Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([NH:15][C:16]1[CH:33]=[CH:32][C:19]([C:20]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[O:14])=[N+]=[N-].[H][H]>CO.O1CCOCC1.[Pd]>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:37]=[CH:36][CH:35]=[CH:34][C:12]=1[C:13]([NH:15][C:16]1[CH:33]=[CH:32][C:19]([C:20]([N:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)=[O:14]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CO
Product: NCc1ccccc1-c1ccccc1C(=O)Nc1ccc(C(=O)N2CCCc3ccccc32)cc1
Reaction time: 3 h
Yield: 78 %

Procedure:
A solution of 1-[4-[2-(2-azidomethylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (535 mg) in a mixture of methanol (35 ml) and dioxane (4 ml) containing catalytic palladium on carbon (60 mg) was stirred under atmospheric pressure of hydrogen at ambient temperature. After 3 hours, the reaction mixture was filtered through a bed of celite, and then concentrated to give 1-{4-[2-(2-aminomethylphenyl)benzoylamino]benzoyl}-1,2,3,4-tetrahydroquinoline (395 mg) which was purified by recrystallization from a mixture of ethyl acetate and diethyl ether.
Reaction SMILES: [NH3:1].C(O)C.Cl.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:19][CH2:20][CH2:21]Cl)[C:14](=[NH:18])OCC)=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=1>>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:19][CH2:20][CH2:21][NH:1][C:14]2=[NH:18])=[C:9]([C:23]([F:26])([F:25])[F:24])[CH:8]=1
Reactant: CCOC(=N)C(CCCCl)c1ccc(Br)cc1C(F)(F)F
Reactant: N
Agent: Cl
Solvent: CCO
Product: N=C1NCCCC1c1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A saturated ammonia-ethanol solution (2.5 mL) was added to ethyl 2-(4-bromo-2-trifluoromethylphenyl)-5-chloropentanimidate hydrochloride obtained in Preparation Example 3-1 (500 mg), and the mixture was stirred at room temperature for eight days. The insoluble matter was removed by filtration and then the filtrate was concentrated under reduced pressure. Methylene chloride and a 1 N sodium hydroxide solution were added to the resulting residue, and the organic layer was separated. The aqueous layer was reextracted with methylene chloride. The combined organic layers were dried over anhydrous potassium carbonate and concentrated under reduced pressure to obtain 320 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: ClC[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](=[S:17])[SH:16])[CH3:13].[Na].[C:21](=O)(O)N>C(O)C>[CH2:12]([N:14]([CH2:18][CH3:19])[C:15]([S:16][CH2:21][C:6]1([CH:5]=[CH:4][CH:3]=[CH:11][CH2:10]1)[C:7]([OH:9])=[O:8])=[S:17])[CH3:13]
Reactant: NC(=O)O
Reactant: CCN(CC)C(=S)S
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: [Na]
Solvent: CCO
Product: CCN(CC)C(=S)SCC1(C(=O)O)C=CC=CC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
4-Chloromethylbenzoic acid (4 g, 0.0234 mol, 1.0 equiv.) was dissolved in warm ethanol (20 mL). Diethyldithiocarbamic acid, sodium salt trihydrate (7.92 g, 0.0328 mol, 1.5 equiv.) was also separately dissolved in warm ethanol (20 mL). The solution of the carbamic acid was then added to the solution of the carboxylic acid. The resulting mixture was then stirred at 40-50° C. for 2 h, then stirred overnight at r.t. The reaction mixture was then evaporated to dryness and separated between dichloromethane and brine. The aqueous layer was separated and acidified with conc. HCl to a pH value of 2. The precipitate that formed on acidification was filtered and air-dried to give a white solid, 4.1 g (yield 62%). 1H NMR (acetone-d6, 400 MHz) δ 1.26, br. s, 6H, 2×CH3; 3.82, br. s, 2H, CH2N, 4.5, br. s, 2H, CH2N, 4.67, s, 2H, CH2S; 7.56 (d, J=8 Hz, 2H, aromatic); 7.98 (d, J=8 Hz, 2H, aromatic) ppm. 13C NMR (acetone-d6, 400 MHz) δ 11.78, 12.98, 41.53, 47.55, 50.45, 130.26, 130.45, 130.69, 143.74, 167.40, 194.94 ppm.
Reaction SMILES: C(NCC)C.CC(O)(C)C.Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)=[O:14].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[CH:25][CH:24]=1>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:13](=[O:14])[CH2:12][CH2:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([Br:22])=[CH:24][CH:25]=2)=[O:31])=[CH:16][CH:17]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: O=C(CBr)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Solvent: CCNCC
Solvent: CC(C)(C)O
Product: O=C(CCC(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To a solution of zinc(II) chloride (19.62 g, 144 mmol) in benzene (108 mL) were added diethylamine (11.16 mL, 108 mmol) and 2-methylpropan-2-ol (10.32 mL, 108 mmol) and the mixture was stirred at room temperature for 2 hours. 2-Bromo-1-(4-bromophenyl)ethanone (20.0 g, (72 mmol) and 1-(4-bromophenyl)ethanone (21.48 g, 108 mmol) were added in one portion, and the mixture was stirred overnight (18 hours). The reaction mixture was quenched with 5% H2SO4 (500 mL) and stirred vigorously to induce precipitation of the product, which was collected by vacuum filtration and washed with benzene, water, methanol, and then dichloromethane, successively. The product was dried under vacuum to give the title compound as a white solid (11.15 g, 39.1% yield).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:23])[CH:8]=2)[N:3]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].C(N(CC)CC)C.O>CN(C=O)C>[Cl:23][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[C:11]([C:12]#[N:13])=[C:10]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=1
Reactant: CCNCC
Reactant: CC(C)c1cccc(-c2c(C#N)c(Cl)nc3ccc(Cl)cc23)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2ccc(Cl)cc2c(-c2cccc(C(C)C)c2)c1C#N
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 90.3 %

Procedure:
A mixture of 2,6-dichloro-4-(3-isopropyl-phenyl)-quinoline-3-carbonitrile (128 mg, 375 μmol, Eq: 1.00), diethylamine (54.9 mg, 78.4 μl, 750 μmol, Eq: 2) and triethylamine (114 mg, 157 μl, 1.13 mmol, Eq: 3) in DMF (1 ml) was heated first to 120° C. for 20 min and then to 180° C. for additional 20 min in a microwave. Then water was added and the mixture was extracted with ethyl acetate (3×). The combined extracts were washed with water and brine, dried with Na2SO4 and evaporated. The remaining residue was purified by column chromatography (silica gel, heptane/EtOAc 90:10 to 85:15) to afford the title compound as yellow oil (128 mg). MS (ESI): 377.1 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[CH3:6].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[NH2:43][CH2:44][C:45]1[C:46]([OH:53])=[N:47][C:48]([CH3:52])=[CH:49][C:50]=1[CH3:51]>ClCCl.O.C(N(CC)CC)C>[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:3]=1[O:4][CH:5]([C:7]1[CH:8]=[CH:9][C:10]([C:11]([NH:43][CH2:44][C:45]2[C:46]([OH:53])=[N:47][C:48]([CH3:52])=[CH:49][C:50]=2[CH3:51])=[O:13])=[CH:14][CH:15]=1)[CH3:6]
Reactant: CC(Oc1ccc(F)cc1F)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccc(F)cc3F)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
To a solution of 4-(1-(2,4-difluorophenoxy)ethyl)benzoic acid (127 mg, 0.5 mmol) in dichloromethane (80 mL) was added N-hydroxybenzotriazole (101.25 mg, 0.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (144 mg, 0.75 mmol) and triethylamine (151 mg, 1.5 mm ol). then the 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (76 mg, 0.5 mmol) was added, the solution was stirred at room temperature for 12 hours, water was added and washed 3 times, the organic layer was evaporated and the residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(1-(2,4-difluorophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (78 mg, 38%).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][NH:8][C@H:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([CH3:13])([CH3:12])[CH3:11].[C:25](=O)(ON1C(=O)CCC1=O)[O:26]N1C(=O)CCC1=O.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C@@H:9]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[C:25]1=[O:26]
Reactant: CC(C)(C)OC(=O)[C@@H](NCCNCc1ccccc1F)C(C)(C)C
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H](N1CCN(Cc2ccccc2F)C1=O)C(C)(C)C
Yield: 101.1 %

Procedure:
A solution of Example 135A (183 mg, 0.54 mmol) and disuccinimidyl carbonate (0.165 g, 0.645 mmol) in dichloromethane (3 mL) was treated with triethylamine (90 uL, 0.645 mmol) at 25° C. for 16 h. The mixture was partitioned between 10% sodium carbonate and dichloromethane. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated to give the crude title compound (199 mg, crude yield).
Reaction SMILES: C(O)(=O)C.[N:5]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[C:8](O)=[CH:7][CH:6]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2cccnc12
Solvent: CC(=O)O
Product: Clc1ccnc2cccnc12
Temperature: 110 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1,5-naphthyridin-4-ol acetic acid salt (D-6) (800 mg, 3.0 mmol, 1.0 eq) in phosphoroxychloride (5 mL, 53 mol, 17.6 eq) is stirred at 110° C. for 30 min, cooled to RT and then concentrated in vacuo. The residue is poured into ice-water (50 mL) and neutralized with saturated aqueous NaHCO3 solution to adjust the pH to 8-9 while keeping the temperature below 5° C. The mixture is stirred at RT for 30 min and then extracted with DCM (3×40 mL). The combined organic layers are washed with brine, dried over Na3SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (1-2% MeOH-DCM) to afford the product, 4-chloro-1,5-naphthyridine (D-7).
Reaction SMILES: [C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2].[I:30]N1C(=O)CCC1=O>CN(C)C=O>[C:1]([O:4][CH:5]1[CH:9]([N:10]2[C:14]3[CH:15]=[C:16]([Cl:20])[C:17]([Cl:19])=[CH:18][C:13]=3[N:12]=[C:11]2[I:30])[CH2:8][CH:7]([CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:6]1[O:26][C:27](=[O:29])[CH3:28])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CC(n2cnc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Product: CC(=O)OCC1CC(n2c(I)nc3cc(Cl)c(Cl)cc32)C(OC(C)=O)C1OC(C)=O
Yield: 39.6 %

Procedure:
(±)(1R*, 2S*, 3S*, 5S*)-3-(Acetoxymethyl)-5-(5,6-dichloro-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate (500 mg, 1.13 mmol) was dissolved in dry N,N-dimethylformamide (4 mL) and heated to 95°-105° C. N-Iodosuccinimide (534 mg, 2.3 mmol as 95%) was added in portions over 5.5 hours. Volatiles were removed in vacuo and the residue chromatographed on silica gel. Elution with 10% ethyl acetate-hexanes followed by solidification from ethanol-water gave (±)(1R*, 2S* 3S*, 5S*)-3-(acetoxymethyl)-5-(5,6-dichloro-2-iodo-1H-benzimidazol-1-yl)-1,2-cyclopentanediyl diacetate as a white powder (255 mg, 40%), m.p.152.5°-153° C.; 1H-NMR(DMSO-d6)δ: 8.32 and 7.94 (both s, 2, 2 aromatic CH), 5.8-5.7 (m, 1, OCH), 5.4-5.3(m, 1, OCH), 5.2-5.0 (m, 1, NCH), 4.35-4.2 (m, 2, OCH2), 2.7-2.6 (m, 1, CH), 2.35-2.25 (m, 2, CH2), 2.11, 2.08, and 1.93 (all s, 3 each, 3 CH3); mass spectrum(CI) 569 (M +1).
Reaction SMILES: [Li].C(CC(O)=O)(CCC=C(C)C)(C=C)C.[C:16]([O:19][C:20]([CH3:29])([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:21]=[CH2:22])(=[O:18])[CH3:17].[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40](Cl)=[O:41]>C1COCC1>[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][C:31]=1[C:40](=[O:41])[CH2:17][C:16]([O:19][C:20]([CH3:29])([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH:21]=[CH2:22])=[O:18]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: C=CC(C)(CCC=C(C)C)OC(C)=O
Agent: C=CC(C)(CCC=C(C)C)CC(=O)O
Agent: [Li]
Solvent: C1CCOC1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(=O)c1ccc2ccccc2c1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamnide (101.0 mL of a 2.0 M solution, 0.202 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition fiunel. The flask is placed in a dry ice-acetone bath. 3,7-Dimethyl-1,6-octadien-3-yl acetate (linalyl acetate) in the amount of (18.66 g, 0.095 mol) is dissolved in THF (5 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min before being treated with a solution of 2-naphthoyl chloride in the amount of (17.43 g, 0.090 mol) dissolved in THF (25 mL) over 30 min. The mixture is warmed to −20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (53 mL). The mixture is poured into a separatory fumnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 5% ethyl acetate dissolved in petroleum ether) to give an oil. Purity of the product is determined by thin layer chromatography and GC analysis and the structure confirmed by mass spectrometry, 1H and 13C NMR.
Reaction SMILES: N#N.[CH3:3][CH:4]1[CH2:8][CH2:7][CH:6]([CH3:9])[NH:5]1.Br[CH2:11][CH2:12][CH2:13][C:14]#[N:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH3:3][CH:4]1[CH2:8][CH2:7][CH:6]([CH3:9])[N:5]1[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15]
Reactant: N#CCCCBr
Reactant: CC1CCC(C)N1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CCC(C)N1CCCCN
Temperature: 25 °C
Reaction time: 15 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), to a solution of 2,5-dimethylpyrrolidine (250 mg, 2.34 mmol) and 4-bromobutyronitrile (0.24 mL, 2.34 mmol) in dry CH3CN (12 mL) was added K2CO3 (1.78 g, 12.89 mmol) at rt followed by KI (39 mg, 0.23 mmol). The reaction mixture was stirred at rt for 15 h. The mixture was filtered and the filtrate partitioned between water and CH2Cl2. The layers were separated and the aq. layer extracted with CH2Cl2 (3×). The combined org. extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The crude nitrile was redissolved in dry THF (19 mL) and treated with LiALH4 (176 mg, 4.50 mmol) at 0° C. The reaction mixture was warmed up to rt and stirred at this temperature until completion of the reaction. Aq. 1N NaOH (7 mL) was then added, the layers separated and the aq. layer extracted with EA (3×). The combined organic extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 4-(2,5-dimethylpyrrolidin-1-yl)butan-1-amine as a yellow oil. GC-MS-conditions 01: tR=1.75 and 1.83 min; [M+H]+=171.30.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:28][CH:29]1[CH2:31][CH2:30]1.CC(C)([O-])C.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:24][CH3:25])[CH2:22][O:23][CH2:28][CH:29]3[CH2:31][CH2:30]3)[C:11](=[O:26])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@@H](CO)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: BrCC1CC1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H](COCC1CC1)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 1.48 g (3.77 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one (Example 68, Step A) and bromomethylcyclopropane (0.828 mL, 7.54 mmol) in DMF (20 mL) was added sodium t-butoxide (0.544 g, 5.66 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h and then warmed to rt. Then the reaction was stirred at rt for 14 h. The reaction was quenched with sat. aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica gel (eluent: 20%-40% EtOAc/Hexanes, gradient elution) provided the title compound as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]>>[C:8]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:19][CH2:20][NH:21][C:22](=[O:36])[C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([N:5]5[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]5)[N:30]=4)=[CH:25][CH:24]=3)[CH:17]=2)[NH:12][CH:11]=1)#[N:9]
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Reactant: OC1CCNCC1
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(N5CCC(O)CC5)n4)cc3)cc12

Procedure:
Using 4-hydroxy-piperidine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. 1H NMR (DMSO) δ 1.36 (m, 2H); 1.82 (m, 2H); 2.98 (t, 2H, J=7 Hz); 3.34 (m, 2H); 3.55 (m, 2H); 3.76 (bs, 1H); 4.39 (bd, 2H); 4.75 (bs, 1H); 7.20 (m, 2H); 7.48 (m, 2H); 7.92 (d, 2H, J=9 Hz); 8.20 (m, 3H); 8.45 (d, 1H, J=5 Hz); 8.67 (bt, 1H); 12.12 (bs, 1H). MS (ion spray) m/z 467 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=[O:10])=[C:4]([F:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:19][NH2:20]>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:20][CH3:19])=[O:10])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1F
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)Cc1ccc(Br)cc1F
Reaction time: 2 h
Yield: 23.5 %

Procedure:
A solution of 2-(4-bromo-2-fluorophenyl)acetic acid (10.56 mmol) in dichloromethane (20 mL) was treated with oxalyl chloride (31.7 mmol) and dimethylformamide (0.106 mmol). Effervescense was observed for fifteen minutes. When the bubbling had ceased, the reaction was concentrated to dryness in vacuo. The resulting oil was dissolved with dichloromethane and was concentrated to dryness in vacuo. The material was then diluted with tetrahydrofuran (20 mL) and was treated with methanamine (31.7 mmol) dropwise. Effervescense was again observed. A precipitate formed as the reaction was stirred over a two hour period. The contents of the reaction were concentrated to dryness in vacuo and were then dissolved in a minimal amount of methanol. Ethyl acetate was then added to this solution until a solid precipitated. The precipitate was collected by vacuum filtration. In a similar manner, two additional crops were collected from the mother liquor. The resulting solids were combined and triturated with dichloromethane. Purification of the solid by silica gel chromatography (0-5% methanol/dichloromethane) afforded the title compound as a white solid (610 mg, 22% yield). MS(ES)+ m/e 246.0/247.8 [M+H]+ (bromide isotope pattern).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:24][C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([C@H:14]3[CH2:18][O:17][C:16]4([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)[O:15]3)[N:10]=2)=[N:6][CH:7]=1.[SH:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36].C(N(CC)C(C)C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:15]1[C:16]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[O:17][CH2:18][C@@H:14]1[C:11]1[N:10]=[C:9]([NH:8][C:5]2[N:6]=[CH:7][C:2]([S:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:3][C:4]=2[O:24][C:25]2[C:26]([CH3:31])=[N:27][CH:28]=[CH:29][CH:30]=2)[S:13][N:12]=1
Reactant: COC(=O)CCS
Reactant: Cc1ncccc1Oc1cc(Br)cnc1Nc1nc([C@H]2COC3(CCCCC3)O2)ns1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCSc1cnc(Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(Oc2cccnc2C)c1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
To a solution of (S)—N-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (3.1 g, 6.14 mmol) in dioxanes (30 mL) continuously purged with nitrogen was added Xanphos (0.177 g, 0.303 mmol), Pd2dba3 (0.14 g, 0.153 mmol), methyl 3-mercaptopropanoate (0.73 g, 6.14 mmol) and N,N-diisopropylethylamine (1.17 mL, 6.45 mmol) and the reaction was heated overnight at 80° C. The reaction was concentrated in vacuo and the residue purified over silica gel (5% MeOH/CH2Cl2) to afford (S)-methyl 3-(6-(3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-ylamino)-5-(2-methylpyridin-3-yloxy)pyridin-3-ylthio)propanoate (2.3 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])=[O:17].ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.[CH3:55][N:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:30]=[C:31]([F:33])[CH:32]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:17])[C:18]1[CH:26]=[CH:25][C:21]([C:22]([N:59]2[CH2:60][CH2:61][N:56]([CH3:55])[CH2:57][CH2:58]2)=[O:24])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]
Reactant: O=C(O)c1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Yield: 99.4 %

Procedure:
4-{[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]carbamoyl}-3-nitrobenzoic acid (500 mg, 1.11 mmol) in DMF (10 mL) was treated with 1-hydroxybenzotriazole (195 mg, 1.44 mmol), EDCI (276 mg, 1.44 mmol) and 1-methylpiperazine (0.16 mL, 1.44 mmol). The reaction was left at room temperature over night. The volatiles were removed by evaporation, the residue was added drop-wise to iced-water (25 mL) with stirring. A yellow solid was obtained which was extracted with DCM (2×25 mL). The combined organic layers were dried over sodium sulphate and evaporated leaving 590 mg of title compound which was employed in the following step without any further purification.