4]=4)=[N:9][C:10]=23)=[CH:35][CH:36]=1)(=[O:31])=[O:30]
Reactant: CN(C)CCNS(=O)(=O)c1ccc(Br)s1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4ccc(S(=O)(=O)NCCN(C)C)s4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (168 mg, 0.5 mmol) and 5-bomo-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.49) (157 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (200 mg, 70%). MS (ISN) 566.2 [(M−H)−]; mp 179° C.
Reaction SMILES: [F:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9](Cl)=[O:10].[CH:12]1([NH:15][CH:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:17][CH3:18])[CH2:14][CH2:13]1.C(N(CC)CC)C.ClCCl.CO>ClCCl>[CH:12]1([N:15]([CH:16]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[CH2:17][CH3:18])[C:9]([C:3]2[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=2[F:1])=[O:10])[CH2:14][CH2:13]1
Reactant: Cc1nn(C)c(F)c1C(=O)Cl
Reactant: CCC(NC1CC1)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(c1ccncc1)N(C(=O)c1c(C)nn(C)c1F)C1CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 0.1 %

Procedure:
At ambient temperature a solution of 0.16 g (0.93 mmol) of 5-fluoro-1,3-dimethyl-1H-pyrazole-4-carbonyl chloride in 2 ml of dichloromethane was added dropwise to a solution of 0.15 g (0.85 mmol) of N-cyclopropyl-1-pyridin-4-yl-propylamine and 0.14 ml of triethylamine in 5 ml of dichloromethane. The reaction mixture was stirred for 12 hrs at ambient temperature and then at 40° C. for 8 hrs and washed with water. The organic layers were filtrated over basic alumina and dried. Column chromatography (gradient dichloromethane/Methanol) yielded 0.18 mg (44% yield) of N-cyclopropyl-N-[1-pyridin-4-yl-propyl]-5-fluoro-1,3-dimethyl-1H-pyrazole-4-carboxamide (M+H=317).
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C@H:18]2[C@H:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1.C(OCC)(=O)C>C(O)C>[C:6]([C@H:4]([C@@H:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C@H:18]2[C@H:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: O=C(N[C@@H]1C2CCN(CC2)[C@H]1Cc1cccnc1)c1cc2ccccc2o1
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Temperature: 25 °C

Procedure:
Tartaric acid (25.6 mg, 0.173 mmol) was added to a solution of (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide (125 mg, 0.346 mmol) in hot ethanol (1 mL). The resulting solution was slowly cooled to ambient temperature. No solids precipitated, so the solution was concentrated to give a white foam. Attempts to crystallize in isopropanol failed. The foam was dissolved in methanol and another half-equivalent of tartaric acid (25.6 mg, 0.173 mmol) was added. The mixture was concentrated to give a white foam, which would not crystallize from mixtures of methanol and isopropanol. The concentrated material (mixture of solid and gummy liquid) was then slurried in ethyl acetate (1 mL), producing a white solid. This was isolated by filtration (ethyl acetate wash) and drying in a vacuum oven (18 h at 40° C.), to give 141 mg (79.7% yield) of the mono stoichiometry salt (NMR), mp 136-140° C. Chiral LC analysis gave a purity of 98.1% (270 nm). 1H NMR (300 MHz, D2O) δ 8.50 (s, 1H), 8.01 (d, 1H), 7.86 (d, 1H), 7.75 (d, 1H), 7.56 (m, 2H), 7.38 (t, 1H), 7.32 (s, 1H), 7.21 (t, 1H), 4.34 (s, 2H, tartaric acid), 4.26 (d, 1H), 3.95 (m, 1H), 3.64 (m, 2H), 3.15-3.55 (m, 4H), 1.90-2.30 (m, 5H).
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][C@@H:10]([NH:12][CH3:13])[C@H:9]([OH:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:21]1([C:31]([Cl:33])=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[ClH:33].[CH:1]1([N:7]2[CH2:8][C@@H:9]([OH:14])[C@H:10]([N:12]([CH3:13])[C:31]([C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)=[O:32])[CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN[C@@H]1CN(C2CCCCC2)C[C@H]1O
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CN(C(=O)c1cccc2ccccc12)[C@@H]1CN(C2CCCCC2)C[C@H]1O
Product: Cl
Reaction time: 2 h
Yield: 56 %

Procedure:
A solution of 10 g (0.05 mole) of trans-1-cyclohexyl-4-methylamino-3-pyrrolidinol in 100 ml of methylene chloride was mixed with 10 g of powdered anhydrous potassium carbonate and stirred while a solution of 10 g (0.05 mole) of 1-naphthoyl chloride in 50 ml of methylene chloride was added dropwise. The mixture was stirred for 2 hrs and then heated at reflux for 24 hrs. After cooling, the mixture was washed with water and the organic fraction was evaporated under vacuum. The residue was chromatographed on silica gel, eluting with acetone. Ten grams of the base, 56% yield, were collected and converted to the hydrochloride. After recrystallization from isopropyl alcohol, the salt melted at 238°-241° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][N:13]=1>C(OCC)(=O)C>[CH:1]([NH:11][C:12]1[N:17]=[C:16]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:15]=[CH:14][N:13]=1)=[O:3]
Reactant: COC(=O)Cc1ccnc(N)n1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: O=CO
Product: COC(=O)Cc1ccnc(NC=O)n1
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
A mixture of acetic anhydride (32.7 g.) and formic acid (16.2 g.) was stirred at 50° to 60° C. for 30 minutes. The solution was added to a suspension of methyl 2-(2-aminopyrimidin-4-yl)acetate (17.93 g.) in ethyl acetate (300 ml.) at room temperature over 10 minutes, and the solution was stirred at room temperature for 3 hours. After removing the insoluble substance by filtration, water (300 ml.) was added to the filtrate, and then the mixture was adjusted to pH 7 with sodium bicarbonate. The aqueous layer was separated and extracted with ethyl acetate. The extract and the organic layer were combined, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, treated with activated charcoal, and then concentrated under reduced pressure. The residue was triturated with diethyl ether to give methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.62 g.), mp 103° to 107° C.
Reaction SMILES: CS[C:3]1[CH:4]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.OO[S:15]([O-:17])=[O:16].[K+].[CH3:19]C(C)=O>>[CH3:19][S:15]([C:7]1[CH:6]=[C:5]([S:9]([NH2:12])(=[O:11])=[O:10])[CH:4]=[CH:3][CH:8]=1)(=[O:17])=[O:16]
Reactant: CSc1cccc(S(N)(=O)=O)c1
Reactant: CC(C)=O
Reactant: O=S([O-])OO
Agent: [K+]
Product: CS(=O)(=O)c1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-methylsulfanylbenzenesulfonamide (500 mg, 2.5 mmol) in acetone was added an aqueous solution of OXONE® (3.2 grams, 5 mmol). The mixture was stirred at room temperature for 12 hours. The reaction was evaporated to dryness in vacuo. The residue was triturated with acetone and filtered. The filtrated was evaporated to give 460 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][N:14]3C(=O)C4=CC=CC=C4C3=O)=[C:11]([CH3:25])[N:10]=[C:9]2[CH2:26][N:27]([CH3:29])[CH3:28])=[C:4]([C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=O)[CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]3[C:9]([CH2:26][N:27]([CH3:29])[CH3:28])=[N:10][C:11]([CH3:25])=[C:12]3[CH2:13][N:14]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[C:4]=2[CH:3]=1
Reactant: Cc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccn2)c1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nc(CN(C)C)n2c1CN=C(c1ccccn1)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 4, N-[[1-[4-chloro2-(2-pyridylcarbonyl)phenyl]-2-[(dimethylamino)methyl]-4-methylimidazol-5-yl]methyl]phthalimide in ethanol is heated with hydrazine hydrate to give 8-chloro-6-(2-pyridyl)-1-[(dimethylamino)methyl]-3-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:6]#[C:7][CH3:8].[N+:17]([O-])([OH:19])=[O:18]>CC(O)=O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH:5]([C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([N+:17]([O-:19])=[O:18])[CH:14]=1)[C:6]#[C:7][CH3:8]
Reactant: CC#CC(CC(=O)OC)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC#CC(CC(=O)OC)c1ccc(O)c([N+](=O)[O-])c1
Yield: 38.3 %

Procedure:
3-(4-Hydroxy-phenyl)-hex-4-ynoic acid methyl ester (1.32 g, 6 mmol) was treated with HNO3 (0.30 mL, 7.2 mmol) in AcOH (10 mL) at 80° C. for 3 h. The solvent was concentrated in vacuo and 3-(3-nitro-4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (613 mg, 2.3 mmol) was isolated from flash chromatography. MS ESI m/e: 264.0 (M+H). The nitro group was then reduced with SnCl2 (2.62 g, 11.6 mmol) in EtOH (10 mL0 and EtOAc (10 mL) at 70° C. for 3 h. The reaction mixture was cooled to 25° C., washed with saturated aqueous Na2CO3, water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was then purified by reverse phase HPLC to give 3-(3-amino-4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (174 mg, 0.74 mmol). MS ESI m/e: 234.0 (M+H). 3-(3-amino-4-hydroxy-phenyl)-hex-4-ynoic acid methyl ester (174 mg, 0.74 mmol) and 3-bromobenzaldehyde (278 mg, 1.5 mmol) in DMF (3 mL) was treated with DDQ (204 mg, 0.9 mmol) for 2 h at 25° C. The producted was purified by reverse phase HPLC. MS ESI m/e: 398.0 (M+H). 3-[2-(3-Bromo-phenyl)-benzooxazol-5-yl]-hex-4-ynoic acid methyl ester (19.6 mg, 0.05 mmol) and trifluorophenylboronic acid (38 mg, 0.2 mmol) in DME (1 mL) and 0.2 mL of 2M solution of aqueous Na2CO3 was treated with Pd(PPh3)4 at 80° C. for 14 h. The product was isolated from flash chromatography. MS ESI m/e: 464.0 (M+H). The methyl ester (7.8 mg, 0.017 mmol) was hydrolyzed with LiOH (4 mg, 0.1 mmol) in a 1 mL of 1:1:1 mixture of MeOH, THF, and water for 2 h at 25° C. The reaction mixture was acidified with 1N HCl, extracted with CH2Cl2 and concentrated to give the pure acid (7.6 mg). MS ESI m/e: 450.1 (M+H). 1H NMR (500 MHz) (CDCl3) δ 8.52 (1H, s); 8.30 (1H, d, J=7.8 Hz); 7.91 (1H, s); 7.83 (2H, d, J=8.2 Hz); 7.82 (1H, s); 7.78 (2H, dd, J=8.0, 8.0 Hz); 7.67 (1H, dd, J=7.8, 7.8 Hz); 7.58 (2H, d, J=8.4 Hz); 7.46 (1H, dd, J=8.4, 1.5 Hz); 4.29 (1H, m); 2.94 (1H, dd, J=15.8, 8.1 Hz); 2.84 (1H, dd, J=15.8, 6.9 Hz); 1.89 (3H, d, J=2.3 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O-].[Na+].[C:13]([OH:16])(=[O:15])C>CN(C)C(=O)[O-]>[CH3:10][O:16][C:13](=[O:15])[NH:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: C[O-]
Reactant: Cc1cc(C)nc(N)n1
Reactant: CC(=O)O
Agent: CN(C)C(=O)[O-]
Agent: [Na+]
Product: COC(=O)Nc1nc(C)cc(C)n1

Procedure:
To 2-amino-4,6-dimethylpyrimidine (10 g) dissolved in dimethylcarbamate (80 ml) was added sodium methoxide (4.4 g) and the mixture refluxed for four hours. The mixture was cooled and acetic acid (5 ml) was added. The mixture was then partitioned between water (100 ml) and methylene chloride (300 ml). A second methylene chloride extraction of the aqueous phase was made and the combined methylene chloride phase washed with water (50 ml) containing NH4Cl. The solvent was evaporated and the residue triturated with a methylene chloride/1-chlorobutane mixture. The filtrate, on concentration and addition of hexane gave 6.7 g of the pure carbamate, m.p. 80°-85° C. IR: NH at 3200 cm-1, carbonyl at 1745 cm-1. NMR: 2.4 ppm, 2×CH3, singlet, ArH 6.75 ppm 1H, singlet, 8.9 ppm, NH, broad.
Reaction SMILES: [CH3:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[C:4]([F:21])[C:3]=1[F:22].[Br:23]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:1][C:2]1[C:3]([F:22])=[C:4]([F:21])[C:5]([C:10]2[C:15]([F:16])=[C:14]([F:17])[C:13]([F:18])=[C:12]([F:19])[C:11]=2[F:20])=[C:6]([F:9])[C:7]=1[F:8]
Reactant: Cc1c(F)c(F)c(-c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1c(F)c(F)c(-c2c(F)c(F)c(CBr)c(F)c2F)c(F)c1F
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixed solution of a mixture comprising the 4-methylperfluorobiphenyl mentioned above, an N-bromo succinic imide (NBS) (26.7 g, 150 mmol), AIBN (0.99 g, 6 mmol) and a carbon tetrachloride (100 mL) was subjected to heating under reflux for 1 week. During this process, the progress of the reaction was confirmed by TLC, and NBS and AIBN were added on a timely basis. Ultimately, 285 mmol NBS and 15 mmol AIBN were added to the solution. After the reaction was completed, the solution was cooled to room temperature, and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate=100:1), and the 4-(bromomethyl)perfluorobiphenyl (7.36 g, 18 mmol, total yield from methyl lithium 60%) was isolated. 1H NMR (CDCl3, 300 MHz) δ 4.58 (s, 2H, CH2Br); 19F NMR (CDCl3, 282 MHz) δ−138.02 (dd, J=10.6, 19.8 Hz, 2F), −138.56 (dt, J=9.1, 20.3 Hz, 2F), −142.36 (dd, J=10.6, 19.8 Hz, 2F), −150.59 (t, J=20.3 Hz, 1F), −161.08 (dt, J=7.1, 20.3 Hz, 2F).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C:11](Cl)(Cl)Cl)[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:7]=2[CH:21]=1.[CH3:22][CH:23]([CH3:43])[CH2:24][NH:25][C@@H:26]1[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][C@H:28]([C:39]([O:41]C)=[O:40])[CH2:27]1.C(=O)([O-])[O-:45].[K+].[K+]>C(#N)C.O>[C:35]([O:34][C:32]([N:30]1[CH2:31][C@@H:26]([N:25]([C:11]([C:9]2[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])[C:7]3[CH:21]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=3[N:10]=2)=[O:45])[CH2:24][CH:23]([CH3:43])[CH3:22])[CH2:27][C@@H:28]([C:39]([OH:41])=[O:40])[CH2:29]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Reactant: O=C([O-])[O-]
Reactant: COCCCCn1c(C(Cl)(Cl)Cl)nc2ccc(OC)cc21
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2ccc(OC)cc21
Temperature: 80 °C
Reaction time: 19 h
Yield: 25.3 %

Procedure:
6-Methoxy-1-(4-methoxybutyl)-2-(trichloromethyl)-1H-benzimidazole (1.42 g) was dissolved in acetonitrile-water (2:1, 150 ml), 1-tert-butyl 3-methyl (3R,5S)-5-{(2-methylpropyl)amino}piperidine-1,3-dicarboxylate (1.02 g) was added, potassium carbonate (5.5 g) was added and the mixture was stirred at 80° C. for 19 hr. The reaction mixture was concentrated under reduced pressure, acidified (pH3) with 6M hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-hexane (5:95)-ethyl acetate-ethyl acetate-methanol (85:15) was concentrated under reduced pressure. The residue was subjected to reversed-phase preparative HPLC, and a fraction eluted with water-acetonitrile (9:1-6:4) was collected, basified (pH 10) with saturated aqueous potassium carbonate solution, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object product (460 mg).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=O)=[CH:22][CH:21]=2)[C:10]1=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:7])[CH2:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27](=[O:29])[NH:31][CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[CH:22][CH:21]=2)[C:10]1=[O:30])([CH3:3])([CH3:2])[CH3:4]
Reactant: NCCc1ccccc1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccc(CC(=O)O)cc2)c(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)Cn1c(=O)n(-c2ccc(CC(=O)NCCc3ccccc3)cc2)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A stirred suspension of [4-(1-tert-butoxycarbonylmethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-acetic acid (Intermediate F) (932 mg, 2.27 mmol), 2-(aminoethyl)benzene (1.2 eq, 344 mg, 2.72 mmol) and HATU (1.2 eq, 1.035 g. 2.72 mmol) in DCM (8 ml) is treated with DIPEA (2 eq, 711 μL, 4.54 mmol). The reaction mixture is stirred at RT for 48 hours. The mixture is diluted with distilled water (5 ml) followed by 0.1 M HCl (5 ml) and extracted with EtOAc (2×15 ml). The combined organic portions are washed with aqueous saturated aqueous NaHCO3, dried (MgSO4) and concentrated in vacuo.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][O:13][CH2:14][CH2:15]Cl.[OH-].[Na+].[I-].[Na+]>C(O)C.C1(C)C=CC=CC=1.O>[CH3:12][O:13][CH2:14][CH2:15][O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COCCCl
Reactant: Oc1cccc2ccccc12
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COCCOc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
In 100 g of ethanol were dissolved 50.0 g (0.0347 mol) of 1-naphthol, 34.4 g (0.0364 mol) of 2-methoxyethyl chloride, 14.6 g (0.0365 mol) of sodium hydroxide, and 2.6 g (0.017 mol) of sodium iodide. The solution was heated and stirred at 80° C. for 8 hours. After cooling, the solution was combined with 100 g of water and 200 g of toluene, from which an organic layer was separated. It was washed 5 times with 100 g of 5 wt % sodium hydroxide aqueous solution and then 4 times with 100 g of water. The organic layer was concentrated, obtaining 45 g of oily matter. On vacuum distillation (110° C./13 Pa), 41 g of the target compound was recovered (yield 58%).
Reaction SMILES: [CH2:1]1[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[C:6]([C:13]([OH:15])=O)=[CH:5][CH:4]=[C:3]3[CH2:2]1.C1C2=C3C(=CC=C2)C(C(Cl)=O)=CC=C3C1.[CH3:31][O:32][CH2:33][CH2:34][N:35]1[C:39]([CH3:40])=[C:38]([CH3:41])[S:37][C:36]1=[NH:42].CCN(CC)CC>S(Cl)(Cl)=O.C1COCC1>[CH3:31][O:32][CH2:33][CH2:34][N:35]1[C:39]([CH3:40])=[C:38]([CH3:41])[S:37]/[C:36]/1=[N:42]\[C:13]([C:6]1[C:7]2[C:12]3[C:3]([CH2:2][CH2:1][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:5]=1)=[O:15]
Reactant: COCCn1c(C)c(C)sc1=N
Reactant: O=C(O)c1ccc2c3c(cccc13)CC2
Agent: O=C(Cl)c1ccc2c3c(cccc13)CC2
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1ccc2c3c(cccc13)CC2
Yield: 21.8 %

Procedure:
The acenaphthene-5-carboxylic acid (Aldrich, 0.29 g, 1.4 mmol) in 5 mL of thionyl chloride was converted to acenaphthene-5-carbonyl chloride using the method described in Example 134A. The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.3 mL, 2.2 mmol) and acenaphthene-5-carbonyl chloride in 30 mL THF were processed as in Example 134B to afford the title compound (87 mg, 0.24 mmol, 22% yield). 1H NMR (300 MHz, CD3OD) δ ppm 2.28 (d, J=0.7 Hz, 3H), 2.33 (d, J=0.7 Hz, 3H), 3.33 (s, 3H), 3.42 (s, 4H), 3.84 (t, J=5.3 Hz, 2H), 4.51 (t, J=5.3 Hz, 2H), 7.30-7.36 (m, 2H), 7.52 (dd, J=8.6, 7.0 Hz, 1H), 8.43 (d, J=7.5 Hz, 1H), 8.81 (d, J=8.8 Hz, 1H); MS (DCI/NH3) m/z 367 (M+H)+; Anal. calculated for C21H22N2O2S: C, 68.82; H, 6.05; N, 7.64. Found: C, 68.63; H, 5.72; N, 7.40.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH:6]([OH:8])[CH2:5][CH:4]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[Cl:16])[C:3]1=[O:17].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([N:31]=[C:32]=[S:33])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>CC(N(C)C)=O.C(OCC)(=O)C>[Cl:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[CH:4]1[CH2:5][CH:6]([OH:8])[CH2:7][N:2]([NH:1][C:32](=[S:33])[NH:31][CH:28]2[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:24])[CH2:30][CH2:29]2)[C:3]1=[O:17]
Reactant: NN1CC(O)CC(c2ccc(F)cc2Cl)C1=O
Reactant: CC(C)(C)OC(=O)N1CCC(N=C=S)CC1
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCC(NC(=S)NN2CC(O)CC(c3ccc(F)cc3Cl)C2=O)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of (3SR,5SR)-1-amino-3-(2-chloro-4-fluorophenyl)-5-hydroxypiperidin-2-one (0.8 g, 2.9 mmol) in dimethylacetamide (1 mL) was added 4-isothiocyanatopiperidine-1-carboxylic acid tert-butyl ester (0.8 g, 3.2 mmol, US2006/14958A1) and the reaction stirred for 2 hours at 80° C. The reaction was diluted with ethyl acetate, washed with water, brine, dried with sodium sulfate and the solvent was evaporated in vacuo. The product was triturated from dichloromethane by addition of heptane to afford the title compound as a colourless powder (1.2 g, 83%). MS ISP (m/e): 501.2 [(M+H)+].