Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9](O)=[O:10])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:12])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CC(C(=O)O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(CO)c1ccc(Cl)cc1

Procedure:
The synthesis of intermediates leading to different values of m and X is within the capability of one skilled in the art. Example 3 details the method of making the compound wherein X is --CH(CH3)-- and m is 2. This synthesis starts with the reduction of 2-(4-chlorophenyl)propionic acid with lithium aluminum hydride, producing 2-(4-chlorophenyl)propanol. Oxidation of this alcohol with pyridinium chlorochromate in methylene chloride produces 2-(4-chlorophenyl)propionaldehyde. This aldehyde is then reacted with (carbethoxymethylene)triphenylphosphorane, yielding ethyl 4-(4-chlorophenyl)-2-pentenoate. Hydrogenation of this ester in the presence of platinum oxide produces ethyl 4-(4-chlorophenyl)pentanoate which is then hydrolyzed with sodium hydroxide to the corresponding pentanoic acid (II). The remaining steps of this synthesis are shown in Schema 1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.Cl[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=1)[CH3:14]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[N:6]1[CH2:7][CH2:8][N:9]([CH:13]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:25])[CH3:24])=[CH:17][CH:16]=2)[CH3:14])[CH2:10][CH2:11]1
Reactant: c1csc(N2CCNCC2)n1
Reactant: CC(=O)NCc1ccc(C(C)Cl)cc1
Product: CC(=O)NCc1ccc(C(C)N2CCN(c3nccs3)CC2)cc1

Procedure:
By similar reaction and treatment to that in Example 1(5) using 1-(2-thiazolyl)piperazine instead of phenylpiperazine and N-(4-(1-chloroethyl)phenylmethyl)acetamide instead of N-(4-chloromethylphenylmethyl) acetamide, the title compound was obtained as a brown oil.
Reaction SMILES: Cl[CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].[C:7](=[S:10])([O-:9])[CH3:8].[K+].O>CN(C=O)C.[Br-].[Na+]>[C:7](=[O:9])([S:10][CH2:2][C:3]([OH:5])([CH3:6])[CH3:4])[CH3:8]
Reactant: CC(C)(O)CCl
Reactant: CC([O-])=S
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SCC(C)(C)O
Temperature: 50 °C
Yield: 113.2 %

Procedure:
To a mixture of 1-chloro-2-methylpropan-2-ol (2.2 g, 20.26 mmol) and potassium ethanethioate (6.94 g, 60.8 mmol) in DMF (20 mL) was added 100 mg of sodium bromide and the resulting mixture was heated at 50° C. for 18 hours. The mixture was then poured into water and extracted with EtOAc. The acetate layer was washed with water, brine, dried with MgSO4 and concentrated under reduced pressure to provide 3.4 g of the title compound.
Reaction SMILES: CC1(C)[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]([CH2:14][C@H:15]2[CH2:20][CH2:19][C:18](=[O:21])[N:17]([CH3:22])[CH2:16]2)[CH2:4][O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.CC(OC(OC(OC(C)(C)C)=O)=O)(C)C>CO>[OH:3][CH2:4][C@@H:5]([NH:6][C:7](=[O:8])[O:9][C:10]([CH3:12])([CH3:11])[CH3:13])[CH2:14][C@H:15]1[CH2:20][CH2:19][C:18](=[O:21])[N:17]([CH3:22])[CH2:16]1
Reactant: CN1C[C@@H](C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)CCC1=O
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CN1C[C@@H](C[C@@H](CO)NC(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-tert-butyl 2,2-dimethyl-4-(((R)-1-methyl-6-oxopiperidin-3-yl)methyl)oxazolidine-3-carboxylate (230 mg, 0.70 mmol) in MeOH (10 mL) was added p-TSA (30 mg, 0.17 mmol) and stirred at rt overnight. TEA (1 mL) was added, followed by Boc2O (30 mg). The reaction mixture was stirred for another 30 min. The solvent was removed under vacuum to give crude product tert-butyl (S)-1-hydroxy-3-((R)-1-methyl-6-oxopiperidin-3-yl)propan-2-ylcarbamate, which was used for next step without further purification. MS ESI +ve m/z 287 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:5]2.[H-].[Na+].I[CH3:21].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:21])[C:6]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[CH:5]2
Reactant: CI
Reactant: Fc1cc(Cl)cc2cc(-c3cccnc3)[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(-c2cccnc2)cc2cc(Cl)cc(F)c21
Reaction time: 0.5 h

Procedure:
To a solution of 5-chloro-7-fluoro-2-pyridin-3-yl-1H-indole (Example 86, 276 mg, 1.12 mmol) in DMF (4 mL) is added 60% sodium hydride in mineral oil (120 mg, 3.0 mmol) and the suspension is stirred for 30 min. Iodomethane (213 mg, 1.5 mmol) is then added to the reaction mixture and stirred at ambient temperature for 1 h. Water (2 mL) is added to quench the reaction. The mixture is filtered and purified by HPLC using Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to afford 5-chloro-7-fluoro-1-methyl-2-pyridin-3-yl-1H-indole. MS (ESI) m/z 261 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH:25]([CH3:27])[CH3:26])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][C:14]=1[CH2:22][CH2:23][CH3:24].C[N:30](C)C=O>>[Cl:1][C:2]1[C:3](=[O:28])[N:4]([CH:25]([CH3:27])[CH3:26])[N:5]=[CH:6][C:7]=1[NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:20])[NH2:30])=[CH:15][C:14]=1[CH2:22][CH2:23][CH3:24]
Reactant: CCCc1cc(C(=O)O)ccc1OCCCNc1cnn(C(C)C)c(=O)c1Cl
Reactant: CN(C)C=O
Product: CCCc1cc(C(N)=O)ccc1OCCCNc1cnn(C(C)C)c(=O)c1Cl
Reaction time: 2 h

Procedure:
A mixture comprising 130 mg of Compound No. 41 i.e. 4 -chloro-5-[3-(2-n-propyl-4-carboxyphenoxy)propylamino]-2-i-propyl-3(2H)pyridazinone, 62 mg of N,N'-carbonyldiimidazole and 20 ml of N,N-dimethylformamide, was stirred at room temperature for 1 hour, and then ammonia gas was bubbled into the mixture for 10 minutes under cooling with ice. The system was closed and left to stand at room temperature for 2 hours. Then, the solvent was distilled off under reduced pressure. The residue was extracted with chloroform, and the chloroform layer was washed sequentially with an aqueous sodium hydroxide solution and a dilute hydrochloric acid aqueous solution, and dried over sodium sulfate. Then, chloroform was distilled off. The residue was treated with ethyl ether to obtain 20 mg of the above identified compound as a white powder.
Reaction SMILES: C[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[N:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:6]([CH:12]([NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]3[C:17]=1[N:18]=[CH:19][NH:20]3)CC)=[N:7]2.NC1C=CC=C(Cl)C=1C(O)=O.NC1C=CC=C(C)C=1C(O)=O.O=C1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)[CH2:64][O:65][C:66]([CH3:69])([CH3:68])[CH3:67].O=C1CCC(=O)N1OC(=O)C(NC(OCC1C=CC=CC=1)=O)CC>>[C:66]([O:65][CH2:64][CH:12]([C:6]1[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:4](=[O:31])[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][CH:2]=2)[N:7]=1)[NH:15][C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][NH:20]2)([CH3:69])([CH3:68])[CH3:67]
Reactant: CC(C)(C)OCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)c2c(=O)n1-c1ccccc1
Agent: CCC(NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Agent: Cc1cccc(N)c1C(=O)O
Agent: Nc1cccc(Cl)c1C(=O)O
Product: CC(C)(C)OCC(Nc1ncnc2[nH]cnc12)c1nc2ccccc2c(=O)n1-c1ccccc1

Procedure:
2-[2-tert-butoxy-1-(9H-purin-6-ylamino)-ethyl]-3-phenyl-3H-quinazolin-4-one was prepared using the general procedure described above with respect to compound 14, but 2-amino-6-chlorobenzoic acid was substituted for 2-amino-6-methylbenzoic acid in step A, 2-benzyloxycarbonylamino-3-tert-butoxy-propionic acid 2,5-dioxo-pyrrolidin-1-yl ester was substituted for 2-benzyloxycarbonylaminobutyric acid 2,5-dioxo-pyrrolidin-1-yl ester in step B, and the conditions used in step C removed both the benzyl protecting group and the A-Ring chloro substituent.
Reaction SMILES: Cl.CO.C(OC([NH:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH3:30])[C:19]2[CH:23]([CH2:24][C:25]([OH:27])=[O:26])[O:22][B:21]([OH:28])[C:20]=2[CH:29]=1)=O)(C)(C)C.[Li+].[OH-]>O>[NH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH3:30])[C:19]2[CH:23]([CH2:24][C:25]([OH:27])=[O:26])[O:22][B:21]([OH:28])[C:20]=2[CH:29]=1
Reactant: Cc1cc(OCCCNC(=O)OC(C)(C)C)cc2c1C(CC(=O)O)OB2O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(OCCCN)cc2c1C(CC(=O)O)OB2O
Reaction time: 18 h
Yield: 15.7 %

Procedure:
1.25M HCl in methanol (5 mL, 6.0 mmol) was added to [6-(3-tert-butoxycarbonylamino-propoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid (0.345 g, 0.80 mmol) at room temperature and stirred for 18 hours then concentrated in vacuo. The residue was dissolved in THF (14 mL) and a solution of LiOH (0.229 g, 5.44 mmol) in water (5 mL) at 0° C. was added. The resulting mixture was stirred at room temperature for 3 hours then acidified to pH=2 with 6M HCl and extracted with EtOAc (3×25 mL). The organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give [6-(3-amino-propoxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid as a white solid (0.035 g, 14%). 1H NMR (400 MHz, methanol-d4) δ ppm 6.93 (br. s., 1H), 6.79 (br. s., 1H), 5.49 (d, J=5.86 Hz, 1H), 4.10 (t, J=5.47 Hz, 2H), 3.15 (t, J=7.03 Hz, 2H), 2.97 (d, J=14.85 Hz, 1H), 2.27 (s, 3H), 2.03-2.21 (m, 3H). MS (ESI) m/z: 280 [M+1]+. HPLC purity: 96.23% (Maxplot), 95.78% (220 nm).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1Br)(=[O:6])=[O:5])[CH3:2].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[CH3:39][O:40][C:41]1[CH:46]=[CH:45][N:44]=[C:43]([CH2:47][CH2:48][C:49]2[NH:58][C:52]3=[N:53][CH:54]=[C:55](I)[CH:56]=[C:51]3[N:50]=2)[CH:42]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:1]([N:3]([CH2:14][CH3:15])[S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:55]2[CH:56]=[C:51]3[N:50]=[C:49]([CH2:48][CH2:47][C:43]4[CH:42]=[C:41]([O:40][CH3:39])[CH:46]=[CH:45][N:44]=4)[NH:58][C:52]3=[N:53][CH:54]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5])[CH3:2]
Reactant: CCN(CC)S(=O)(=O)c1ccccc1Br
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: [Fe+2]
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: C1COCCO1
Solvent: O
Product: CCN(CC)S(=O)(=O)c1ccc(-c2cnc3[nH]c(CCc4cc(OC)ccn4)nc3c2)cc1
Temperature: 90 °C
Yield: 34.1 %

Procedure:
A mixture of 0.438 g of N,N-diethylbromobenzenesulfonamide, 0.42 g of bis-(pinacolato)diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 90° C. in a sealed tube under N2 for 7 hours. To the resulting mixture 10 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphos-phine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 10 ml of degassed water are added under N2. The mixture is heated to reflux under N2 for 16 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30-25:1). Concentration of the chromatographically pure fractions and crystallisation from ethylacetate gives 0.155 g of the title compound as a solid of m.p. 127-129° C. The mass spectrum shows the molecular peak MH+ at 466.3 Da.
Reaction SMILES: [CH2:1]([C:4]1[O:8][C:7]([NH2:9])=[N:6][N:5]=1)[CH2:2][CH3:3].[C:10]1([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17](Cl)=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:20]1([CH:16]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:17]([NH:9][C:7]2[O:8][C:4]([CH2:1][CH2:2][CH3:3])=[N:5][N:6]=2)=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCCc1nnc(N)o1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCCc1nnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, viscous oil and MS: m/e=322.4 (M+H+) was prepared in accordance with the general method of example 44a from 5-propyl-[1,3,4]oxadiazol-2-ylamine and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:16])=[C:6]([C@:8]2([CH3:15])[CH2:13][S:12][CH2:11][C:10]([NH2:14])=[N:9]2)[CH:7]=1.C(N(CC)CC)C.[CH3:24][O:25][C:26]1[CH:47]=[CH:46][C:29]([C:30](Cl)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)=[CH:28][CH:27]=1>ClCCl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([C:30]([C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:47][CH:46]=2)([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[NH:14][C:10]2[CH2:11][S:12][CH2:13][C@:8]([C:6]3[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[F:16])([CH3:15])[N:9]=2)=[CH:36][CH:35]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CSCC(N)=N1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)CSC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution (R)-5-(5-bromo-2-fluorophenyl)-5-methyl-5,6-dihydro-2H-1,4-thiazin-3-amine (910 mg, 3 mmol, Eq: 1.00) and triethylamine (607 mg, 836 μl, 6.00 mmol, Eq: 2) in dichloromethane (30.0 ml) at 23° C. was added 4,4′-dimethoxytrityl chloride (1.12 g, 3.3 mmol, Eq: 1.1) and the mixture was stirred at 23° C. for 2 h. The solution was concentrated in vacuum and directly subjected to silica gel flash chromatography with n-heptane and ethyl acetate to give the (R)—N-(bis(4-methoxyphenyl)(phenyl)methyl)-5-(5-bromo-2-fluorophenyl)-5-methyl-5,6-dihydro-2H-1,4-thiazin-3-amine (1.67 g, 2.76 mmol, 91.9% yield) as an off-white foam. MS (ISP): m/z=605.1 [M+H]+ and 607.2 [M+2+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:28])[C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH3:27])=[O:16])=[CH:7]2.Br[CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:11]([O:12][CH2:30][C:31]#[N:32])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:13][N:14]([CH3:28])[C:15]([C:17]1[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[O:19][C:18]=1[CH2:26][CH3:27])=[O:16])=[CH:7]2
Reactant: N#CCBr
Reactant: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1oc2ccccc2c1C(=O)N(C)Cc1ccc2c(Br)c(OCC#N)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
A mixture of 2-ethyl-benzofuran-3-carboxylic acid (5-bromo-6-hydroxy-naphthalen-2-ylmethyl)-methyl-amide (0.5 g, 1.14 mmol), prepared in the previous step, bromoacetonitrile (95 μL, 1.36 mmol) and potassium carbonate (0.79 g, 5.7 mmol) in 20 mL of DMF was stirred under nitrogen at room temperature for 18 h (overnight). The reaction was diluted with ethyl acetate and extracted multiple times with water. The organic layer was dried (MgSO4) and the solvent removed under reduced pressure to give a dark brown oil. The oil was chromatographed on 50 g of silica gel (230-400 mesh) using 5% ethyl acetate in methylene chloride as the eluent. Isolation of the desire component gave 2-ethyl-benzofuran-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (0.39 g, 72%) as a light yellow foam, MS m/z: 477 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([N:7]([CH2:23][C:24]1[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)=[O:6])[CH3:2].[CH:32]#[C:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[CH2:1]([O:3][C:4](=[O:31])[C:5]([N:7]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:32]#[C:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:26][CH:25]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:11][CH:10]=1)=[O:6])[CH3:2]
Reactant: CCCCCCC#Cc1ccc(CN(Cc2ccc(Br)cc2)C(=O)C(=O)OCC)cc1
Reactant: C#CCCCCCC
Product: CCCCCCC#Cc1ccc(CN(Cc2ccc(C#CCCCCCC)cc2)C(=O)C(=O)OCC)cc1
Yield: 32 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step c) but using ethyl[(4-bromobenzyl)(4-oct-1-ynylbenzyl)amino](oxo)acetate and 1-octyne gave the title compound as a pale yellow oil (32%). 1H NMR (CDCl3, 300 MHz) δ 7.38 (m, 4H), 7.16 (d, 2H, J=8.3 Hz), 7.12 (d, 2H, J=7.9 Hz), 4.45 (s, 2H), 4.35 (q, 2H, J=7.2 Hz), 4.28 (s, 2H), 2.42 (t, 4H, J=7.1 Hz), 1.62 (m, 4H), 1.47 (m, 4H), 1.33 (m, 11H), 0.92 (t, 6H, J=6.8 Hz). M+(LC/MS(ESI)): 514.0. HPLC (Condition A), Rt: 6.54 min (HPLC purity: 99.3%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])([F:10])[F:9])=[C:4]([N+:19]([O-])=O)[CH:3]=1>CCOC(C)=O.CCO.[Pd]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])([F:9])[F:10])=[C:4]([NH2:19])[CH:3]=1
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(C)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Commercially available 4-iodo-3-nitrotoluene was reacted with diethyl bromodifluoromethylphosphonate under Cd coupling conditions using Example 25 to yield diethyl (4-methyl-2-nitrophenyl)difluoromethylphosphonate. The diethyl (4-methyl-2-nitrophenyl)difluoromethylphosphonate (500 mg, 1.55 mmol) was dissolved in EtOAc (10 mL) and EtOH (10 mL). Five percent Pd—C (approximately 20 mg) was added and the mixture placed under H2 (1 atm.) and stirred at room temperature overnight. The mixture was then filtered and concentrated in vacuo to give diethyl (4-methyl-2-aminophenyl)difluoromethylphosphonate. The diethyl (4-methyl-2-amino-phenyl)difluoromethylphosphonate was converted to diethyl (2-iodo-4-methylphenyl)-difluoromethylphosphonate using Example 86. Compound 95 was synthesized from this corresponding diethyl phosphonate using procedures similar to those of Example 40. MS (ES−): m/z 347.1 (M−H). 1H NMR: (CD3OD, 400 MHz) δ 7.90 (s, 1H), 7.49 (dd, J=0.8, 8.2, 1H), 7.27 (d, J=8.2, 1H), 2.31 (s, 3H).
Reaction SMILES: [C:1]1([CH:7]=[CH:8][C:9](=[O:21])[CH2:10][C:11](=[O:20])[CH:12]=[CH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(OCC)(=O)C>[C:14]1([CH2:13][CH2:12][C:11](=[O:20])[CH2:10][C:9](=[O:21])[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(C=Cc1ccccc1)CC(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)CC(=O)CCc1ccccc1
Yield: 71.3 %

Procedure:
1,7-Diphenyl-1,6-heptadiene-3,5-dione (3b, 0.56 g, 2.0 mmol) and palladium on activated carbon (0.25 g, 5%) were combined in ethyl acetate (40 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 4 hr at room temperature. The resulting mixture was filtered through celite and the solvent evaporated to afford an oil. The crude oil was purified by preparative thin layer chromatography with ethyl acetate/hexane to give 0.40 g (70%) of an orange-yellow oil; 1H NMR: δ enol form: 2.53 (m, 4H), 2.83 (m, 4H), 5.47 (s, 1H), 7.30 (m, 10H); keto form: 2.53 (m, 4H), 2.83 (m, 4H), 3.54 (s, 2H), 7.30 (m, 10H); 13C NMR: δ 29.4, 31.5, 39.9, 45.0, 99.5, 126.1, 128.3, 128.5, 140.5, 170.4, 172.0, 192.8.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.[C:12]1([NH2:19])[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[NH2:1][C:2]1[C:3]([C:9]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH2:19])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: Nc1ncc(Br)nc1C(=O)O
Reactant: Nc1ccccc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ccccc1NC(=O)c1nc(Br)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-amino-6-bromopyrazine-2-carboxylic acid (140 g, 0.64 mol), o-phenylenediamine (70 g, 0.65 mol) and TBTU (247 g, 0.77 mol) in DMF (1.5 L) at 0° C. was added drop wise DIPEA (166 g, 1.29 mol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water and the resultant precipitate isolated by filtration and washed with water. The precipitate was dried at 50° C. to give the sub-title compound as a brown solid that was used in the next step without further purification product (140 g, 70% Yield). 1H NMR (400 MHz, DMSO) δ 4.95 (br s, 2H), 6.59 (m, 1H), 6.79 (d, 1H), 6.95 (m, 1H), 7.30 (d, 1H), 7.70 (bs, 2H), 8.40 (s, 1H) and 9.65 (s, 1H) ppm; MS (ES+) 307.8.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7]C=2)[C:3]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:2]1.O1C2(CCC(C3C4C(=CC=CC=4)N[N:28]=3)CC2)OCC1>>[NH:1]1[C:9]2=[N:28][CH:7]=[CH:6][CH:5]=[C:4]2[C:3]([CH:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:2]1
Reactant: O=C1CCC(c2c[nH]c3ccccc23)CC1
Reactant: c1ccc2c(C3CCC4(CC3)OCCO4)n[nH]c2c1
Product: O=C1CCC(c2c[nH]c3ncccc23)CC1
Yield: 95 %

Procedure:
This compound was prepared in the manner described above for intermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-azaindole (2.48 g) to afford 1.96 g (95%) of the title compound as a white solid: mp 162-164° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][NH:24][C:25](=[O:34])[CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[NH2:33])[CH2:19][CH2:18]1)=[O:16]>CC#N>[CH3:13][O:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH2:23][N:24]2[C:25](=[O:34])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[NH:33][C:2]2=[O:4])[CH2:19][CH2:18]1)=[O:16]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)[C@H]1CC[C@H](CNC(=O)Cc2ccccc2N)CC1
Solvent: CC#N
Product: COC(=O)[C@H]1CC[C@H](CN2C(=O)Cc3ccccc3NC2=O)CC1
Temperature: 80 °C

Procedure:
Triphosgene (1.3 mmol, 0.39 g) was added portion wise to a solution of trans-4-{[2-(2-amino-phenyl)-acetylamino]-methyl}-cyclohexanecarboxylic acid methyl ester (2.6 mmol, 0.75 g) in dry CH3CN (20 mL) under argon at 0° C. Then the mixture was heated at 80° C. for 1 h with microwave irradiation. The excess of reagent was quenched by careful addition of H2O (2 mL), the solvent was removed under reduced pressure and the crude was purify by flash chromatography on silica (EtOAc-ETP 10:90 to 50:50) to obtain the titled compound (0.24 g, yield 30%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.C[Si](C)(C)O[SiH](C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: C[SiH](C)O[Si](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A 30-mL eggplant flask equipped with a magnetic stirrer was heat dried while pumping to a vacuum of 5 Pa before its interior was purged with nitrogen atmosphere. To the flask, 4-methoxybenzaldehyde (140 mg, 1.0 mmol) and 1,1,1,3,3-pentamethyldisiloxane (371 mg, 2.5 mmol) were added through a syringe, and iron complex A (5 mg, 0.01 mmol) was admitted as catalyst. The solution was stirred at room temperature for 3 hours. At 0° C., THF (1 mL) and tetrabutylammonium fluoride in THF (1 M, 1 mL) were then added to the solution, which was stirred at 0° C. for 1 hour. THF was distilled off in vacuum. The crude product was purified by silica gel-packed column chromatography using hexane/ethyl acetate (3/1) as developing solvent, obtaining 4-methoxybenzyl alcohol (131 mg, 0.95 mmol, 95%). The results as are shown as Entry 2 in Table 6. The resulting alcohol was identified for geometry by 1H and 13C-NMR spectroscopy.