Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[NH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:26][CH2:25][C:24]3[N:23]=[C:22]([CH3:27])[NH:21][C:20]=3[C:19]3[CH:28]=[C:29]([Cl:32])[CH:30]=[CH:31][C:18]2=3)=[O:16])=[CH:11][C:10]=1[CH3:33].CCN(C(C)C)C(C)C>ClCCl>[Cl:32][C:29]1[CH:30]=[CH:31][C:18]2[N:17]([C:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][NH:7][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[C:10]([CH3:33])[CH:11]=3)=[O:16])[CH2:26][CH2:25][C:24]3[N:23]=[C:22]([CH3:27])[NH:21][C:20]=3[C:19]=2[CH:28]=1
Reactant: Cc1nc2c([nH]1)-c1cc(Cl)ccc1N(C(=O)c1ccc(CN)c(C)c1)CC2
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c([nH]1)-c1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)C(C)C)c(C)c1)CC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 85 %

Procedure:
Isobutyryl chloride (0.07 ml, 0.07 mmol) was added to a solution of (4-aminomethyl-3-methyl-phenyl)-(9-chloro-2-methyl-4,5-dihydro-1H-1,3,6-triaza-benzo[e]azulen-6-yl)-methanone from Example E125.3 (24 mg, 0.07 mmol) in dichloromethane (3 ml) and DIEA (0.10 ml, 0.57 mmol) at 0° C. The mixture was stirred for 20 h at room temperature then solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 5% methanol:95% dichloromethane to 10% methanol:90% di-chloromethane) to give a colourless oil identified as the title compound 24 mg, 85%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1.[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH2:15].O>CCO.Cl>[F:12][C:13]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][NH:5][C:4](=[O:11])[CH:3]=1
Reactant: Nc1ccc(I)cc1F
Reactant: O=c1cc(Cl)c([N+](=O)[O-])c[nH]1
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1cc(Nc2ccc(I)cc2F)c([N+](=O)[O-])c[nH]1
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 45 %

Procedure:
To the mixture of 4-chloro-5-nitropyridin-2(1H)-one (90.1 mg, 0.517 mmol) and 2-fluoro-4-iodoaniline (137.5 mg, 0.58 mmol) dissolved in EtOH (5 mL) was added 6 drops of HCl (37% wt in water). The reaction vessel was closed and heated at 90° C. for 48 hours. After cooling to room temperature, water was added, and the solution was stirred at room temperature for 20 min. The precipitate was filtered, washed with water, dried under vacuum and used for the next reaction without further purification. (87.3 mg, 45% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:24][C@@H:25]1[CH2:29][CH2:28][NH:27][CH2:26]1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:27]2[CH2:28][CH2:29][C@@H:25]([F:24])[CH2:26]2)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: F[C@@H]1CCNC1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CC[C@@H](F)C2)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following similar methods to those described in Preparation 352 starting from (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester and (R)-3-fluoro-pyrrolidine. MS: [M+H]+=392.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[Na+]>OS(O)(=O)=O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]2[CH2:5][CH2:4][NH:3][CH2:2][CH2:1][C:7]=2[CH:8]=1)([O-:14])=[O:13]
Reactant: c1ccc2c(c1)CCNCC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Temperature: 0 °C
Reaction time: 0.38 h
Yield: 46 %

Procedure:
A solution of 2,3,4,5-tetrahydro-1H-benzo[d]azepine dissolved in conc. H2SO4 (1.5 mL) was cooled to 0° C. and a mixture of concentrated H2SO4 (0.12 mL) and fuming HNO3 (0.06 mL) (also cooled to 0° C.) was added dropwise. After the addition was complete, the mixture was stirred for 15-30 min. The reaction mixture was poured onto 10 g of crushed ice, followed by the dropwise addition of 20% NaOH solution. The mixture was extracted with EtOAc (3×). The organic layer was washed with H2O, dried (Na2SO4), concentrated and under vacuum to afford 7-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a brown liquid (0.12 g, 46% yield). LC-MS (EI) m/z: 193.0 (M+H+).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:24][CH:23]=1)=O.C(O)(=O)C>C(#N)C>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]2[C:13](=[CH:12][CH:11]=1)[NH:16][C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=1)=[C:19]2[CH3:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NNc1ccc(OCc2ccccc2)cc1
Reactant: CCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1c(-c2ccc(OCc3ccccc3)cc2)[nH]c2ccc(OCc3ccccc3)cc12
Temperature: 81.5 °C

Procedure:
4-Benzyloxy phenyl hydrazine hydrochloride (1.0 g, 4 mmol), 4-benzyloxy propiophenone (0.96 g, 4 mmol) and acetic acid (10 μl, 0.17 mmol) were suspended in 15 ml of acetonitrile and the mixture was refluxed for 12 hrs at a temperature of 81-82° C. Then mixture was cooled to 10-15° C. within 1 hr. The white product was filtered and washed with chilled acetonitrile (3 ml). 5-Benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-1H-indole (1) melting at 149-150° C. was obtained in a yield of 1.0 g (60%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=1.[CH3:23][O:24][CH2:25][CH2:26][O:27][P:28]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([O:43][CH3:44])[CH:37]=1)(=[O:34])[O:29][CH2:30][CH2:31][O:32][CH3:33]>>[CH3:33][O:32][CH2:31][CH2:30][O:29][P:28]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=3[C:11](=[O:12])[NH:13][CH3:14])[C:5]([C:19]([F:22])([F:21])[F:20])=[CH:4][N:3]=2)=[C:38]([O:43][CH3:44])[CH:37]=1)(=[O:34])[O:27][CH2:26][CH2:25][O:24][CH3:23]
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1C(F)(F)F
Reactant: COCCOP(=O)(Cc1ccc(N)c(OC)c1)OCCOC
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc(CP(=O)(OCCOC)OCCOC)cc2OC)ncc1C(F)(F)F
Yield: 61.7 %

Procedure:
The title compound was prepared according to Example 102 using 2-{[2-chloro-5-(trifluoromethyl)pyrimidin-4-yl]amino}-N-methylbenzamide (Compound 104A, 50.0 mg, 0.15 mmol) and bis(2-methoxyethyl)(4-amino-3-methoxybenzyl)phosphonate (Compound 217C, 55.4 mg, 0.17 mmol). 58.1 mg (61%) of the desired product obtained after purification. 1H NMR (400 MHz, MeOD) δ ppm 8.24-8.35 (m, 2H), 7.95 (d, J=8.08 Hz, 1H), 7.62 (dd, J=7.83, 1.52 Hz, 1H), 7.46 (ddd, J=8.53, 7.39, 1.52 Hz, 1H), 7.16 (td, J=7.58, 1.01 Hz, 1H), 6.96 (t, J=2.02 Hz, 1H), 6.72-6.80 (m, 1H), 4.05-4.16 (m, 4H), 3.87 (s, 3H), 3.50-3.57 (m, 4H), 3.33 (s, 6H), 3.20-3.29 (m, 2H), 2.89 (s, 3H). MS (ES+): m/z 628.16/629.20 (100/98) [MH+]. HPLC: tR=1.39 min (Micromass TOF: polar—3 min).
Reaction SMILES: C(OC[C:6]1[O:7][C:8]2[C:14]([F:15])=[CH:13][CH:12]=[C:11]([F:16])[C:9]=2[CH:10]=1)(=O)C.C(=O)([O-])[O-:18].[K+].[K+].C(OCC)(=O)C>CO>[F:16][C:11]1[C:9]2[CH:10]=[C:6]([OH:18])[O:7][C:8]=2[C:14]([F:15])=[CH:13][CH:12]=1
Reactant: CC(=O)OCc1cc2c(F)ccc(F)c2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1cc2c(F)ccc(F)c2o1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
The 2-acetoxymethyl-4,7-difluorobenzofuran (252 mg) was dissolved in methanol (5 ml). After adding potassium carbonate (455 mg) at room temperature, the resulting mixture was stirred at the same temperature for 2 hr. Then ethyl acetate was added to the liquid reaction mixture and the organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: 5% ethyl acetate/n-hexane) to give 4,7-difluoro-2-hydroxybenzofuran (161 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[Cl:26][C:27]1[C:28]([O:36][CH3:37])=[N:29][CH:30]=[CH:31][C:32]=1B(O)O>CN(C=O)C>[Cl:26][C:27]1[C:28]([O:36][CH3:37])=[N:29][CH:30]=[CH:31][C:32]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: COc1nccc(B(O)O)c1Cl
Solvent: CN(C)C=O
Product: COc1nccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 3-chloro-2-methoxypyridine-4-boronic acid (CAS RN 957060-88-7) and using DMF as solvent. Pale yellow sticky solid (11%). MS (ESI): m/z=489.9 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[CH:2].S(Cl)([Cl:14])=O>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([Cl:14])=[O:7])#[CH:2]
Reactant: O=S(Cl)Cl
Reactant: C#Cc1cccc(C(=O)O)c1
Product: C#Cc1cccc(C(=O)Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Air in a 20 ml Schlenk tube was replaced by Ar gas and 1.02 g (7 mmol) of m-ethynylbenzoic acid and 5 g (42 mmol) of thionyl chloride were added to the tube and the mixture was stirred at 50° C. for 2 hours and then excess thionyl chloride was removed by distillation under reduced pressure to obtain m-ethynylbenzoyl chloride. To the m-ethynylbenzoyl chloride obtained was added a solution having 2.44 g (14.4 mmol) of diphenylamine dissolved in 7 ml of dichloromethane under ice-cooling and then the resultant mixture was stirred at room temperature for one hour. After completion of the stirring, dichloromethane was removed by distillation under reduced pressure and 35 ml of water was added to the resultant residue. The mixture was extracted with 35 ml of ethyl acetate, the extract was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure using an evaporator. The resultant crude reaction product was purified by column chromatography (hexane/AcOEt10/1) using silica gel to obtain 0.7 g of 3-ethynyl-N,N-diphenylbenzamide which is a desired product as pale yellow liquid. (Yield: 35%)
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:29])[CH2:15][N:16]2[CH:19]([S:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][C:17]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:38])C=1.S([O-])([O-])=O.[Na+].[Na+].C(=O)([O-])O.[Na+]>ClCCl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH:13][C:14](=[O:29])[CH2:15][N:16]2[CH:19]([S:20]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:38])[CH2:18][C:17]2=[O:28])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CN1C(=O)CC1SCc1ccccc1)NCCCCCCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(CN1C(=O)CC1S(=O)Cc1ccccc1)NCCCCCCc1ccccc1
Reaction time: 1 h
Yield: 20.3 %

Procedure:
A solution of N-(6-phenylhexyl)-4-benzylthio-2-oxoazetidin-1-yl acetamide (18.0 g, 43.8 mmol) in dichloromethane (500 ml) was cooled to -70° C. and a solution of m-chloroperbenzoic acid (6.7 g, 43.8 mmol) in dichloromethane (500 ml) added dropwise with stirring over 60 min. After a further 3 h at -60° C., the reaction mixture was shaken with a mixture of saturated aqueous sodium sulphite and saturated sodium hydrogen carbonate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to a solid which was titurated with ether and filtered. Two recrystallisations from ethyl acetate gave (4R,SR/4S,SS) N-(6phenylhexyl)-4-benzylsulphinyl-2-oxoazetidin-1-yl acetamide (3.8 g, 20%) mp 138-140° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:14])/[CH:6]=[CH:7]/[C:8]1[N:9]=[N:10][N:11]([CH3:13])[CH:12]=1>>[CH3:13][N:11]1[CH:12]=[C:8](/[CH:7]=[CH:6]/[C:5]([OH:14])=[O:4])[N:9]=[N:10]1
Reactant: COC(=O)/C=C/c1cn(C)nn1
Agent: [Na+]
Agent: [OH-]
Product: Cn1cc(/C=C/C(=O)O)nn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.5 %

Procedure:
10% Sodium hydroxide solution (3 ml) was added to a solution of the product from step 1 (3.2 g). The mixture was stirred at room temperature for 15 hours, further 10% sodium hydroxide solution (2 ml) added and then heated to reflux for 3 hours. On cooling the reaction mixture was partitioned between ethyl acetate and water. The organics were re-extracted with saturated sodium hydrogen carbonate solution and the combined aqueous extracts acidified to pH 1 with conc. hydrochloric acid. After extraction into ethyl acetate and dying over magnesium sulphate the solvent was removed to afford the title compound, (748 mg); 1H NMR (d6 -DMSO) 4.07 (3H, s), 6.53 (1H, d, J16.0 Hz), 7.53 (1H, d, J16.0 Hz), 8.44 (1H, s), 12.48 (1H, br).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.Br[CH:10]([CH3:19])[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([CH3:19])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:8]=2)[N:7]=1
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: Nc1ccc(Cl)nn1
Solvent: CC#N
Product: Cc1c(-c2ccccc2)nc2ccc(Cl)nn12
Yield: 80.9 %

Procedure:
A stirred solution of 6-chloropyridazin-3-amine (1.00 g, 7.71 mmol) and 2-bromo-1-phenylpropan-1-one (Sigma-Aldrich, 1.54 g, 7.71 mmol) in acetonitrile (50 mL) is heated at 80° C. for 16 hours. The mixture is concentrated to dryness and purified via chromatography (hexanes to EtOAc) to afford the title compound (1.52 g, 81%) as a tan solid: Rf 0.52 (1:1 EtOAc:hexanes); LCMS (m/z)=244.2, 246.3 [M+H]+, tR=2.61 min.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@H:8]2[N:12](C(=O)C(C)(C)C)[C:11](=[O:19])[C@H:10]([CH3:20])[CH2:9]2)=[CH:3][CH:2]=1.[ClH:27].C(O)(=[O:30])C>>[ClH:27].[NH2:12][C@H:8]([CH2:7][C:4]1[CH:3]=[CH:2][C:1]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:6][CH:5]=1)[CH2:9][C@@H:10]([CH3:20])[C:11]([OH:19])=[O:30]
Reactant: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)C(C)(C)C)C1=O
Reactant: CC(=O)O
Agent: Cl
Product: C[C@H](C[C@H](N)Cc1ccc(-c2ccccc2)cc1)C(=O)O

Procedure:
5 g (3R,5S)-5-biphenyl-4-ylmethyl-3-methylpyrrolidin-2-one of example 6 were mixed with a mixture of acetic acid and concentrated hydrochloric acid (50 ml ratio 1:1) and stirred under reflux for about 20 hours. The solution was then concentrated under vacuum and the residue crystallised from acetic acid/ethyl acetate to yield 4.7 g of (2R,4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid hydrochloride (3-a, R1=R2=R3=H). 1H-NMR (DMSO): 1.10 (3H, s, CH3); 1.58 (1H, m, 3-CHH); 1.88 (1H, m, CHH); 2.64 (1H, m, 4-CH); 2.88 (1H, dd, 5-CHH); 3.01 (1H, dd, 5-CHH); 3.45 (1H, m, 2-CH); 7.38 (3H, m, aromatic); 7.47 (2H, m, aromatic); 7.66 (4H, m, aromatic); 8.07 (2H, s, NH); 12.25 (1H, s, CO2H). m/z: 284 (MH+, 100%); 267 (25); 249 (47); 221 (13); 193 (24).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:14][C:15]#[N:16]>>[Br:1][C:2]1[O:6][C:5](/[CH:7]=[C:14](/[C:13]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:11]([O:10][CH3:9])[CH:12]=2)\[C:15]#[N:16])=[CH:4][CH:3]=1
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccc(Br)o1
Product: COc1ccc(/C(C#N)=C/c2ccc(Br)o2)cc1OC
Yield: 83.6 %

Procedure:
5-Bromo-2-furaldehyde (350 mg) was condensed with 3,4-dimethoxybenzyl cyanide (354 mg) through Method A (production step 2), to thereby yield the target product (yield: 558 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][C:25]=1[C:33]([F:36])([F:35])[F:34]>C1COCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:32])=[CH:26][C:25]=1[C:33]([F:34])([F:35])[F:36]
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 58.9 %

Procedure:
To a solution of 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) in 1.6 mL THF was added 4-chloro-3-(trifluoromethyl)phenyl isocyanate (16.8 mg, 0.076 mmol) and the reaction stirred at rt. After 45 min, the reaction was briefly warmed to approximately 50° C. and then allowed to cool to rt. After 1.5 hours the stirring was stopped and the reaction left to stand at rt overnight. Then using a stream of nitrogen and gentle heating, the THF was evaporated to 1 mL, let mixture stand for 30 minutes, then filtered and rinsed with 50% EtOAc in hexane to give the title compound as an off-white solid (20.9 mg, 59%). 1H NMR (DMSO-d6) δ: 10.69 (br. s, 1H), 9.14 (br. s, 1H), 8.82 (br. s, 1H), 8.10 (d, J=2.3 Hz, 1H), 7.97-7.99 (m, 1H), 7.59-7.65 (m, 2H), 7.42-7.45 (m, 3H), 7.26 (d, J=8.8 Hz, 2H), 7.05-7.08 (m, 1H), 7.01 (d, J=7.9 Hz, 1H), 4.20-4.24 (m, 1H), 3.70-3.75 (m, 1H), 3.52-3.59 (m, 2H), 2.94-3.01 (m, 1H).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1.[I-:12].[K+]>>[I:12][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][O:7][C:8]2=[O:9])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: Nc1ccc2c(c1)C(=O)OC2
Agent: [K+]
Product: O=C1OCc2ccc(I)cc21
Yield: 23 %

Procedure:
The 6-iodophthalide was prepared in 23% yield via diazotization of 6-aminophthalide and subsequent treatment of the diazonium salt with potassium iodide according to the method of Tassman (Rec. Trav. Chim. Pays-Bas, 46, 653).
Reaction SMILES: C([O:4][C:5]1[CH:15]=[CH:14][C:8]2[O:9][C:10]([CH3:13])([CH3:12])[O:11][C:7]=2[CH:6]=1)(=O)C.[OH-].[K+].Cl>CO.O>[CH3:12][C:10]1([CH3:13])[O:9][C:8]2[CH:14]=[CH:15][C:5]([OH:4])=[CH:6][C:7]=2[O:11]1
Reactant: CC(=O)Oc1ccc2c(c1)OC(C)(C)O2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)Oc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
A solution of 0.6 gram (0.003 mole) of 2,2-dimethylbenzo[3,4-d]1,3-dioxolan-5-yl acetate in 5 mL of methanol was stirred and a solution of 1.1 grams (0.02 mole) of potassium hydroxide in 5 mL of water was added in one portion. Upon completion of addition the reaction mixture was stirred at ambient temperature during a two hour period. After this time the reaction mixture was diluted with 50 mL of water and acidified with concentrated hydrochloric acid. The mixture was then extracted with two 100 mL portions of ethyl acetate. The combined extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure, yielding 0.36 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([O:25][CH2:26][CH:27]=[C:28]([Cl:30])[Cl:29])[CH:6]=[C:7]([CH2:23][CH3:24])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16](OCC)[O:17]CC)[CH3:2].C(O)(=O)C.Cl>O>[CH2:23]([C:7]1[CH:6]=[C:5]([O:25][CH2:26][CH:27]=[C:28]([Cl:29])[Cl:30])[CH:4]=[C:3]([CH2:1][CH3:2])[C:8]=1[O:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]=[O:17])[CH3:24]
Reactant: CCOC(COCCCCOc1c(CC)cc(OCC=C(Cl)Cl)cc1CC)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a mixture of 9.27 g of 3,5-diethyl-1-(3,3-dichloro-2-propenyloxy)-4-(4-(2,2-diethoxyethoxy)butyloxy)benzene, 25 ml of acetic acid, and 5 ml of water was added 1 ml of concentrated hydrochloric acid at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, aqueous sodium hydrogencarbonate solution, and aqueous sodium chloride solution in this order, dried over anhydrous magnesium sulfate, and concentrated, which afforded 7.62 g (yield, 98%) of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]1[N:17]3[N:18]=[CH:19][CH:20]=[N:21][C:16]3=[N:15][N:14]=1)=[CH:7][CH:6]=2.[CH3:22][N:23]1[CH:27]=[C:26](B2OC(C)(C)C(C)(C)O2)[CH:25]=[N:24]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[CH3:22][N:23]1[CH:27]=[C:26]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][C:8]([CH2:12][C:13]2[N:17]4[N:18]=[CH:19][CH:20]=[N:21][C:16]4=[N:15][N:14]=2)=[CH:7][CH:6]=3)[CH:25]=[N:24]1
Reactant: Brc1cnc2ccc(Cc3nnc4nccnn34)cc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cnc3ccc(Cc4nnc5nccnn45)cc3c2)cn1
Temperature: 135 °C

Procedure:
A mixture of 3-bromo-6-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl-quinoline (69 mg, 0.204 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (51 mg, 0.25 mmol), potassium carbonate (56 mg. 0.41 mml), 1,4-dioxane (2 mL) and water (1 mL) was bubbled nitrogen gas through for 10 minutes. After such time dichlorobis(triphenylphosphine)palladium (8 mg, 5 mol %) was added, the vial sealed and heated in a microwave for 1500 seconds at 135° C. The mixture was diluted with dichloromethane and brine, before the organic phase was concentrated onto silica gel and via flash column chromatography (SiO2 4 g, dichloromethane/CH3OH 0-10%) to return the title compound a white solid (11 mg, 16%). Analytical data presented in Table 2.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH2:21])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7].Cl[C:24]([O:26][CH3:27])=[O:25]>>[CH3:1][CH:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][NH:21][C:24]([O:26][CH3:27])=[O:25])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7]
Reactant: COC(=O)Cl
Reactant: CC(C)CCNC(=O)c1ccccc1-c1ccccc1CN
Product: COC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCC(C)C

Procedure:
From 0.34 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid (3-methylbutyl)amide (precursor 5c) and methyl chloroformate, according to the general working procedure followed by extraction with EA and purification by flash chromatography 29 mg of 2′-(methoxycarbonylaminomethyl)-biphenyl-2-carboxylic acid (3-methylbutyl)amide were obtained as a resin.
Reaction SMILES: [C:1]([CH2:9][C:10]([N:12]1[CH2:19][CH2:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[S:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+](=[CH2:22])=[N-]>CO.C(O)(=O)C>[CH3:22][O:15][C:14](=[O:16])[C@@H:13]1[CH2:17][CH2:18][CH2:19][N:12]1[C:10](=[S:11])[CH2:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(CC(=S)N1CCC[C@H]1C(=O)O)c1ccccc1
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CCCN1C(=S)CC(=O)c1ccccc1
Reaction time: 0.25 h

Procedure:
1-(2-Benzoylthioacetyl)-L-proline obtained in Example 1, is dissolved in methanol and an ethereal solution of diazomethane is added until there is a persistent yellow color. After 15 minutes, a few drops of acetic acid are added and the solvent is removed in vacuo to obtain 1-(2-benzoylthioacetyl)-L-proline methyl ester.