Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OCC)(=O)C>ClCCl>[C:32]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN(c1ccc2[nH]ccc2c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CN(c1ccc2c(ccn2C(=O)c2ccccc2)c1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
50 mg tert.butyl [(3,5-dichloro-phenylsulphonyl)-(1H-indol-5-yl)-amino]-acetate are dissolved in 2 ml dichloromethane. 5 mg powdered sodium hydroxide and 19 μl benzoyl chloride are added. Then the mixture is stirred for 4 hours at ambient temperature, divided between 1 N sodium hydroxide solution and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried with magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1:2).
Reaction SMILES: CN(C)C=O.Br[C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:10][C:11]#[N:12].C(=O)([O-])[O-].[K+].[K+].[CH2:24](B(CC)CC)[CH3:25]>O>[CH2:24]([C:7]1[CH:8]=[C:9]([CH2:10][C:11]#[N:12])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH3:25]
Reactant: COc1ccc(CC#N)cc1Br
Reactant: CCB(CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(CC#N)ccc1OC
Temperature: 70 °C
Reaction time: 5 h
Yield: 37.1 %

Procedure:
N,N-Dimethylformamide (75 ml) was added to 3-bromo-4-methoxybenzyl cyanide (9.0 g, 40 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II)-dichloromethane adduct (400 mg, 0.49 mmol) and potassium carbonate (24.0 g, 174 mmol) at room temperature. Further, triethylborane (1M n-hexane solution, 50 ml, 50 mmol) was added dropwise thereto and the reaction mixture was stirred at 70° C. for 5 hours. After the temperature of the reaction mixture was returned to room temperature, the mixture was poured into water and extracted with ethyl acetate. The organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=8/1-5/1) to give (3-ethyl-4-methoxyphenyl)acetonitrile (2.6 g, yield: 38%) as an oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:13]=[C:5]2[C:3]([OH:4])=[O:2])=[CH:15][CH:16]=1
Reactant: COC(=O)c1cc2ccccc2n1-c1ccc(OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-n2c(C(=O)O)cc3ccccc32)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 3 g 1-(4-Methoxy-phenyl)-1H-indole-2-carboxylic acid methyl ester in 50 ml THF, 10 ml water and 0.58 g lithium hydroxide monohydrate were added. After stirring for 2 h at 60° C. the reaction was cooled to RT. The mixture was acidified with half concentrated hydrochloric acid and the precipitate was collected by filtration and was washed with 10 ml water The product was obtained as a white solid which was dried under reduced pressure. Yield: 520 mg.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7](=[C:8]([OH:17])[C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:16]2[C:7](=[C:8]([O:17][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(O)c3ccccc3nc12
Reactant: CCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1c2ccccc2nc2c(OC)cccc12
Temperature: 120 °C
Yield: 31.8 %

Procedure:
4-methoxyacridin-9-ol (2.0 g, 8.88 mmol), 1-bromooctane (2.17 g, 11.24 mmol), and potassium carbonate (7.91 g, 57.2 mmol) was mixed in N,N-dimethylformamide and heated at 120° C. for 8 h and the potassium carbonate was filtered off. The reaction mixture was quenched with water and extracted two times with ether and the combined organic phases was then washed once with 1M HCl, two times with water, and evaporated to obtain a yellow solid. The solid was recrystallised in methanol to give 4-methoxy-9-(octyloxy)acridine (0.95 g, 2.82 mmol) as yellow crystals. 1H-NMR (CDCl3, δ): 0.881 (t, 3H), 1.2-1.4 (m, 10H), 1.924 (m, 2H), 3.985 (s, 3H), 4.507 (t, 2H), 7.2-7.3 (m, 3H), 7.621 (d, 1H), 7.707 (m, 1H), 8.181 (m, 1H), 8.498 (m, 1H) MS MALDI-TOF (m/z): 337.146
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[CH:11]=[N:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[CH:4][CH:3]=1.[Li]CCCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C1COCC1.CCCCCC>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:9]1[N:10]=[C:11]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:12]([CH3:13])[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: Cn1cnc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 1.1 g (3.25 mmol) of 5-(4-chlorophenyl)-4-(2,4-dichlorophenyl)-1-methyl-imidazole in 30 mL of dry THF was cooled in a −78° C. bath and 1.7 mL of 2.5 M n-BuLi in hexane was dropwise added. After stirring the solution for 1 h it was added with a canula to 0.623 mL of ethyl chloroformate in THF cooled in a −78° C. bath. The cold bath was removed and the reaction was stirred for 1 h then quenched with water. The mixture was extracted with EtOAc. The EtOAc layer was washed with brine, dried and concentrated. The residue was chromatographed using a gradient of 10-20% EtOAc-hexane to isolate the desired product.
Reaction SMILES: C(O[C:6](=O)[N:7]([C@@H:9]([C:21](=[O:36])[N:22]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[O:32][CH2:33][CH2:34][OH:35])[CH3:23])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1)C)(C)(C)C.C(=O)([O-])O.[Na+].O>ClCCl>[OH:35][CH2:34][CH2:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][CH2:24][N:22]([CH3:23])[C:21](=[O:36])[C@H:9]([NH:7][CH3:6])[CH2:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1
Reactant: CN(CCc1ccccc1OCCO)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)CCc1ccccc1OCCO
Temperature: 0 °C
Reaction time: 3 h
Yield: 92.1 %

Procedure:
At 0° C., trfluoroacetic acid (4 ml) was added to a solution of N-((1 R)-1-(N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methylcarbamoyl)-2-(2-naphthyl)ethyl)-N-methylcarbamic acid tert-butyl ester (986 mg, 1.95 mmol) in dichloromethane (4 ml). The solution was stirred for 3 h at 0° C. Dichloromethane (50 ml) was added. A saturated solution of sodium hydrogen carbonate (30 ml) was added. Solid sodium hydrogen carbonate was added until pH 7 was obtained. Water was added until a clear solution was obtained. The phases were separated. The aqueous phase was extracted with dichloromethane (2×20 ml). The combined organic layers were dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using dichloromethne/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 730 mg of (2R)-N-(2-(2-(2-hydroxyethoxy)phenyl)ethyl)-N-methyl-2-(methylamino)-3-(2-naphthyl)propionamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13]([N:15]2[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]2)[CH:12]=[C:11]([Cl:23])[C:10]=1[CH:24]([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>O1CCCC1>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([CH:24]([C:10]2[C:9]([Cl:8])=[CH:14][C:13]([N:15]3[C:20](=[O:21])[NH:19][C:18](=[O:22])[CH:17]=[N:16]3)=[CH:12][C:11]=2[Cl:23])[C:25]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[O:26])=[CH:29][CH:30]=1
Reactant: O=C(Cl)C(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(C(=O)C(c2ccc(Cl)cc2)c2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)CC1
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a stirred mixture of 10 parts of 1-methylpiperazine in 45 parts of tetrahydrofuran was added dropwise a solution of 6.7 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetyl chloride in 45 parts of tetrahydrofuran during a period of 5 minutes. Upon complete addition, stirring was continued for 2 hours at room temperature. After evaporation in vacuo, the residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was boiled in acetonitrile. After cooling, the precipitated product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 4.8 parts (62.8%) of 1-[2-(4-chlorophenyl)-2-[2,6-dichloro-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)phenyl]acetyl]-4-methylpiperazine: mp. 261.5° C. (intermediate 36).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>ClC(Cl)C>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[CH:19]([C:20]([CH:19]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: O=C(C(c1ccccc1)c1ccc(O)cc1O)C(c1ccccc1)c1ccc(O)cc1O
Reaction time: 1 h
Yield: 90.9 %

Procedure:
55 g (0.5 mole) of resorcinol were suspended in 250 ml of dichloro ethane and at 20° C. 67 g (0.502 mole) of anhydrous aluminum chloride were added. To the obtained homogeneous dark solution, containing the hydrogen-aluminum-trichloro-3-hydroxy-phenolate, 77.2 g (0.5 mole) of phenyl-acetyl chloride in 100 ml of dichloro ethane were added over one hour while the temperature raised to 35°-40° C. The reaction mixture was stirred for one hour, the solution thus obtained was added to an aqueous hydrochloric acid solution, the two layers were separated, the organic layer was washed with water to neutral, the solvent was distilled off and the residue was optionally crystallized from toluene. 96.9 g of 2,4-dihydroxy-phenyl-benzyl-ketone were obtained, m.p.: 112°-114° C., yield: 85%. After an optional recrystallization from toluene the melting point was 113°-114° C. Elemental analysis for C14H12O3 (Mw: 228):
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4](O)=[O:5].CO.Cl>O1CCCC1>[NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1cc(Cl)cc(C(=O)O)c1N
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cl)cc(CO)c1N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
The 2-amino-5-chloro-3-methylbenzoic acid (15.6 g, 84.3 mmol) was dissolved in tetrahydrofuran (200 ml) and cooled to 0° C. A solution of borane dimethylsulfide complex (16.8 mL, 16.8 mmol) was dissolved in tetrahydrofuran (40 mL) and added dropwise. The solution was kept at 0° C. for an additional 30 minutes and warmed to room temperature for 2 h and finally refluxed for 16 h. The solution was cooled to room temperature and methanol (10 mL) added slowly to control the gas evolution. The solution was stirred for 30 minutes at room temperature and 1 N hydrochloric acid added. The solution was stirred for 3 h and solvent removed to a volume of about 100 mL. Water (200 mL) was added and the solution extracted with diethylether (200 mL). The aqueous layer was collected, adjusted to pH=12 with 1N sodium hydroxide which formed a solid in the solution. The solid was collected, dissolved in ethyl acetate (100 mL), dried over sodium sulfate and solvent removed at reduced pressure. (2-Amino-5-chloro-3-methylphenyl)methanol (10.8 g, 63.1 mmol) was obtained as a light yellow solid (75% yield). HRMS m/z 172.0544; calcd for M+H 172.0524.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C([O:13][C:14](=O)[C:15]([F:18])([F:17])[F:16])C>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:14](=[O:13])[C:15]([F:18])([F:17])[F:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(F)(F)F
Reactant: CC(=O)c1ccc(C)cc1
Product: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1

Procedure:
In the step 2, the p-Methyl acetophenone was condensed with Ethyltrifluoroacetate under alkaline conditions to give the 1-(4-Methylphenyl)-4,4,4-trifluorobutane-1,3-dione intermediate.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:30])[C:6]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:7]2[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.[CH3:31][N:32]([CH3:36])[CH2:33][C:34]#[CH:35].C(N(CC)CC)C>O1CCCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:26]([O:25][CH:19]([C:6]1[C:5]([CH3:30])=[CH:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[C:35]#[C:34][CH2:33][N:32]([CH3:36])[CH3:31])[C:7]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:27])([CH3:28])[CH3:29]
Reactant: C#CCN(C)C
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(Br)cccc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2c(C#CCN(C)C)cccc2c1-c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 6.6 %

Procedure:
To a solution of ethyl 2-(5-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate (100 mg, 0.20 mmol) and N,N-dimethylprop-2-yn-1-amine (0.065 mL, 0.61 mmol) in anhydrous tetrahydrofuran was added copper iodide (8 mg, 0.04 mmol) and PdCl2(PPh3)2 (14 mg, 0.02 mmol). The reaction was heated to 100° C. overnight. After cooling to room temperature the reaction was charged with PdCl2(PPh3)2 (14 mg, 0.02 mmol), copper iodide (8 mg, 0.04 mmol), N,N-dimethylprop-2-yn-1-amine (0.065 mL, 0.61 mmol) and triethylamine (1 mL). The reaction was heated to 100° C. overnight. To the reaction was then added N,N-dimethylprop-2-yn-1-amine (0.065 mL, 0.61 mmol) and heated to 100° C. overnight. The crude reaction mixture was absorbed onto silica gel and purified by flash column chromatography (silica gel, ethyl acetate/hexanes, methanol/ethyl acetate) to give a yellow oil (6.5 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H35ClNO3: 492.22; found: 492.15.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH2:7][NH:8][C:9]2[C:13]([CH:14]=1)=[CH:12][C:11]([P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26])([P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18])[CH:10]=2.[C:31]([O-:34])(=[S:33])[CH3:32].[Na+]>CC(C)=O>[C:31]([S:33][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH2:7][NH:8][C:9]2[C:13]([CH:14]=1)=[CH:12][C:11]([P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26])([P:15]([O:20][CH2:21][CH3:22])(=[O:19])[O:16][CH2:17][CH3:18])[CH:10]=2)(=[O:34])[CH3:32]
Reactant: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=C(CCCCBr)CNC2=C1
Reactant: CC([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOP(=O)(OCC)C1(P(=O)(OCC)OCC)C=C2C=C(CCCCSC(C)=O)CNC2=C1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of dihydro-3-(4-bromobutyl)-1-pyrindine-6,6-bisphosphonic acid, tetraethyl ester (5.0 mmol) is stirred in dry acetone (35 ml) and sodium thioacetate (5.2 mmol) is added. The mixture is stirred at 50° C. for 12 hours. After cooling to room temperature the solvent is removed under reduced pressure. The crude residue is dissolved in methylene chloride and washed with water. The organic layer is then dried and concentrated under reduced pressure. The desired product is purified by flash chromatography using a 5-10% isopropanol in methylene chloride gradient on silica gel.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:5]=1)[CH3:2].[C:22](C#N)#[N:23].N1C=CC=CC=1.CN1CCCC1=O>Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:22]#[N:23])=[CH:17][CH:16]=2)=[O:12])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)OCc2ccc(Br)cc2)cc1
Reactant: N#CC#N
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: c1ccncc1
Product: CCOc1ccc(CC(=O)OCc2ccc(C#N)cc2)cc1

Procedure:
A mixture of 34.9 g of p-bromobenzyl p-ethoxyphenylacetate (obtainable by esterification), 10 g of Cu2 (CN)2, 120 ml of pyridine and 60 ml of N-methylpyrrolidone is heated at 150° for 2 hours. The mixture is cooled; a solution of 120 g of FeCl3.6H2O in 600 ml of 20% hydrochloric acid is added; and the mixture is warmed at 70° for 1.5 hours while stirring and worked up in a customary manner to give p-cyanobenzyl p-ethoxyphenylacetate, m.p. 59°, c.p. -40°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@@H:13]3[CH:17]=[C:16]([CH:18]4[CH2:20][CH2:19]4)[CH2:15][NH:14]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:30][O:31][C:32]([NH:34][C@@H:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH3:30][O:31][C:32](=[O:33])[NH:34][C@H:35]([C:36]([N:14]1[CH2:15][C:16]([CH:18]2[CH2:20][CH2:19]2)=[CH:17][C@H:13]1[C:10]1[NH:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:37])[CH:39]([CH3:41])[CH3:40]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: Brc1ccc(-c2c[nH]c([C@@H]3C=C(C4CC4)CN3)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CC(C2CC2)=C[C@H]1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-bromo-phenyl)-2-((S)-4-cyclopropyl-2,5-dihydro-1H-pyrrol-2-yl)-1H-imidazole (1.8 g, 5.45 mmol) in DCM (30 mL) was added DIPEA (3.52 g, 27.25 mmol), (S)-2-methoxycarbonylamino-3-methyl-butyric acid (1.14 g, 6.54 mmol) and HATU (2.49 g, 6.54 mmol). The mixture was stirred at RT overnight washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. The resulting material was combined with the product of a separate batch prepared at the 0.61 mmol scale by the same process and purified by column chromatography (20%-50% EtOAc in petroleum ether) to give the desired product, which was purified by SFC separation to give the title intermediate (800 mg, 30% yield). m/z): [M+H]+ calcd for C23H27BrN4O3 487.13, 489.12 found 487.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[CH:6]=[CH:7]/[C:8]1[O:9][C:10]2[C:11](=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][CH:16]=2)[N:12]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[CH:6]=[CH:7]/[C:8]1[O:9][C:10]2[C:11](=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][CH:16]=2)[N:12]=1
Reactant: COC(=O)c1cccc2oc(/C=C/c3ccc(OC)c(OC)c3)nc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(/C=C/c2nc3c(C(=O)O)cccc3o2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a stirred solution of (E)-methyl 2-(3,4-dimethoxystyryl)benzo[d]oxazole-4-carboxylate (240 mg, 0.71 mmol) in THF (10 mL) and MeOH (5 mL) was added 2 N NaOH solution (1.77 mL) dropwise at room temperature. The resulting mixture was stirred at room temperature for two hours then quenched with a 1N HCl solution. The mixture was then extracted with DCM and the organic phase was washed with saturated aqueous NaCl solution and dried over sodium sulfate. The solvent was then removed under reduced pressure to give (E)-2-(3,4-Dimethoxystyryl)benzo[d]oxazole-4-carboxylic acid (170 mg, 74%). 1H-NMR (400 MHz, DMSO-d6) δ 3.81 (s, 3H), 3.85 (s, 3H), 7.03 (d, J=8.0 Hz, 1H), 7.33-7.39 (m, 2H), 7.46 (app t, J=8.0 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H), 7.80 (d, J=16.0 Hz, 1H), 7.87 (dd, J=8.0, 1.2 Hz, 1H), 7.93 (dd, J=8.0, 1.2 Hz, 1H); LC-MS (ES-API): rt 8.88 min; m/z calculated for C18H15NO5 [M−H]− 324.1, found 324.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]2[CH2:17][O:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH2:24][CH2:23]1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]([OH:16])[CH2:17][NH:20][CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]([F:33])([F:31])[F:32])[CH2:24][CH2:23]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CCN(CCC(F)(F)F)CC1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2)cc1
Product: O[C@@H](CNCC1CCN(CCC(F)(F)F)CC1)COc1ccc(OCc2ccccc2)cc1
Yield: 3.8 %

Procedure:
Prepared from 2-(S)-(4-benzyloxy-phenoxymethyl)-oxirane (0.40 g, 1.57 mmol) and 4-aminomethyl-1-(3,3,3-trifluoropropyl)-piperidine (0.329 g, 1.57 mmol) according to the procedure used for Example 2 to provide 0.0280 g of product as a white solid.
Reaction SMILES: [H-].[Na+].[C:3]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[Br:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1F>CN(C=O)C.CCOC(C)=O>[C:3]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[Br:17])[CH2:12][CH2:11]1)([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: Fc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2Br)CC1
Reaction time: 2 h
Yield: 80.4 %

Procedure:
To a slurry of NaH (60% dispersion in oil, 5.9 g, 148.5 mmol, 3.0 eq.) in DMP (40 mL) at 65° C. under N2 was added a solution of N-boc-4-hydroxy piperidine (10 g, 49.5 mmol, 1.0 eq.) in DMF (50 mL). After stirring for about 2 hours, a solution of 1-bromo-2-fluoro benzene (11.0 mL, 99.0 mmol, 2.0 eq.) in DMF (10 mL) was added dropwise. The resulting mixture was stirred at 65° C. overnight. The mixture was diluted with EtOAc (250 mL) and washed with water (100 mL) and brine (100 mL). The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (250 g SiO2, linear gradient, 40 mL/min, 0% to 30% EtOAc/Hexane over 20 minutes and 30% EtOAc for 13 minutes) afforded title compound (14.2 g, 39.8 mmol, 81%). LRMS (electrospray): 358.0.