Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH2:3][C@H:4]([C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[N:13]=2)=[CH:10][N:11]=1)[CH2:5][OH:6].C(N(CC)CC)C.Cl[C:27](Cl)([O:29]C(=O)OC(Cl)(Cl)Cl)Cl.O>C(Cl)(Cl)Cl>[Br:18][C:14]1[N:13]=[C:12]([C:9]2[S:8][C:7]([C@@H:4]3[CH2:5][O:6][C:27](=[O:29])[NH:3]3)=[N:11][CH:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: N[C@@H](CO)c1ncc(-c2cccc(Br)n2)s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1N[C@H](c2ncc(-c3cccc(Br)n3)s2)CO1
Temperature: -78 °C
Reaction time: 2 h
Yield: 232.2 %

Procedure:
To a solution of (S)-2-amino-2-[5-(6-bromopyridin-2-yl)thiazol-2-yl]ethanol dihydrochloride (1.00 g, 2.68 mmol) obtained in Step 3, triethylamine (3.7 ml, 2.68 mmol) in chloroform (15 ml), a solution of triphosgene (278 mg, 0.94 mmol) in chloroform (5 ml) was added dropwise while cooled to −78° C., and the mixture was stirred at the same temperature for 2 hours. The reaction solution was warmed to room temperature and water was added and it was extracted with ethyl acetate. After washed with a saturated brine, the organic layer was dried over magnesium sulfate. After concentrated, the residue was purified by flash chromatography on silica gel (chloroform:methanol:ethyl acetate=15:1:1) and the title compound (712 mg, 82%) was obtained.
Reaction SMILES: O1CCOCC1.CO.C([O:11][C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]1[S:19][C:20]2[C:26]([F:27])=[CH:25][C:24]([F:28])=[C:23]([F:29])[C:21]=2[N:22]=1)C.[OH-].[Na+]>O>[F:29][C:23]1[C:21]2[N:22]=[C:18]([S:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]([OH:30])=[O:11])[S:19][C:20]=2[C:26]([F:27])=[CH:25][C:24]=1[F:28]
Reactant: CCOC(=O)CCCCSc1nc2c(F)c(F)cc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)CCCCSc1nc2c(F)c(F)cc(F)c2s1
Yield: 26.5 %

Procedure:
To a mixture of dioxane (5 ml), methanol (2.5 ml) and water (2.5 ml) was added 5-(4,5,7-trifluorobenzothiazol-2-ylthio)pentanoic acid ethyl ester (590 mg, 2 mmol) and sodium hydroxide (100 mg, 2.5 mmol) and the resultant mixture was stirred for 15 hours at room temperature. The reaction mixture was diluted with water and washed with ether. The aqueous phase was then acidified with 7% hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with an aqueous saturated saline solution, dried and then evaporated. The resulting oily residue was purified on a silica gel column and crystallized from hexane-isopropyl ether to give 5-(4,5,7-trifluorobenzothiazol-2-ylthio)pentanoic acid (170 mg, 31%) as a colorless powder.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][C:14]([C:17](OC)=[O:18])=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([C:7](OC)=[O:8])=[CH:3][CH:2]=1.C1COCC1.O>C(Cl)Cl>[C:11]1([C:1]2[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=2)[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(-c2ccc(C(=O)OC)cc2)cc1
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc(C=O)cc2)cc1
Reaction time: 4.5 h
Yield: 86.1 %

Procedure:
Next, 27.1 g (0.10 mole) of dimethyl 4,4′-biphenyldicarboxylate and 133.4 g of THF were introduced to a 2000-ml four-necked reaction vessel. To this solution was added the reagent solution prepared above in drops at 5° C. or below. After the dropwise addition, stirring was continued at 15° C. for 4.5 hours. Upon completion of the reaction, extraction was performed by adding in drops 622.2 g of methylene chloride and 411.2 g of water. The methylene chloride layer obtained was concentrated until dryness under reduced pressure. The residue was dissolved in acetone by adding 303.2 g of acetone in drops and then 1600.3 g of water was added in drops at 20° C. Thereafter, the mixture was stirred day and night at 5° C. and a solid was recovered by filtration. The solid thus obtained was washed with acetone and dried under reduced pressure to give 18.1 g of 4,4′-biphenyldicarboxaldehyde.
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[CH:9]=[C:8]([SH:10])[N:7]=[CH:6][N:5]=1.[C:11]1([CH3:21])C=CC(S([O-])(=O)=O)=CC=1.[CH2:22]([OH:24])C.O>>[NH2:3][C:4]1[CH:9]=[C:8]([S:10][CH2:21][CH2:11][O:24][CH3:22])[N:7]=[CH:6][N:5]=1
Reactant: CCO
Reactant: Nc1cc(S)ncn1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCSc1cc(N)ncn1
Temperature: 60 °C
Yield: 80 %

Procedure:
20 g of sodium hydroxide (0.5 mol) are dissolved in 500 ml of ethanol/water at 1:1. 63.5 g of 4-amino-6-mercaptopyrimidine (0.5 mol) are added to the solution and the temperature of the solution is brought to 60° C. 115 g of p-toluene sulphonate of β-methoxyethyl (0.5 mol) are added drop by drop over 30 minutes, maintaining the temperature at 60° C. with a water bath. The addition terminated, the reaction mixture is refluxed for three hours. Then the solvent is evaporated and the residue is recovered with 250 ml of water. The aqueous solution is repeatedly extracted with chloroform (6×100 ml) and the amalgamated extracts are evaporated until dry. The solid residue is crystallised from ethyl acetate plus petroleum ether. 74 g of product are obtained (80% yield) with a melting point of 78°-80° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[Cl:8][C:9]1[CH:10]=[C:11]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1>C(O)C>[CH2:6]([O:5][C:1](=[O:4])[CH:2]([N:18]1[CH2:17][CH2:16][N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[CH:10]=2)[CH2:20][CH2:19]1)[CH3:3])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: Clc1cccc(N2CCNCC2)c1
Solvent: CCO
Product: CCOC(=O)C(C)N1CCN(c2cccc(Cl)c2)CC1
Reaction time: 0.67 h

Procedure:
Over a period of 40 minutes, 108 ml of ethyl acrylate are added to 38.3 g of N-(3-chlorophenyl)piperazine dissolved in 300 ml of anhydrous ethanol and 0.5 ml of Triton B. The temperature reaches 40° C. when addition is complete. After heating at reflux for 3 hours, the reaction mixture is concentrated in vacuo and the residue is distilled. 139 g of 4-(3-chlorophenyl)piperazin-1-ylpropionic acid ethyl ester are obtained, b.p/0.33 mmHg=176°-179° C.
Reaction SMILES: [Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5]([O:8]C)[O:4]1.C(O)(C)C.[C:14]1([CH3:24])[CH:19]=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][CH2:2][C@@H:3]1[CH2:7][O:6][C@@H:5]([O:8][CH:14]([CH3:19])[CH3:24])[O:4]1
Reactant: CO[C@@H]1OC[C@@H](CBr)O1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CC(C)O
Product: CC(C)O[C@@H]1OC[C@@H](CBr)O1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of cis and trans 4-(bromomethyl)-2-methoxy-1,3-dioxolane (example 1) (5.37 g, 27.3 mmol) in benzene (100 mL) was added isopropanol (2.2 mL, 28.6 mmol, 1.05 eq.) and p-toluenesulfonic acid (pTSA, few crystals). The mixture was stirred for 24 hr at 88°-90° C. followed by addition of isopropanol (0.5 mL, 0.24 eq.). The mixture was stirred for further 24 hr at 90° C., cooled to room temperature and benzene was removed under reduced pressure. The crude material was obtained in quantitative yield consisting of a mixture of isopropoxy and methoxy orthoesters in a 9:1 ratio respectively. The ratio of cis and trans isomers was about 1:1.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[CH:6][N:5]=[CH:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].[CH:19](=O)[CH3:20].FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.O>[CH2:19]([N:8]([CH:9]1[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1)[C:7]1[C:2]([CH3:1])=[C:3]([C:15]([O:17][CH3:18])=[O:16])[CH:4]=[N:5][CH:6]=1)[CH3:20]
Reactant: COC(=O)c1cncc(NC2CCOCC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCN(c1cncc(C(=O)OC)c1C)C1CCOCC1
Reaction time: 16 h
Yield: 62.6 %

Procedure:
To a stirred solution of methyl 4-methyl-5-[(oxan-4-yl)amino]pyridine-3-carboxylate (600 mg, 2.40 mmol) in DCE (20 ml) under a nitrogen atmosphere was added acetaldehyde (1.07 ml, 19.2 mmol) followed by trifluoroacetic acid (367 μl, 4.79 mmol) and the reaction was left to stir for 5 min before the addition of sodium triacetoxyborohydride (3.05 g, 14.4 mmol). The reaction was stirred for 16 h at room temperature after which time more acetaldehyde (500 μl) and sodium triacetoxyborohydride (1.0 g) were added and the reaction stirred for a further 16 h. Distilled water (20 ml) was added and solid NaHCO3 was added until pH8. The phases were separated and then the aqueous phase was washed with DCM (2×50 ml), the combined organics were washed with brine (50 ml), dried using Na2SO4, filtered and evaporated. The residue was purified using a 25 g Isolute silica column using a gradient of 0% to 50% EtOAc in heptane to afford the title compound as a pale yellow oil (418 mg, 60%). LC-MS 96%, m/z=279.1, 1H NMR (500 MHz, Chloroform-d) δ 8.76 (s, 1H), 8.44 (s, 1H), 3.97 (d, J=11.0 Hz, 2H), 3.93 (s, 3H), 3.33 (td, J=11.6, 2.1 Hz, 2H), 3.13 (q, J=7.1 Hz, 2H), 3.04 (tt, J=10.9, 4.0 Hz, 1H), 2.54 (s, 3H), 1.76-1.59 (m, 4H), 0.89 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1C=[C:4]2[C:9](=[CH:10][CH:11]=1)C(S(O)(=O)=O)=CC=C2.[C:16]1(=[O:26])[O:21][C:19](=O)[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[Na+].[NH2:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[C:35]([S:39]([O-:42])(=[O:41])=[O:40])=[CH:34][CH:33]=[CH:32]2.C([NH+](CC)CC)C>N1C=CC=CC=1>[NH+:1]1[CH:2]=[CH:11][CH:10]=[CH:9][CH:4]=1.[C:19]1(=[O:21])[N:28]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[C:35]([S:39]([O-:42])(=[O:40])=[O:41])=[CH:34][CH:33]=[CH:32]3)[C:16](=[O:26])[C:17]2=[CH:25][CH:24]=[CH:23][CH:22]=[C:18]12
Reactant: Nc1ccc2c(S(=O)(=O)[O-])cccc2c1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc2c(S(=O)(=O)O)cccc2c1
Agent: CC[NH+](CC)CC
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1c1ccc2c(S(=O)(=O)[O-])cccc2c1
Product: c1cc[nH+]cc1
Reaction time: 16 h

Procedure:
223 g (1 mol) of 6-amino-1-naphthalenesulfonic acid and 148 g (1 mol) of phthalic anhydride are boiled for 0.5 h in 1 liter of pyridine. After boiling, the reaction mixture is left at room temperature for 16 h. The precipitated product is filtered and washed with pyridine and water, and then recrystallized from boiling water. Yield 298 g (69%); mp 234°-237° C.; Anal. Calcd. for C23H16N2SO5 :C 63.88, H 3.73, N 6.48, S 7.42; Found:C 63.74, H 3.81, N 6.52, S 6.99. When the 6-phthalimido-1-naphthalenesulfonic acid pyridinium salt was synthesized starting from 6-amino-1-naphthalenesulfonic acid sodium salt or triethylammonium salt, the calculated yields were 63% and 58% respectively.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=[O:12])=[CH:2]1.[OH-].[CH2:15]([N+](CC)(CC)C1C=CC=CC=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC>[CH2:15]([O:12][C:11](=[O:13])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC[N+](CC)(Cc1ccccc1)c1ccccc1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(Cc1c[nH]c2ccccc12)OCc1ccccc1
Yield: 80.4 %

Procedure:
Indole 3-acetic acid 1 (9.45 g, 0.054 mol) was dissolved in methanolic benzyl diethyl anilinium hydroxide (0.54 mol) and the solvent removed in vacuo. The oily residue of the benzyl dimethyl anilinium salt was agitated with benzene, the benzene evaporated and the salt refluxed in toluene (170 ml, 1 h). Traces of unreacted acid and dimethyl aniline by-product were removed by extracting the toluene solution with water, dilute hydrochloric acid (1N) and water. The organic layer was dried over sodium sulphate and concentrated in vacuo to obtain the crude product. Final purification was obtained by crystallization in EtOAc:Hexane to give 11.52 g (80%) indole-3-acetic acid benzyl ester 13 as white crystals (melting point 71°-72° C.); IR (Nujol, cm-1); 3 400, 1, 720; 1H-NMR (CDCl3,δ): 3.8 (s, 2 H), 5.1 (s, 2 H) 6.8-8.0 (m, 1 H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1.[F:15][CH:16]([F:33])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:20]=1[S:29](Cl)(=[O:31])=[O:30].N1C=C(C)C=C(C)C=1>CS(C)=O>[F:33][CH:16]([F:15])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[C:20]=1[S:29]([NH:1][C:2]1[N:10]=[C:9]2[N:4]([C:5]([O:13][CH3:14])=[N:6][CH:7]=[C:8]2[O:11][CH3:12])[N:3]=1)(=[O:30])=[O:31]
Reactant: O=S(=O)(Cl)c1c(OCC(F)F)cccc1C(F)(F)F
Reactant: COc1cnc(OC)n2nc(N)nc12
Agent: Cc1cncc(C)c1
Solvent: CS(C)=O
Product: COc1cnc(OC)n2nc(NS(=O)(=O)c3c(OCC(F)F)cccc3C(F)(F)F)nc12
Reaction time: 8.5 h
Yield: 93.1 %

Procedure:
2-Amino-5,8-dimethoxy[1,2,4]triazolo[1,5-c]pyrimidine (7.8 g, 0.040 mol) and 2-(2,2-difluoroethoxy)-6-(trifluoromethyl)benzenesulfonyl chloride (13 g, 0.040 mol) were combined in 3,5-lutidine (31 g, 0.29 mol). The slurry was treated with DMSO (0.040 g, 0.012 eq) and stirred at ambient conditions for 8.5 hours, with a slight rise in temperature noted in the first hours resulting from a reaction exotherm. The reaction slurry was filtered, and the wet cake solids were transferred to a separate vessel and slurried in a mixture of 15% sulfuric acid (80 mL) and acetonitrile (20 mL). The mixture was stirred for 25 minutes, then filtered and the solids washed with water. After drying under vacuum at 55° C., 18 g of product was obtained as a white solid assaying at 97 wt % (90% yield).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(C(C)C)C(C)C)C>CS(C)=O>[CH:7]([C:5]1[S:6][C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[CH:3][CH:4]=1)=[O:8]
Reactant: O=Cc1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C=O)s2)CC1
Temperature: 130 °C
Reaction time: 18 h
Yield: 72.5 %

Procedure:
A mixture of 5-bromothiophene-2-carboxaldehyde (3.82 g, 20.0 mmol), tert-butyl piperazine-1-carboxylate (4.1 g, 22.0 mmol), N-ethyl-N,N-diisopropylamine (7.0 ml, 40.0 mmol) and dimethylsulphoxide (5.0 ml) were stirred at 130° C. under an atmosphere of nitrogen for 18 h. The cooled mixture was partitioned between ethyl acetate and water. The organics were washed with water, brine, dried over magnesium sulphate and evaporated. The resultant dark red solid was purified by silica column chromatography, eluting with dichloromethane followed by ethyl acetate/dichloromethane (15%) to give tert-butyl 4-(5-formylthien-2-yl)piperazine-1-carboxylate (4.3 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>C(Cl)(Cl)Cl>[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[NH:31][C:32]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][N:7]=2)=[CH:17][CH:18]=1)=[O:33]
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C=Nc1ccc(F)cc1F
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)c2cc1OC
Yield: 72 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and 2,4-difluorophenyl isocyanate (24 μl) was then added to the solution. The mixture was heated under reflux overnight. The precipitated crystal was collected by filtration and was washed to give 55 mg (yield 72%) of the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ 3.98 (s, 3H), 3.99 (s, 3H), 7.04-7.08 (m, 2H), 7.24 (d, J=8.8 Hz, 2H), 7.29-7.35 (m, 1H), 7.38 (s, 1H), 7.54 (d, J=9.0 Hz, 2H), 7.56 (s, 1H), 8.06-8.14 (m, 1H), 8.51-8.54 (m, 1H), 8.54 (s, 1H), 9.11-9.12 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=2)=[CH:7][CH:6]=1.C(O)(=O)C.[CH2:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:25]3[CH2:26][C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24]3)[CH:12]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(-c2cccc(C=O)c2)cc1
Reactant: c1ccc2c(c1)CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(-c2cccc(CN3Cc4ccccc4C3)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.3 %

Procedure:
(3′-Formyl-biphenyl-4-yl)-acetic acid methyl ester (1.22 g), acetic acid (0.23 mL) and iso-indoline (0.48 g) were combined in methanol (10 mL). After 1 hour, sodium triacetoxyborohydride (1.27 g) was added and stirred for 18 hours, at room temperature, under nitrogen. The reaction was quenched with 0.880 ammonia solution and concentrated. The residue was dissolved in methanol and loaded onto a conditioned SCX cartridge (50 g Varian). The cartridge was washed with methanol (3×50 mL), then eluted with methanolic ammonia solution (2×50 mL) and the combined elution fractions evaporated. Purification on silica, eluting with triethylamine/ethyl acetate/iso-hexane [1:19:80], to give the subtitle compound as a dark brown oil (450 mg).
Reaction SMILES: [Li]CCCC.[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][O:18][CH3:19])([CH3:9])([CH3:8])[CH3:7].CN(C)CCN(C)C.CN(C)[CH:30]=[O:31]>CCOCC.C(OCC)(=O)C.CCCCCC>[C:6]([C:10]1[C:11]([O:16][CH2:17][O:18][CH3:19])=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH:30]=[O:31])([CH3:9])([CH3:7])[CH3:8]
Reactant: CN(C)C=O
Reactant: COCOc1ccccc1C(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: CCCCCC
Product: COCOc1c(C=O)cccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.1 %

Procedure:
A 2.6 M hexane solution of n-BuLi was gradually added to a solution of the 1-(tert-butyl)-2-(methoxymethoxy)benzene (1013 g, 4.67 mol) and tetramethylethylenediamine (754 g, 6.5 ml) in dry ether while cooling on ice, and the mixture was stirred at room temperature for 3 hours. After recooling to 0° C., dimethylformamide (1000 ml, 14 mol) was gradually added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was gradually added to ice water, extraction was performed with ethyl acetate, and the organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to yield a crude product of the title compound (1247 g) as a red oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1>CN(C=O)C.O.C(OCC)(=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[C:10]([N:12]2[CH2:13][CH2:14][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17]2)=[O:11])=[CH:32][CH:31]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CCOC(=O)C1CCN(C(=O)c2nc3ccccc3[nH]2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(C(=O)c2nc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
ethyl 1-(1H-benzo[d]imidazole-2-carbonyl)piperidine-4-carboxylate (80 mg, 0.265 mmol) and cesium carbonate (130 mg, 0.398 mmol) were dissolved in DMF (Volume: 2.0 ml). 1-chloro-4-(chloromethyl)benzene (0.051 ml, 0.398 mmol) was added and the reaction was heated at 80° C. overnight. After 18 hours, the reaction was cooled to room temperature and diluted with water and ethyl acetate. The organic phase was washed with saturated sodium chloride four times before it was dried over magnesium sulfate, filtered and concentrated. The crude material was taken directly to the next step without purification. (Yield: 85 mg, beige solid). 1H-NMR (400 MHz, DMSO-d6) 7.74, 7.66, 7.47-7.21, 5.51, 5.15, 4.48, 4.43-4.32, 4.08, 3.96-3.85, 3.16, 2.99, 2.69-2.55, 1.98-1.87, 1.76-1.66, 1.52-1.38, 1.26-1.12
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].[C:22](N1C=CN=C1)(N1C=CN=C1)=[O:23].CN(CCN)C.COC1C=C(N2CCNCC2)C=CC=1>O1CCCC1>[CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:23][CH3:22])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: COc1cccc(N2CCNCC2)c1
Solvent: C1CCOC1
Product: COc1cccc(N2CCN(C(=O)NCCN(C)C)CC2)c1
Yield: 51 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 4.9 g (0.03 mole) of 1,1'-carbonyldiimidazole, 2.6 g (0.03 mole) of unsym-dimethylethylenediamine, and 5.8 g (0.03 mole) of 1-(3-methoxyphenyl)piperazine in a total of 200 ml of tetrahydrofuran gave an oil which solidified. After trituration with petroleum ether (30°-60° C.), the collected solid was recrystallized from cyclohexanebenzene to yield 4.7 g (51%) of the title compound as a white crystalline solid, m.p. 70°-72° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([N:15]([CH2:22][CH3:23])[CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:12]([CH3:24])=[C:11]([C:25]([NH:27][CH2:28][C:29]3[C:30](=[O:37])[NH:31][C:32]([CH3:36])=[CH:33][C:34]=3[CH3:35])=[O:26])[CH:10]=2)=[CH:5][CH:4]=1.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][C:39]1=[O:44].[H-].[Na+]>CN(C=O)C>[CH3:35][C:34]1[CH:33]=[C:32]([CH3:36])[NH:31][C:30](=[O:37])[C:29]=1[CH2:28][NH:27][C:25]([C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:38]3[CH2:43][CH2:42][O:41][CH2:40][C:39]3=[O:44])=[CH:4][CH:5]=2)[CH:14]=[C:13]([N:15]([CH2:22][CH3:23])[CH:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[C:12]=1[CH3:24])=[O:26]
Reactant: CCN(c1cc(-c2ccc(CBr)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: O=C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(c1cc(-c2ccc(CN3CCOCC3=O)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 29.1 %

Procedure:
To an ice cooled stirred solution of 4′-(bromomethyl)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-[1,1′-biphenyl]-3-carboxamide (250 mg, 0.44 mmol) and morpholin-3-one (67 mg, 0.66 mmol) in DMF (30 mL) was added sodium hydride (27 mg, 0.66 mmol). After 10 minutes, ice was removed and stirring continued for 16 h at room temperature. On completion, water was added and extracted with DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic and prep. HPLC purification afforded the title compound (75 mg, 29%). LCMS: 587.35 (M+1)+; HPLC: 98.69% (@254 nm) (Rt; 4.604; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.50 (bs, 1H), 8.25 (m, 1H), 7.65 (m, 2H), 7.37-7.35 (m, 3H), 5.87 (s, 1H), 4.59 (m, 2H), 4.29 (d, 2H), 4.12 (s, 2H), 3.82 (m, 4H), 3.28 (m, 4H), 3.17-3.09 (m, 2H), 2.32-2.28 (m, 4H), 2.22 (s, 3H), 2.11 (s, 3H), 1.57 (m, 4H), 0.86 (t, 3H).