Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5].[C:17]([N:25]=[C:26]=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCOCC>[C:17]([NH:25][C:26]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:5])=[S:27])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1ccccc1C(=O)Nc1ccccc1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CCOCC
Product: O=C(NC(=S)Nc1ccccc1C(=O)Nc1ccccc1)c1ccccc1
Yield: 97.8 %

Procedure:
To a stirred mixture of 10 g of 2-amino-N-phenylbenzamide and 500 ml of ether was added dropwise, a solution of 7.7 g of benzoyl isothiocyanate in 100 ml of ether over 20 minutes. After standing several hours the solid was collected, giving 17.3 g of 2-[[(benzoylamino)thioxomethyl]amino]-N-phenylbenzamide.
Reaction SMILES: [Br:1]C1CC2C(=CC=CC=2F)C1=O.[Cl:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[Cl:23])[C:19](=[O:24])[CH2:18][CH2:17]2>[Cu](Br)Br.O1CCOCC1>[Br:1][CH:18]1[CH2:17][C:16]2[C:20](=[CH:21][C:22]([Cl:23])=[C:14]([Cl:13])[CH:15]=2)[C:19]1=[O:24]
Reactant: O=C1CCc2cc(Cl)c(Cl)cc21
Reactant: O=C1c2cccc(F)c2CC1Br
Agent: Br[Cu]Br
Solvent: C1COCCO1
Product: O=C1c2cc(Cl)c(Cl)cc2CC1Br

Procedure:
The 2-bromo-5,6-dichloro-1-indanone is prepared as in Example 14 for the preparation of 2-bromo-4-fluoro-1-indanone but starting with 5.48 g of 5,6-dichloro-1-indanone, 16.1 g of copper bromide and 175 ml of dioxane. After purifying by silica column chromatography with an ethyl acetate-cyclohexane mixture (10-90 by volume) as eluent, 4.07 g of 2-bromo-5,6-dichloro-1-indanone are obtained which melt at 85° C.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([CH3:19])[CH2:3][C:4]([NH:6][NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=O.C([N+](CC)(CC)S(NC(=O)OC)(=O)=O)C>O1CCCC1>[CH2:3]([C:4]1[O:18][C:8]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[N:7][N:6]=1)[C:2]([CH3:20])([CH3:19])[CH3:1]
Reactant: CC(C)(C)CC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Solvent: C1CCOC1
Product: CC(C)(C)Cc1nnc(-c2ccc([N+](=O)[O-])cc2)o1
Temperature: 120 °C

Procedure:
A mixture of N′-(3,3-dimethylbutanoyl)-4-nitrobenzohydrazide (0.556 g, 1.991 mmol) and methyl N-(triethylammoniumsulfonyl)carbamate (0.572 g, 2.389 mmol) in tetrahydrofuran (10 ml) was heated to 120° C. in a microwave for 45 minutes. The crude reaction mixture was concentrated and purified by normal phase chromatography to give the title compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:22][CH2:23][CH2:24][CH3:25])[N:9]([CH:12]2[C:20]3[C:15](=[CH:16][C:17]([Br:21])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[C:10]=1[Cl:11])=O)C.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl>[Br:21][C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[CH:12]([N:9]1[C:10]([Cl:11])=[C:6]([CH2:4][OH:3])[N:7]=[C:8]1[CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14]2
Reactant: CCCCc1nc(C(=O)OCC)c(Cl)n1C1CCc2cc(Br)ccc21
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CCCCc1nc(CO)c(Cl)n1C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 92.3 %

Procedure:
To a solution of 1-(5-bromo-indan-1-yl)-2-butyl-5-chloro-1H-imidazole-4-carboxylic acid ethyl ester (486 mg, 1.13 mmol)in CH2Cl2 (5.0 mL) at 0° C. was added diisobutylaluminum hydride (Dibal-H) (1M solution in CH2Cl2, 5.0 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 0.75 hour, carefully quenched with saturated aqueous NH4Cl (1 mL) and diluted with CH2Cl2 (100 mL). The organic solution was separated and washed with saturated aqueous NaHCO3 (2×10 mL), saturated aqueous NaCl (2×10 mL), dried (MgSO4) and concentrated in vacuo. The crude residue was chromatographed on SiO2 -gel using 100% EtOAC to give 400 mg of a colorless oil. 1H NMR (250 MHz, d6 -DMSO): d 7.55 (s, 1 H), 7.36 (d, 1 H), 6.83 (d, 1 H), 5.95 (t, 1 H), 4.85 (bs, 1 H), 4.18 (s, 2 H), 3.05 (m, 2 H), 2.70 (m, 3 H), 2.26 (m, 1 H), 1.64 (m, 2 H), 1.30 (m, 2 H), 0.90 (m, 3 H).
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:14][CH2:15][S:16][CH3:17])[C:6]1=[O:18])(=O)[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:1]([NH:4][C@@H:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:14][CH2:15][S:16][CH3:17])[C@H:6]1[OH:18])[CH3:2]
Reactant: CSCOc1cccc2c1CC(NC(C)=O)C2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCN[C@@H]1Cc2c(OCSC)cccc2[C@H]1O

Procedure:
The residue from Step D is dissolved in 50 ml of THF and added to 3.8 g (0.1 m) of LiAlH4 in 50 ml of THF dropwise. The mixture is refluxed for one hour after completion of the addition. The mixture is cooled and sufficient saturated aqueous Na2SO4 solution is added to quench the excess LiAlH4. Methylene chloride and solid anhydrous Na2SO4 is added and the mixture is filtered. Concentration provides the crude product.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][C:14]([SH:16])=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][C:20]=1[C:27]([F:30])([F:29])[F:28]>>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][S:16][C:14]2[O:15][C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:12][N:13]=2)=[CH:21][C:20]=1[C:27]([F:28])([F:30])[F:29]
Reactant: COc1ccc(CBr)cc1C(F)(F)F
Reactant: Sc1nnc(-c2ccc3ncccc3c2)o1
Product: COc1ccc(CSc2nnc(-c3ccc4ncccc4c3)o2)cc1C(F)(F)F
Yield: 74 %

Procedure:
In the same manner as in Example 7 and using 5-(6-quinolyl)-1,3,4-oxadiazole-2-thiol instead of 5-(1H-indazol-5-yl)-1,3,4-oxadiazole-2-thiol and 4-methoxy-3-(trifluoromethyl)benzyl bromide instead of 3-(trifluoromethyl)benzyl chloride, the title compound (yield 74%) was obtained as colorless crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10]C)=[O:9])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:21][C:22]1[NH:23][CH:24]=[CH:25][N:26]=1.C(OCC)(=O)C>CN1CCCC1=O>[CH3:21][C:22]1[N:23]([C:2]2[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][CH:3]=2)[CH:24]=[CH:25][N:26]=1
Reactant: Cc1ncc[nH]1
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1nccn1-c1ccc(C(=O)O)cn1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A mixture of methyl 6-chloropyridine-3-carboxylate (0.75 g), N,N-diisopropyl-ethyl-amine (1.75 mL) and 2-methyl-1H-imidazole (0.58 g) in N-methylpyrrolidone (6 mL) is heated to 100° C. overnight. Additional 2-methyl-1H-imidazole (0.58 g) is added and the reaction continues at 100° C. for two days. Ethyl acetate is added and the mixture is washed with saturated ammonium chloride. The organic phase is dried over MgSO4 and concentrated in vacuo. The crude ester is dissolved in MeOH (4 mL) and KOH (1.5 g) in water (2 mL) is added and kept at room temperature for 2 h. The MeOH is removed in vacuo and the aqueous phase is acidified with 1N HCl and extracted with dichloromethane. The organic phase is dried over MgSO4 and concentrated to afford the title compound. LC (method 20): tR=0.51 min; Mass spectrum (APCI): m/z=204 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[S:14][C:13]3[C:12]([C:15]#[N:16])=[CH:11][N:10]=[C:9]([NH:17]CC4C=CC(OC)=CC=4)[C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH:27]S(O)(=O)=O>>[NH2:17][C:9]1[C:8]2[CH:7]=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[S:14][C:13]=2[C:12]([C:15]([NH2:16])=[O:27])=[CH:11][N:10]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(CNc2ncc(C#N)c3sc(-n4ccnc4)cc23)cc1
Product: NC(=O)c1cnc(N)c2cc(-n3ccnc3)sc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 2-imidazol-1-yl-4-(4-methoxy-benzylamino)-thieno[3,2-c]pyridine-7-carbonitrile 37 (0.050 g, 0.14 mmol) was added H2SO4 (0.25 mL). After stirring at room temperature for 1 h, 2 g of ice were added to the solution. The precipitate was filtered, washed with H2O, then dissolved in 30% methanol, 2.5% triethylamine in CH2Cl2. The solution was concentrated, the solid was suspended in H2O, then filtered and rinsed with H2O resulting in pure 38. 1H NMR (400 MHz, d6-DMSO) δ 8.57 (s, 1H), 8.17 (s, 1H), 8.02 (bs, 1H), 7.77 (s, 1H), 7.67 (bs, 1H), 7.39 (bs, 1H), 7.18 (m, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:3]=1.[I:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([C:4]2[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([N:23]3[CH:24]=[C:20]([I:19])[N:21]=[CH:22]3)[N:3]=2)=[CH:13][CH:14]=1
Reactant: Ic1c[nH]cn1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccc(Cl)cc2)c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)nc(-n2cnc(I)c2)c1

Procedure:
The title compound was prepared 2-chloro-6-(4-chloro-phenyl)-4-trifluoromethyl-pyridine (example A.16) (10.14 g, 35 mmol) and commercially available 4-iodo-imidazole (8.081 g, 42 mmol) according to the general procedure IVa. Obtained as a white solid (2.80 g, 18%). MS (ISP) 450.0 [(M+H)+] and 452 [(M+2+H)+].
Reaction SMILES: C(OP([CH:9]([F:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])(OCC)=O)C.[CH3:16][C:17]1([CH3:32])[CH:19](/[CH:20]=C(\Br)/C(OCCC)=O)[CH:18]1[C:29]([OH:31])=[O:30].[H-].[Na+].P(O)(O)([O-])=O.[Na+]>COCCOC>[CH3:16][C:17]1([CH3:32])[CH:19](/[CH:20]=[C:9](/[F:15])\[C:10](=[O:11])[O:12][CH2:13][CH3:14])[CH:18]1[C:29]([OH:31])=[O:30]
Reactant: CCCOC(=O)/C(Br)=C/C1C(C(=O)O)C1(C)C
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)/C(F)=C\C1C(C(=O)O)C1(C)C
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
A solution of 7.7 g of ethyl diethyl-phosphono-fluoroacetate (prepared by process of Ann. Chem., 1964, p. 6741), 60 ml of 1,2-dimethoxyethane and 4 g of (1R, trans) 2,2-dimethyl-3-formyl-cyclopropane-carboxylic acid was added over 30 minutes at 2° to 10° C. to a suspension of 2.6 g of a 60% sodium hydride in oil suspension and 60 ml of 1,2-dimethoxyethane and the mixture was stirred at 5° C. for 15 minutes, and then at room temperature for 3 hours. The resulting solution was poured into aqueous monosodium phosphate solution at 5° C. and the mixture was stirred for 10 minutes. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried and evaporated to dryness at 40° C. under reduced pressure to obtain 6.5 g of an oil residue. The latter was chromatographed over silica gel and was eluted with a 70-30-1 hexane-ethyl acetate-acetic acid mixture to obtain 4 g of (1R,trans) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxypropenyl]-cyclopropane-1-carboxylic acid
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH2:21][CH2:20][CH:19](O)[CH2:18][CH2:17]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8](=[CH:15][N:16]([CH3:21])[CH3:17])[CH2:9][C:10]([O:12][CH:19]2[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH2:18]2)=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: CN1CCC(O)CC1
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Product: CN(C)C=C(CC(=O)OC1CCN(C)CC1)C(=O)c1ccc(Cl)cc1

Procedure:
35.1 g of 1-methyl-4-piperidyl 3-p-chlorobenzoyl-4-dimethylamino-3-butenoate [obtainable by esterification of 3-p-chlorobenzoyl-propionic acid with 1-methyl-piperidin-4-ol to produce 1-methyl-4-piperidyl 3-p-chloro-benzoylpropionate and subsequent reaction of the latter with dimethylformamide dimethyl acetal in the presence of acetic acid at 120°] and 12 g of phenylhydrazine are warmed for 4 hours at 100°. The reaction mixture is subjected to the customary working up (benzene/water) and 1-methyl-4-piperidyl 5-p-chlorophenyl-1-phenyl-pyrazol-4-yl-acetate is obtained; m.p. 90°-93°. Hydrochloride, m.p. 234°-235°.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13]C)=[O:12])=[CH:6][CH:5]=1.FC(F)(F)S(O[CH2:21][CH:22]([F:24])[F:23])(=O)=O.[Li+].[OH-].O.Cl>C1COCC1>[F:23][CH:22]([F:24])[CH2:21][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]([OH:13])=[O:12])=[CH:8][CH:9]=1
Reactant: COC(=O)Cc1ccc(O)cc1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(OCC(F)F)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 107.8 %

Procedure:
Step AX (1): Sodium hydride (60% in mineral oil, 1.70 g, 42.5 mmol) was carefully added portionwise to a solution of methyl 2-(4-hydroxyphenyl)acetate (7.06 g, 42.5 mmol) in THF (200 mL) maintained at 0° C. The cold bath was removed and the mixture was allowed to warm to rt and stir for 30 min. A solution of 2,2-difluoroethyl trifluoromethanesulfonate (10.0 g, 46.7 mmol) in THF (20 mL) was added and the resulting mixture was left to stir for 18 h. A solution of 2 N LiOH/water (40 mL, 80 mmol) was added to the crude reaction mixture and the resulting solution stirred at rt for 3 h. The reaction mixture was poured into 1 N HCl (250 mL) and extracted with Et2O. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. The residue was triturated with hexane. The crystalline solid was collected by vacuum filtration to afford 2-(4-(2,2-difluoroethoxy)phenyl)acetic acid (9.90 g, 45.8 mmol, 108% yield) as an off-white solid. LC-MS (M−H)− 215.1. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.23 (d, J=8.5 Hz, 2 H), 6.89 (d, J=8.5 Hz, 2 H), 6.03-6.14 (m, 1 H), 4.18 (td, J=13.0, 4.1 Hz, 2 H), 3.61 (s, 2 H).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[N:16][C:5]2[NH:6][C:7]3[CH2:15][CH:14]4[N:10]([CH2:11][CH2:12][CH2:13]4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:31][CH2:32][C:33]2[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:17]=[N:16][C:5]2[N:6]([CH2:31][CH2:32][C:33]3[CH:34]=[N:35][C:36]([CH3:39])=[CH:37][CH:38]=3)[C:7]3[CH2:15][CH:14]4[N:10]([CH2:11][CH2:12][CH2:13]4)[CH2:9][C:8]=3[C:4]=2[CH:3]=1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C)nc2)CC2CCCN2C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-methyl-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine (80 mg, 0.352 mmol) in DMF (1 mL) was added a suspension of NaH (42.0 mg, 1.05 mmol) in DMF (1 mL). After stirring for 5 min at rt, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (307 mg, 1.05 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 2 h. The progress of reaction was monitored by TLC and LCMS. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by reverse phase HPLC to yield 3-methyl-11-(2-(6-methylpyridin-3-yl)ethyl)-7,8,9,9a,10,11-hexahydro-5H-pyrido[3′,2′:4,5]pyrrolo[3,2-f]indolizine;
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:25]([OH:27])=[O:26])[CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(=O)([O-])[O-].[Ca+2].C(OCC)(=O)C.O.[CH2:40](Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C)C=O>[CH2:40]([O:26][C:25](=[O:27])[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[NH:11][C:1]([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The reaction sequence is shown in FIG. 5. Nε-(tert-butoxycarbonyl)-L-lysine (2 g, 8.12 mmol) was dissolved in methanol (40 ml) and water (40 ml), and the pH was adjusted to 8 with triethylamine. A solution of N-(benzyloxycarbonyl-oxy)succinimide in dioxane (2.4 g, 9.7 mmol in 20 ml) was added to the above mixture and the pH was maintained at 8-9 with triethylamine. The reaction mixture was stirred overnight. The solvent was removed by rotary evaporation to obtain crude Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine. Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine was treated with 0.2 M calcium carbonate (4 ml) and the aqueous layer was removed to obtain a white solid. The solid was resuspended in N,N-dimethylformamide(40 ml) and benzyl bromide (1.16 ml). The reaction mixture was stirred overnight at room temperature. The reaction mixture was worked up with ethyl acetate and water, and the organic layer was dried over magnesium sulphate. The solvent was removed to obtain crude Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine benzyl ester which was purified by silica gel chromatography using 25% hexane in ethyl acetate as a solvent. To Nα-CBZ-Nε-(tert-butoxycarbonyl)-L-lysine benzyl ester (1 g, 2.2 mmol) in methylene chloride (10 ml) was added trifloroacetic acid at 0° C. The reaction mixture was stirred for 10 minutes at 0° C., then stirred for further 2.5 hr at room temperature. The solvent was removed and the crude product was obtained. Pure Nα-CBZ-L-lysine benzyl ester was obtained by silica gel chromatography.
Reaction SMILES: C([Si](C)(C)[O:6][C@@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[CH2:9][CH2:8]1)(C)(C)C.[Li+].CC([N-]C(C)C)C.[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Br)=[C:32]([Cl:38])[CH:31]=1.Cl>CO.O.C1COCC1>[Br:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][CH:15]2[CH2:16][CH2:17][N:13]([C@H:10]3[CH2:9][CH2:8][C@@H:7]([OH:6])[CH2:12][CH2:11]3)[C:14]2=[O:18])=[C:32]([Cl:38])[CH:31]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@H](N2CCCC2=O)CC1
Reactant: Clc1cc(Br)ccc1CBr
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C1C(Cc2ccc(Br)cc2Cl)CCN1[C@H]1CC[C@@H](O)CC1
Temperature: -78 °C

Procedure:
Charge a flask with cis-1-[4-(tert-butyl-dimethyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (Preparation 17) (1.0 g, 3.4 mmol), dissolve with THF (0.2 M) and cool to −78° C. Add LDA (1.1 to 1.5 eq) and stir at −78° C. for 5 minutes. Add 4-bromo-1-bromomethyl-2-chloro-benzene (1.4 g, 5.0 mmol) and warm to room temperature overnight. Dilute with methanol (0.2 M) and add concentrated HCl (10 eq.) and stir at room temperature. Pour into water after reaction complete by HPLC and extract with methylene chloride, dry over sodium sulfate, filter and concentrate in vacuo. Purify the residue over silica gel (20% hexane in ethyl acetate) to afford 911 mg (70%) of the title compound: Mass spectrum (apci) m/z=387.9 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][NH:6]1.CCN(C(C)C)C(C)C.[C:29](Cl)(=[O:32])[O:30][CH3:31]>C(Cl)Cl>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][CH:5]1[CH2:10][CH:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][CH2:7][N:6]1[C:29]([O:30][CH3:31])=[O:32]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(Cc2c(F)cccc2F)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(Cc2c(F)cccc2F)C1
Yield: 98.2 %

Procedure:
Methyl 2-(2,6-difluorobenzyl)piperidine-4-carboxylate (5.008 g, 18.60 mmol) was dissolved in DCM (121 mL) and DIPEA (3.89 mL, 22.32 mmol) followed by methyl carbonochloridate (2.050 mL, 26.04 mmol) were added. After 3.5 h at room temperature the solution was washed with 0.1 M HCl and satd NaHCO3. The organic phase was dried and concentrated to yield dimethyl 2-(2,6-difluorobenzyl)piperidine-1,4-dicarboxylate (5.98 g, 98%). MS m/z 328 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:27])[C:11]([O:25][CH3:26])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=3[CH3:22])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].O>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:27])[C:11]([O:25][CH3:26])=[C:12]([CH2:14][NH:15][C:16]3[C:17]([CH3:24])=[C:18]([CH:19]=[CH:20][C:21]=3[CH3:22])[O:23][CH2:35][C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)CBr
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(C)ccc(O)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: O
Product: COc1c(C)cc(-c2cccc(F)c2)cc1CNc1c(C)ccc(OCC(=O)OC(C)C)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.4 %

Procedure:
To a solution of 3-[[5-(3-fluorophenyl)-2-methoxy-3-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (115 mg, 0.31 mmol, 1.0 eq) in acetone (4 mL) was added Cs2CO3 (154 mg, 0.47 mmol, 1.5 eq). The reaction mixture was stirred for 30 min at room temperature then isopropyl bromoacetate (68.4 mg, 0.38 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 2 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether:EtOAc 30:1 to 20:1) to give the title compound as a colorless oil (155 mg, 100%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH:10]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=[C:25]([CH3:33])[CH:24]=3)=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4].[OH-].[Li+].Cl>C1COCC1.CO.O.C(OCC)(=O)C>[CH3:33][C:25]1[CH:24]=[C:23]([CH2:22][O:21][C:18]2[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:10]3[CH2:9][CH2:8][O:7][CH2:6][CH:5]3[C:3]([OH:4])=[O:2])(=[O:13])=[O:14])=[CH:16][CH:17]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1
Reactant: COC(=O)C1COCCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CCOCC3C(=O)O)cc2)c2ccccc2n1

Procedure:
A solution of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid methyl ester (0.3 g, 0.64 mmol) and lithium hydroxide (0.153 g, 6.38 mmol) in THF:methanol:H2O (2.5: 1.5:1.5 mL) was stirred at 25° C. for 19 h. The solution was diluted with ethyl acetate (2×30 mL) and the aqueous layer was acidified with 2N HCl to pH ˜2. The aqueous layer was washed with ethyl acetate (3×40 mL). The combined organic layers were dried over MgSO4, filtered and concentrated to provide 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic acid as a crude solid (0.280 g, 97%). MS: 457 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[S:20][CH2:21][CH2:22][N:23]=1>>[S:20]1[CH2:21][CH2:22][N:23]=[C:19]1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: NC1=NCCS1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Product: FC(F)(F)c1cc(NC2=NCCS2)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethyl-pyrimidine (75 mg, 0.289 mmol) and 2-amino-2-thiazoline (37 mg, 0.362 mmol) similar to Example 166 and was isolated as a white solid (20 mg, 0.61 mmol, 21%). 1H NMR (CDCl3/MeOH-d4) 9.45 (s, 1H), 8.73 (dt, 1.8, 8.1 Hz, 1H), 8.58 (dd, J=1.8, 5.1 Hz, 1H), 7.47 (m, 1H), 6.70 (s, 1H), 3.93 (t, J=6.6 Hz, 2H), 3.04 (t, J=7.2 Hz, 2H).