Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:19][CH3:20])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH:13]3[CH2:15][CH2:14]3)[CH2:9][C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])[C:25]([Cl:40])=[CH:24][N:23]=1>>[Cl:40][C:25]1[C:26]([NH:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[N:27][C:22]([NH:1][C:2]2[C:3]([O:19][CH3:20])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH:13]4[CH2:14][CH2:15]4)[CH2:9][C:8](=[O:16])[N:7]([CH3:17])[C:6]=3[CH:18]=2)=[N:23][CH:24]=1
Reactant: COc1cc2c(cc1N)N(C)C(=O)CN(CC1CC1)C2
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@@H]3CCCC[C@H]3NS(C)(=O)=O)n1)N(C)C(=O)CN(CC1CC1)C2

Procedure:
The title compound was prepared from 8-Amino-4-cyclopropylmethyl-7-methoxy-1-methyl-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide in an analogous manner to example 730 (0.062 g, 47%) Mp 131-132° C.; LCMS (m/e) 578 (M); 1H-NMR (DMSO, 400 MHz) δ 8.23 (s, 1H), 7.98 (s, 1H), 7.75 (s, 1H), 7.22-7.20 (d, 1H, J=8.59 Hz), 7.03 (s, 2H), 6.88-6.86 (d, 1H, J=7.83 Hz), 3.89 (s, 3H), 3.88-3.80 (m, 1H), 3.55 (d, 2H, J=3.03 Hz), 3.27 (s, 3H), 3.10-3.09 (d, 2H, J=3.82 Hz), 2.89 (s, 3H), 2.41-2.40 (d, 2H, J=6.82 Hz), 2.05-1.92 (m, 2H), 1.68-1.55 (m, 2H), 1.40-1.17 (m, 4H), 1.13-1.97 (m, 1H), 0.90-0.79 (m, 1H), 0.50-0.48 (d, 2H, J=7.83 Hz), 0.170-0.16 (d, 2H, J=4.55 Hz).
Reaction SMILES: C(O)=O.[CH2:4]=O.[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH:17]3[CH2:18][CH2:19][CH:14]([CH2:15][CH2:16]3)[NH:13]2)[CH:7]=1.[OH-].[Na+]>O>[CH3:4][N:13]1[CH:12]([C:8]2[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=2)[CH:17]2[CH2:18][CH2:19][CH:14]1[CH2:15][CH2:16]2
Reactant: c1cncc(C2NC3CCC2CC3)c1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Product: CN1C2CCC(CC2)C1c1cccnc1
Temperature: 0 °C
Yield: 88 %

Procedure:
Formic acid (5 mL, 95-97%) and formaldehyde (0.5 mL, 37%) were added to 3-(3-pyridyl)-2-azabicyclo[2.2.2]octane (XIII) (170 mg) and refluxed for 24 hours under N2. The reaction mixture was cooled to 0° C. (ice bath), basified by addition of a solution of 40% w/v NaOH in water (pH=9) and extracted with chloroform (4×10 mL). The combined extracts were dried over anhydrous K2CO3, filtered and concentrated. The resulting oil was purified by distillation under reduced pressure (116°-118° C. /0.4 mm Hg) to give 160 mg (88%) of (+/-)-2-methyl-3-(3-pyridyl)-2-azabicyclo[2.2.2]octane (XV).
Reaction SMILES: [CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][C:3]=1[C:15](OC)=[O:16].CC(C[AlH]CC(C)C)C.[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:14]2[C:5]([C:6]3[CH:7]=[CH:8][CH:9]=[N:10][C:11]=3[CH:12]=[CH:13]2)=[N:4][C:3]=1[CH2:15][OH:16]
Reactant: COC(=O)c1nc2c3cccnc3ccn2c1C
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c(CO)nc2c3cccnc3ccn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.5 %

Procedure:
A solution of methyl 3-methylimidazo[2,1-f][1,6]naphthyridine-2-carboxylate (100 mg, 0.39 mmol) in DCM (8 mL) was cooled to 0° C. DIBAL-H (1 M in cyclohexane, 1.2 mL, 1.2 mmol) was added dropwise over 10 min. The mixture was stirred at 0° C. for 1 h. 2 mL of saturated ammonium chloride aqueous solution was added slowly to quench the reaction. Then 5 mL of saturated sodium bicarbonate aqueous solution was added. The mixture was extracted with DCM (3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to give the crude product, which was purified by column chromatography to give 42 mg of the product as a yellow solid. ESI MS: m/z 214.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:29]2[CH:28]=[N:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=2)[N:11]=1)=[O:5])[CH3:2]
Reactant: COc1ccc(B(O)O)cn1
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(Cl)cc3)c2c1O
Product: CCOC(=O)c1nc(-c2ccc(OC)nc2)c2snc(-c3ccc(Cl)cc3)c2c1O

Procedure:
The title compound was synthesized in analogy to Example 1 from 7-bromo-3-(4-chloro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester and 2-methoxy-5-pyridineboronic acid: MS (m/z) 440.1 (M−1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10](=[O:33])[N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:29]([F:32])([F:31])[F:30])=[N:18][C:19]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[O:21])=[C:13]2[CH2:12]1)(C)(C)C.[ClH:45]>C(OCC)(=O)C>[ClH:45].[NH2:7][C@H:8]([CH2:34][C:35]1[CH:40]=[C:39]([F:41])[C:38]([F:42])=[CH:37][C:36]=1[F:43])[CH2:9][C:10]([N:11]1[CH2:16][CH2:15][N:14]2[C:17]([C:29]([F:30])([F:32])[F:31])=[N:18][C:19]([C:20]([N:22]3[CH2:27][CH2:26][NH:25][C:24](=[O:28])[CH2:23]3)=[O:21])=[C:13]2[CH2:12]1)=[O:33]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCNC(=O)C3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCNC(=O)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 93 %

Procedure:
(R)-[3-Oxo-3-[1-(3-oxo-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 19a (0.14 g, 0.22 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.3 N hydrochloric acid in 4 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-4-{7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carbonyl}-piperazin-2-one hydrochloride 19 (0.12 g, yield 93%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:34]I.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([CH3:34])[C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)c2ccc(Br)cc2)[C@H](c2ccc(Cl)c(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccc(Br)cc1)[C@@H]1CCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a solution of the compound (1.16 g) obtained in step 1 in DMF (22 mL) was added sodium hydride (60% in oil, 175 mg) at 0° C., and the mixture was stirred for 10 min. Then, methyl iodide (681 μL) was added, and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10→90% ethyl acetate/hexane) to give tert-butyl (3R,4R)-4-{[(4-bromophenyl)carbonyl](methyl)amino}-3-(3,4-dichlorophenyl)piperidine-1-carboxylate (1.09 g, 92%) as a white powder.
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=O)C.Cl.[OH-].[Na+]>>[OH:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1
Reactant: CC(=O)OC1CCCc2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: OC1CCCc2cccnc21
Reaction time: 8 h
Yield: 100 %

Procedure:
8-Acetoxy-5,6,7,8-tetrahydroquinoline (630 mg, 3.3 mmol) was mixed with 10% hydrochloric acid aqueous solution and stirred overnight while heating under reflux. After returning to room temperature, this was neutralized with sodium hydroxide aqueous solution and the reaction product was extracted with chloroform. The extract was washes with saturated brine and dried with anhydrous sodium sulfate and then the solvent was removed by evaporation under a reduced pressure to obtain 490 mg (3.3 mmol, 100%) of the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]=[C:6]([C@:8]23[CH2:13][C@H:12]2[CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]3)[O:5][N:4]=1>C(O)C>[C@:8]12([C:6]3[O:5][N:4]=[C:3]([CH3:2])[N:7]=3)[CH2:13][C@H:12]1[CH2:11][NH:10][CH2:9]2
Reactant: Cc1noc([C@]23C[C@H]2CN(C(=O)OC(C)(C)C)C3)n1
Agent: Cl
Solvent: CCO
Product: Cc1noc([C@@]23CNC[C@@H]2C3)n1
Temperature: 50 °C

Procedure:
2.5 M HCl (4.5 mL, 0.0113 mpl) was added to (1R,5R)-tert-butyl 1-(3-methyl-1,2,4-oxadiazol-5-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (143) (0.75 g, 0.0028 mmol) in 4 mL of ethanol. The solution was heated to 50° C. for 2.5 hours, cooled and condensed to a white solid. The material crystallized from 5 mL hot ethanol and 20 mL t-butyl methyl ether. The solids were isolated by filtration and washed with t-butyl methyl ether (2×5 mL) and dried under vacuum over night to 0.48 g white crystalline solid. The optical parity (99.68%) was determined by HPLC analysis (Chiral Technologies Chiral-AGP, 4.0 mm×150 mm, 0.5% methanol, 20 mM sodium phosphate pH=7). MS (ESI) m/z 166 [M+H]+. 1H NMR (DMSO-d6) δ 1.66-1.69 (m, 1 H), 1.73-1.76 (m, 1 H), 2.31 (s, 3 H), 2.47-2.49 (m, 1 H), 3.37-3.41 (m, 2 H), 3.70-3.74 (m, 2 H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:17][C:18]([CH3:23])([CH2:21][OH:22])[CH2:19][OH:20].OCCCOCC1C=CC=C(C)C=1C(OC(C)(C)C)=O>>[OH:20][CH2:19][C:18]([CH3:23])([CH3:17])[CH2:21][O:22][CH2:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(CO)CO
Reactant: Cc1cccc(CBr)c1C(=O)OC(C)(C)C
Agent: Cc1cccc(COCCCO)c1C(=O)OC(C)(C)C
Product: Cc1cccc(COCC(C)(C)CO)c1C(=O)OC(C)(C)C

Procedure:
tert-Butyl 2-(3-hydroxy-2,2-dimethylpropoxymethyl)-6-methylbenzoate is prepared from tert-butyl 2-bromomethyl-6-methylbenzoate and 2,2-dimethylpropane-1,3-diol in analogy to the synthesis of tert-butyl 2-(3-hydroxypropoxymethyl)-6-methylbenzoate.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH-].[K+].Cl[O-].[Na+]>>[O:11]([C:8]1[CH:9]=[CH:10][C:4]2=[N+:1]([O-:3])[O:2][N:6]=[C:5]2[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(Oc2ccccc2)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Product: [O-][n+]1onc2cc(Oc3ccccc3)ccc21

Procedure:
Following the procedure of Example 4, N-methylcarbonyl 2-nitro-5-fluoroaniline (1.0 g, 5.1 mmol), phenol (0.47 g, 5.1 mmol) and potassium carbonate (1.4 g, 10.2 mmol) are reacted together to give N-methylcarbonyl 2-nitro-5-phenoxyaniline, 1.2 g of which is then reacted with 20% hydrochloric acid (50 ml) to give 2-nitro-5-phenoxyaniline. The 2-nitro-5-phenoxyaniline (0.9 g, 3.9 mmol) is reacted with potassium hydroxide (0.2 g, 3.9 mmol) and sodium hypochlorite (11 ml of 5.2% solution, 0.6 g, 7.8 mmol) to yield 5-phenoxybenzo-2,1,3-oxadiazole N-oxide, m.p. 76°-77°.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Br:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:17]=[CH:16][C:13]([C:14]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: Nc1ccccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Brc1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 64.5 %

Procedure:
o-Phenylenediamine 7.79 g (72 mmole), 4-bromobenzaldehyde 16 g (87 mmole), and 2.8 g of PTSA (14 mmole) was stirred in 150 ml of Toluene, the reaction mixture was then heated to reflux for 16 hours, after cooling, the reaction mixture was extracted with water, and then the organic layer was evaporated to dry, the residue was then recrystallized with acetone to get 12.69 g of product (yield=64.54%).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:18](=O)[CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.O.NN.[OH-].[Na+]>C(O)COCCO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH2:18][CH2:19][CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(CC1CCNCC1)c1cc(-c2ccccc2)nc2cc(Cl)ccc12
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Product: Clc1ccc2c(CCC3CCNCC3)cc(-c3ccccc3)nc2c1
Yield: 34.7 %

Procedure:
The operation is as in Example 18, starting from 13.5 g of 1-(7-chloro-2-phenyl-4-quinolyl)-2-(4-piperidyl)-ethanone prepared as indicated in Example 10, 6 g of 98% hydrazine hydrate and 2.4 g of sodium hydroxide in 200 ml of diethylene glycol. 4.5 g of 7-chloro-2-phenyl-4-[2-(4-piperidyl)-ethyl]-quinoline are obtained, the monohydrochloride of which, formed by the action of hydrochloric acid in isopropanol, melts at 195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](I)=[N:6][CH:7]=1.C1([Mg]Cl)C=CC=CC=1.[CH3:20][C:21]1[C:26]([CH:27]=[O:28])=[C:25]([CH3:29])[CH:24]=[CH:23][N:22]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([CH:27]([C:26]2[C:21]([CH3:20])=[N:22][CH:23]=[CH:24][C:25]=2[CH3:29])[OH:28])=[N:6][CH:7]=1
Reactant: Cc1ccnc(C)c1C=O
Reactant: O=[N+]([O-])c1cc(Cl)cnc1I
Agent: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: Cc1ccnc(C)c1C(O)c1ncc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 5-Chloro-2-iodo-3-nitro-pyridine (2.5 g, 8.77 mmol) in anhydrous THF (20 mL) at −78° C. was added 2 M phenylmagnesiumchloride in THF (4.8 mL, 9.6 mmol) and stirred at the same temperature for 30 minutes and then 2,4-Dimethyl-pyridine-3-carbaldehyde (1.82 g, 13.15 mmol) was added in one portion and the progress of the reaction was followed by LCMS. The reaction mixture was warmed to room temperature and stirred overnight (18 h). It was then quenched with saturated aqueous NH4Cl (10 mL), and extracted with EtOAc. The combined extracts were washed with aqueous NaHCO3, brine, and then dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography to (5-Chloro-3-nitro-pyridin-2-yl)-(2,4-dimethyl-pyridin-3-yl)-methanol. Mass spectrum m/z: 294.4 (M+H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=1>>[CH3:22][C:20]1[NH:19][N:18]=[C:17]([NH:16][C:4]2[N:3]=[C:2]([NH:23][C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[C:7]([O:14][CH3:15])[C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:21]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1OC
Product: COc1ccc2c(Nc3ccc(C#N)cc3)nc(Nc3cc(C)[nH]n3)cc2c1OC

Procedure:
Similar procedure as described in example 273 was used, starting from (1-chloro-5,6-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-amino-benzonitrile to give 4-[3-(5-methyl-1H-pyrazol-3-ylamino)-5,6-dimethoxy-isoquinolin-1-ylamino]-benzonitrile. LC-MS m/e 401(MH+).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:39])[CH:6]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)=[CH:17][CH:16]=1)[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>CO.C1COCC1.O>[C:11]([O:10][C:8](=[O:9])[CH2:7][CH:6]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[CH:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:38])[F:36])=[CH:31][CH:30]=3)[CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:20]=1)[C:5]([OH:39])=[O:4])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CC(C(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide (121 mg, 5 mmol) was added to a solution of 50.2 in MeOH/THF/H2O (1:1:1, 90 mL). The resulting mixture was stirred at room temperature overnight. The organic solvent was removed under reduced pressure. The reaction mixture was extracted with dichloromethane (10 mL×3). The organic extracts were combined, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified via flash chromatography (50% ethyl acetate in hexanes) to yield acid 50.3 (860 mg). MS ESI (pos.) m/e: 523 (M+Na). 1H NMR (400 MHz) (CDCl3) δ 7.72 (4H, s); 7.67 (1H, s); 7.59-7.47 (3H, m); 7.29-7.25 (2H, m); 6.98-6.97 (2H, m); 5.14 (2H, s); 4.04-4.0 (1H, m); 3.1-3.053 (1H, m); 2.64-2.60 (1H, m); 1.4 (9H, s).
Reaction SMILES: C[O:2][C:3](=[O:13])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[NH2:5].[CH3:14][O:15][CH2:16][CH2:17][C:18]1([C:23](O)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:14][O:15][CH2:16][CH2:17][C:18]1([C:23]([NH:5][C@H:4]([C:3]([OH:2])=[O:13])[CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: COCCC1(C(=O)O)CCCC1
Product: COCCC1(C(=O)N[C@@H](Cc2ccccc2)C(=O)O)CCCC1

Procedure:
4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)]-N-[[1-(2-methoxyethyl)cyclopentyl]carbonyl]-L-phenylalanine was prepared from 4-(1,3-dimethyl-2,4-dioxo-5-pyrimidinyl)]-L-phenylalanine methyl ester and 1-(2-methoxyethyl)cyclopentane carboxylic acid (see WO 9910312) using the general procedures described in example 2. EI-HRMS m/e calcd for C24H31N3O5 (M+H) 458.2292, found 458.2279.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].F[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1Oc1ccc(Cl)cc1Cl
Yield: 97.5 %

Procedure:
Previously described: Burnistov, S. I.; Karpishchenko, L. S. Izvestiya Vysshikh Uchebnykh Zavedenii, Khimiya i Khimicheskaya Tekhnologiya 1976, 19(1), 39-41. Commercially available Literature mp: 57-58° C. 69-69.6° C. AMR01025 A mixture of 2,4-dichlorophenol (2.00 g, 12.27 mmol), 1-fluoro-2-nitrobenzene (2.07 g, 14.72 mmol) and potassium carbonate (2.04 g, 14.72 mmol) in dimethylformamide (DMF, 10 mL) was stirred under reflux for 1.5 h. After removal of DMF, the residue was dissolved in DCM and washed with NaOH (5%, 3×20 mL) and brine. The organic layer was dried (MgSO4), filtered and evaporated. Flash chromatography on silica gel of the crude product using DCM as eluent gave 1-(2,4-dichlorophenoxy)-2-nitrobenzene (3.4 g, 97%) as a cream oil. Rf: 0.73 (DCM) 1H NMR (270 MHz, CDCl3) δ 6.85 (1H, dd, J=8.4, 1.2 Hz), 6.97 (1H, d, J=8.9 Hz), 7.23 (2H, m), 7.48 (1H, d, J=2.5 Hz), 7.51 (1H, m) and 7.98 (1H, dd, J=8.2, 1.7 Hz). AMR01043 Following the same procedure, from 2,4-dichlorophenol (3.00 g, 18.40 mmol), 1-fluoro-2-nitrobenzene (2.60 g, 18.40 mmol) and potassium carbonate (2.54 g, 18.40 mmol) in dimethylformamide (DMF, 15 mL), and after a reaction time of 3 h, gave AMR01043 (4.89 g, 93%) as a cream solid, mp: 51-54° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][NH:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([OH:32])[CH2:27][CH2:28][N:29]([CH2:3][CH2:4][NH:5][CH:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:30][CH2:31]2)=[CH:22][CH:21]=1
Reactant: ClCCNC(c1ccccc1)c1ccccc1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: OC1(c2ccc(Cl)cc2)CCN(CCNC(c2ccccc2)c2ccccc2)CC1

Procedure:
A mixture of 10 parts of N-(2-chloroethyl)-α-phenylbenzenemethanamine hydrochloride 7 parts of 4-(4-chlorophenyl)-4-piperidinol, 10.6 parts of sodium carbonate, 0.1 parts of potassium iodide and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is taken up in water and the layers are separated. The aqueous phase is extracted with 4-methyl--pentanone. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of methylbenzene and 2,2'-oxybispropane. The product is filtered off and dried, yielding 4.5 parts of 4-(4-chlorophenyl)-1-{2-[(diphenylmethyl)amino]ethyl}-4-piperidinol; mp. 113.9° C.
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C([O-])(=O)C.[Na+].C(OCC)C>C(Cl)Cl>[CH:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCCCCO
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution comprising 10 g (85 mmole) of 1-hexadecanol in 100 ml of methylene chloride was added to a mixture comprising 10 g (139 mmole) of pyridinium chlorochromate, 30 g of celite and 12.0 g (146 mmole) of anhydrous sodium acetate in 400 ml of methylene chloride in a dropwise fashion. Following addition, the reaction mixture was stirred at room temperature for three hours then 300 ml of diethyl ether was added. The reaction mixture was filtered and a precipitate was collected and washed with diethyl ether until clear. The solvent was removed under reduced pressure and the residue passed through Florisil with diethyl ether as the eluent. The solvent was removed under reduced pressure and the residue purified by flash chromatography on silica (230 to 400 mesh) with hexanes and ethyl acetate at a ratio of approximately 39 to 1. The synthesis yielded hexadecanal having a mass of approximately 17.5 g and of approximately 88.4% purity. Hexadecanal is a white wax having a melting point of approximately 33°-34 C. The 1H NMR spectrum of the compound at 300 MHz using CDCl3 comprised the following peaks: δ 0.892 (3H, t, J=6.5Hz), 1.267 (24H, bs), 1.61 to 1.66 (2H, m), 2.430 (2H, dt, J=1.7 and 7.3 Hz), and 9.776 (1H, s).