Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([Mg]I)=CC=1.[CH3:10][O:11][C:12](=[O:30])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1CCC(C1C=CC(F)=CC=1)=O>C(OCC)C>[CH3:10][O:11][C:12](=[O:30])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]1
Reactant: COC(=O)C1CCCCN1CCC(=O)c1ccc(F)cc1
Agent: Clc1ccc([Mg]I)cc1
Solvent: CCOCC
Product: COC(=O)C1CCCCN1
Temperature: 0 °C
Yield: 4 %

Procedure:
7 ml (2 mmol) of 0.28 M solution of 4-chlorophenylmagnesium iodide in diethyl ether [prepared from 1-chloro-4-iodobenzene (Aldrich) and magnesium] was added dropwise to an ice-cooled solution of 0.605 g (2 mmol) N-[3-4-fluorophenyl)-3-oxopropyl]pipecolic acid methyl ester (from Step 1) in 12 ml anhydrous diethyl ether with stirring under nitrogen. The mixture was stirred at room temperature for 16 hours, poured onto crushed ice and extracted with dichloromethane. The combined organic extracts were washed with brine, concentrated and the residue purified by preparative silica gel TLC with 25% ethyl acetate in hexanes to give 0.037 g (yield 4.5%) N-[3-4-chlorophenyl)-3-(4-fluorophenyl)-3-hydroxypropyl]pipecolic acid methyl ester (Compound B30).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:16]2[CH2:18][CH2:17]2)[CH:9]=[C:10]([F:15])[C:11](OC)=[O:12])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:16]2[CH2:17][CH2:18]2)[CH:9]=[C:10]([F:15])[CH2:11][OH:12])=[CH:6][CH:7]=1
Reactant: COC(=O)C(F)=CC(c1ccc(Cl)cc1)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OCC(F)=CC(c1ccc(Cl)cc1)C1CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 78 %

Procedure:
Methyl 4-(4-chlorophenyl)-4-cyclopropyl-2-fluorobut-2-enoate prepared as described in Example 1 (0.91 g) in dry diethyl ether (20 ml) was added dropwise to a stirred suspension of lithium aluminium hydride (0.34 g) in dry diethyl ether (25 ml) at 0° C. Stirring was continued during 40 minutes, while the mixture warmed to room temperature. Water (4 ml) was added, and the mixture was extracted with diethyl ether (3×20 ml). The combined organic layers were washed with water (3×10 ml), dried and evaporated under reduced pressure. The residual oil was chromatographed on silica gel using diethyl ether/hexane (2:3) to yield 4-(4-chlorophenyl)-4-cyclopropyl-2-fluorobut-2-enol (0.61 g, 78%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:22]([O-])=O)[CH:8]=2)[N:3]=1.C([O-])=O.[NH4+]>[Pd].CO.C1COCC1>[NH2:22][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([CH3:1])[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]2[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)c1c(C)nc2ccc([N+](=O)[O-])cc2c1-c1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(C)nc2ccc(N)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
10% palladium on carbon (0.22 g) was added to a solution of the product of Step 1 (1.05 g, 3.25 mmol) and ammonium formate (2.05 g, 32.5 mmol) in MeOH/THF mixture (1:1, 125 ml) under N2. The resulting mixture was stirred for 30 min at room temperature, filtered through Celite bed and filtrate evaporated to dryness. The residue was diluted to 50 ml with CH2Cl2, washed with H2O, dried over anhydrous MgSO4, filtered and filtrate evaporated to dryness to give the title product as a heavy oil (0.91 g, 98%), which was used in next step without further purification. 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J=8.9 Hz, 1H), 7.44(m, 3H), 7.31(m, 2H), 7.13 (dd, J=2.5, 8.9 Hz, 1H), 6.61(d, J=2.5 Hz, 1H), 3.78(broad s, 2H), 3.53(s, 3H), 2.67(s, 3H).
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1N.[NH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:19]([S:23]([OH:26])(=[O:25])=[O:24])=[CH:18][C:17]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:16][C:15]=2[C:14]=1S(O)(=O)=O.NC1C=CC2C(=C(S(O)(=O)=O)C=C(S(O)(=O)=O)C=2)C=1>OS(O)(=O)=O.O=S(=O)=O>[CH:22]1[C:13]([NH2:12])=[CH:14][C:15]2[C:20](=[C:19]([S:23]([OH:26])(=[O:25])=[O:24])[CH:18]=[C:17]([S:27]([OH:30])(=[O:28])=[O:29])[CH:16]=2)[CH:21]=1
Reactant: Nc1ccc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1S(=O)(=O)O
Agent: Nc1ccc2cc(S(=O)(=O)O)cc(S(=O)(=O)O)c2c1
Agent: Nc1ccc2ccccc2c1
Agent: O=S(=O)(O)O
Product: Nc1ccc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1

Procedure:
When 2-naphthylamine (BNA) is sulfonated in oleum, the sulfonation products are principally 2-amino-1,5,7-naphthalene trisulfonic acid and 2-amino-6,8-naphthalenedisulfonic acid (Amino G Acid). Hydrolysis of the trisulfonic acid provides Amino J Acid (2-amino-5,7-naphthalenedisulfonic acid). Thus, using this so-called BNA route, it is possible to prepare a fixed ratio of both Amino J Acid and Amino G Acid. However, because of the known carcinogenicity of 2-naphthylamine, this route is not used. Amino J Acid is primarily made by the sulfonation of 2-amino-1-naphthalenesulfonic acid (Tobias Acid) with 30% oleum followed by hydrolysis of the intermediate 1,5,7-trisulfonic acid. Amino G Acid, on the other hand, is made by the sulfonation of beta naphthol with sulfuric acid and then with 20% oleum, in controlled steps from 15°-80°C., followed by amination by the Bucherer Reaction.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH:7]=[CH:8][CH:9]1[O:13][N:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:16][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[NH3:34]>CO>[C:1]([O:5][C:6](=[O:33])[CH2:7][CH:8]([NH2:34])[CH:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)=[CH:18][CH:19]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: N
Reactant: Cc1cc(COc2ccc(C3=NOC(C=CC(=O)OC(C)(C)C)C3)cc2)c2ccccc2n1
Solvent: CO
Product: Cc1cc(COc2ccc(C3=NOC(C(N)CC(=O)OC(C)(C)C)C3)cc2)c2ccccc2n1
Temperature: 60 °C
Yield: 97 %

Procedure:
The product from step 10c (0.3 g, 0.67 mmol) was dissolved in methanol (10 mL) and condensed ammonia (10 mL) in a stainless steel pressure reactor and heated to 60° C. for 5 h. The reaction was complete and was concentrated to give 3-amino-3-{3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-propionic acid tert-butyl ester (0.3 g, 97%) as an oil. MS found: (M+H)+=462.
Reaction SMILES: [Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([C:23]1[N:24]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:5].[O-]S(C(F)(F)[F:47])(=O)=O.F[N+]1C(Cl)=CC=CC=1Cl>ClC(Cl)C>[Cl:1][C:2]1[CH:41]=[CH:40][CH:39]=[CH:38][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH3:18])=[N:16][N:15]=[C:14]1[CH2:19][NH:20][C:21]([C:23]1[N:24]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:25]2[C:30]([C:31]=1[F:47])=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[O:5]
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: CCOC(=O)Cn1c(C(=O)NCc2nnc(C)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: CC(Cl)Cl
Product: CCOC(=O)Cn1c(C(=O)NCc2nnc(C)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)c(F)c2ccccc21

Procedure:
Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetate is dissolved in dichloroethane, and reacted with 1-fluoro-2,6-dichloropyridiniumtriflate to give ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-methyl[1,2,4]triazol-3-ylmethylcarbamoyl)-3-fluoroindole-1-acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9].[Cl:14][C:15]1[N:16]=[N:17][C:18]([Cl:22])=[C:19](Cl)[N:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:14][C:15]1[N:16]=[N:17][C:18]([Cl:22])=[C:19]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([CH:11]([CH3:13])[CH3:12])(=[O:10])=[O:9])[N:20]=1
Reactant: Clc1nnc(Cl)c(Cl)n1
Reactant: CC(C)S(=O)(=O)c1ccccc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Temperature: 25 °C

Procedure:
To a solution of 1-Amino-2-(isopropylsulphonyl)benzene (350 mg, 1.6 mmol) and 3,5,6-trichloro-1,2,4-triazine (1.6 mmol) in CH2Cl2, is added triethylamine (2 mmol). The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:46][CH3:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][O:40]C(OCC)C)[CH:29]=[C:28]([CH2:48][CH3:49])[N:27]=1.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH:33]([CH2:46][CH3:47])[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40])[CH:29]=[C:28]([CH2:48][CH3:49])[N:27]=1
Reactant: CCOC(C)OCCCCCCC(CC)Nc1cc(CC)nc(Cl)n1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: Cl
Solvent: CCO
Product: CCc1cc(NC(CC)CCCCCCO)nc(Cl)n1
Yield: 90 %

Procedure:
In 50 ml of ethanol was dissolved 4.7 g of dl-5-chloro-6-ethyl-4-[1-ethyl-7-(1-ethoxyethoxy)heptyl]aminopyrimidine, and 10 ml of 1N-HCl was added to the solution and the mixture was refluxed for one hour under stirring After removing ethanol under reduced pressure, the residue was was made alkaline with a sodium hydroxide aqueous solution and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=2:1) to give 3.8 g of the title compound as pale yellow oily liquid. nD23.0 1.5263.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:20]([O:21]C(=O)C)[C@H:19]([O:25]C(=O)C)[C@@H:18]([CH2:29][O:30]C(=O)C)[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2].C[O-].[Na+]>CO>[C:1]([NH:4][C@H:5]1[C@@H:20]([OH:21])[C@H:19]([OH:25])[C@@H:18]([CH2:29][OH:30])[O:17][C@@H:6]1[S:7][CH2:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1SCC=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)N[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1SCC=Cc1ccccc1
Yield: 90.5 %

Procedure:
Compound 8 (120 mg) is deacetylated with sodium methoxide in methanol to give 9 (80 mg); m.p. 156°-157° C. (MeOH--EtOAc).
Reaction SMILES: I/[CH:2]=[CH:3]/[C@@H:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br-].[CH2:25]([Zn+])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]1([CH2:25]/[CH:2]=[CH:3]/[C@H:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:13][CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: CCOC(=O)C[C@@H](/C=C/I)c1ccc(OC2CCCCO2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C[C@H](/C=C/Cc1ccccc1)c1ccc(OC2CCCCO2)cc1
Reaction time: 17.5 h

Procedure:
To a stirred solution of 83.4 (571.9 mg, 1.33 mmol, 1 eq., MW 430.29) in THF (15 mL) at 23° C. was added Pd(PPh3)4 (153.6 mg, 0.133 mmol, 0.1 eq., MW 1155.58) followed by dropwise addition of benzylzinc bromide solution (3.2 mL, 1.6 mmol, 1.2 eq., 0.5 M). After 17.5 hours, water (10 mL) was added to quench the reaction. The mixture was extracted with EtOAc (2×50 mL), dried with MgSO4, and filtered. The organic layer was concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0 to 20% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated providing a colorless oil that was used without further purification.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1.[I:20]I>CCCCCC.O1CCCC1>[I:20][C:13]1[CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[N:10]=[N:9][C:8]=1[O:7][CH3:6]
Reactant: II
Reactant: COc1ccc(-c2ccncc2)nn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1nnc(-c2ccncc2)cc1I
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
45 ml 1.6M solution of n-butyllithium in hexane are added at −30° C. to a 10.2 g 2,2,6,6-tertamethylpiperidine in 100 ml THF and the mixture stirred at 0° C. for 30 min. After cooling to −75° C. 11.2 g 3-methoxy-6-pyridin-4-yl-pyridazine dissolved 300 ml THF are added and the solution stirred at −75° C. for 35 min. The cold (−75° C.) reaction mixture is subsequently added at a cold (−75° C.) solution of 18.3 g iodine in 400 ml THF (tetrahydrofuran) and stirred at −75° C. for 1.5 h. The reaction is quenched by adding 80 ml methanol/THF (1:1) at −75° C. and 300 ml saturated aqueous NaHCO3 at room temperature and extracted with dichloromethane. The organic layer is ished with 5% aqueous Na2S2O3 and saturated sodium chloride solution, dried (MgSO4) and the solvens removed. The crude product is purified by chromatography on silica gel to yield 14.4 g of 4-iodo-3-methoxy-6-pyridin-4-yl-pyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.CN(C)C=O.[H-].[Na+].Br[CH2:21][CH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O>[O:25]1[CH2:26][CH2:27][CH:22]([CH2:21][N:7]2[C:6]3[CH:12]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:23][CH2:24]1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: BrCC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2c(c1)N(CC1CCOCC1)C(=O)CO2
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
4.9 g (0.03 mol) of 6-amino-3,4-dihydro-2H-1,4-benzoxazin-3-one is introduced into 50 ml of dimethylformamide. At 5° C., 0.79 g (0.033 mol) of sodium hydride is added, and the mixture is stirred for 30 minutes at this temperature. Subsequently, 5.9 g (0.033 mol) of 4-bromomethyltetrahydropyran is added, the mixture is stirred for 3 hours at 60° C., 200 ml of water is added, extraction is carried out twice with methylene chloride, followed by drying and evaporation of the solvent under reduced pressure. There is obtained 5 g (64%) of 4-(tetrahydropyran-4-ylmethyl)-6-amino-3,4-dihydro-2H-1,4-benzoxazin-3-one as an oil.
Reaction SMILES: [Br-].[O:2]([CH2:9][CH2:10][CH2:11][CH2:12][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:32]([C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:36][CH:35]=1)=O>>[O:2]([CH2:9][CH2:10][CH2:11][CH:12]=[CH:32][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[CH:38][CH:39]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: c1ccc(OCCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCOC(=O)CCc1ccc(C=O)cc1
Agent: [Br-]
Product: CCOC(=O)CCc1ccc(C=CCCCOc2ccccc2)cc1

Procedure:
Preparation takes place in analogy to Example XLIII from (4-phenoxybutyl)-(triphenyl)phosphonium bromide and ethyl 3-(4-formylphenyl)propanoate. The product is obtained as an E/Z mixture.
Reaction SMILES: C([O:3][C:4](=[O:16])[CH:5]([CH3:15])[CH2:6][CH:7]=[CH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)C>[OH-].[Na+].CO>[CH3:15][CH:5]([CH2:6][CH:7]=[CH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:4]([OH:16])=[O:3]
Reactant: CCOC(=O)C(C)CC=Cc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(CC=Cc1cccnc1)C(=O)O

Procedure:
A solution of 9.95 g of (R,S)-Z]-2-methyl-5-(3-pyridinyl)-4-pentenoic acid ethyl ester in 75 mL of 1N NaOH and 75 mL of methanol were stirred at reflux for 3 hours, then most of the methanol was removed under reduced pressure. After the solution was extracted with dichloromethane (3×50 mL). the aqueous layer was neutralized with 75 ml of 1N HCl and extracted with dichloromethane (4×40 mL). The dried (Na2SO4) extracts were evaporated to give 7.28 g of a solid which was crystallized from ether-hexane to yield 6.12 g of [(R,S)-Z]-2-methyl-5-(3-pyridinyl)-4-pentenoic acid, mp 79°-82° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.Cl.[CH3:25][NH:26][O:27][CH3:28].C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH3:10])[C:11]([N:26]([O:27][CH3:28])[CH3:25])=[O:13])=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 81.5 %

Procedure:
To a solution of Boc-alanine (20 grams, 105.7 mmol) in dichloromethane (170 ml) was added HOBT (14.28 g, 105.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (10.31 g, 105.7 mmol). The mixture was chilled with an ice water bath then triethylamine (30 ml, 211.4 mmol) and 1,3-dicyclohexylcarbodiimide (21.81 g, 105.7 mmol) were added. The reaction was stirred in the ice water bath for 1 hour and then allowed to warm to room temperature overnight. The crude reaction was then chilled in an ice water bath and the precipitate filtered. The resulting organic solution was then washed twice with 1N aqueous sodium hydroxide (50 mL), twice with 10% aqueous citric acid (50 mL), and once with brine. The solution was then dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The resulting residue was purified by chromatography on a normal phase silica gel column with 30-100% ethyl acetate in hexanes. Fractions containing clean product were combined and the solvent evaporated to give the title compound (20 g, 81%): ES-MS (m/z) 233.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1.[Cl-].[Cl-].[Cl-].[Al+3].[C:18](Cl)(=[O:20])[CH3:19].Cl>ClCCCl>[CH3:1][O:2][C:3]1[C:13]([C:18](=[O:20])[CH3:19])=[CH:12][C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][O:10][C:5]=2[CH:4]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)OCCN2C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc2c(cc1C(C)=O)N(C)CCO2
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 7.6 %

Procedure:
7-Methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazine (11.17 g, 0.625 mol) in 400 mL of 1,2-dichloroethane was stirred at 0° C. under nitrogen. Aluminum trichloride (8.3 g, 0.625 mol) was added in portions, followed by dropwise addition of acetyl chloride (4.9 mL, 0.678 mol). The reaction mixture was stirred at 0° C. for 2.5 hours. Aluminum trichloride (3 g) was added, and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice and 550 mL 3N HCl was added. The aqueous mixture was extracted with methylene chloride, and the combined organic layers were dried (MgSO4), filtered, and evaporated under reduced pressure to yield 10.48 g of 1-(7-Methoxy-4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-ethanone. (M+H)=222.
Reaction SMILES: N1C=CC(N)=C(N)C=1.O=C1C2C(=CC=CC=2)C(=O)N1CCCCC(O)=O.[N:27]1[C:35]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[NH:29][C:28]=1[CH2:36][CH2:37][CH2:38][CH2:39][N:40]1[C:48](=[O:49])[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]1=O>O>[N:27]1[C:35]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[NH:29][C:28]=1[C:36]1[CH2:37][CH2:38][CH2:39][N:40]2[C:48](=[O:49])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]=12
Reactant: O=C1c2ccccc2C(=O)N1CCCCc1nc2ccncc2[nH]1
Agent: Nc1ccncc1N
Agent: O=C(O)CCCCN1C(=O)c2ccccc2C1=O
Solvent: O
Product: O=C1c2ccccc2C2=C(c3nc4ccncc4[nH]3)CCCN12
Temperature: 210 °C

Procedure:
4 g of pyridine-3,4-diamine and 9.5 g of 5-(1,3-dioxo-1,3-dihydroisoindol-2-yl)pentanoic acid are introduced into a 250 ml round-bottomed flask, followed by 45 g of polyphosphoric acid (PPA). The solid mixture is heated to 210° C. in an oil bath. During the reaction, the transient formation of 2-{4-(3H-imidazo[4,5-c]pyridin-2-yl)butyl}isoindole-1,3-dione is noted. After heating for 16 hours, the reaction is complete. After cooling, the reaction mixture is taken up in water. The impurities are eliminated by extraction with ethyl acetate. The aqueous phase is neutralized (pH 7) with 2N sodium hydroxide. The product is recovered after 6 successive extractions with a mixture of ethyl acetate and methanol (9/1 by volume). After purification by flash chromatography silica, elution being carried out with a mixture of dichloromethane and methanol (95/5 by volume), 1.46 g of 1-{3-H-imidazo[4,5-c]pyridin-2-yl}-3,4-dihydro-2H-pyrido[2,1-a]isoindole-6-one are obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: C(OC(=O)C)C.[ClH:7].[O:8]=[C:9]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:13]([S:27][CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)=[N:12][C:11]2=[CH:38][S:39][CH:40]=[C:10]12>CO>[ClH:7].[NH2:30][CH2:29][CH2:28][S:27][C:13]1[N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:19][CH:20]=2)[C:9](=[O:8])[C:10]2[C:11](=[CH:38][S:39][CH:40]=2)[N:12]=1
Reactant: CC(C)(C)OC(=O)NCCSc1nc2cscc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: NCCSc1nc2cscc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixed solution of 4N hydrogen chloride ethyl acetate solution (20 ml) and methanol (10 ml) was added tert-butyl [2-({4-oxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydrothieno[3,4-d]pyrimidin-2-yl}sulfanyl)ethyl]carbamate (1.7 g), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with a mixture of ethyl acetate/ether (1/1) to give the title compound (1.48 g) as a white solid.