Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].O1CCCC1.[BH4-].[Na+]>C(O)C>[OH:3][CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(O)c1ccc(-c2ccc(C(=O)OCc3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
33.0 g (0.1 mol) of benzyl 4'-acetyl-4biphenylcarboxylate, 200 ml of tetrahydrofuran and 50 ml of ethanol were supplied into the same flask as used in Example 9. Then 3.8 g (0.1 mol) of sodium borohydride was added at 15°-25° C. over a period of 10 minutes. After standing at the same temperature for 2 hours, the reaction solution was poured into ice-water and extracted twice with 300 ml of chloroform. The organic layer was washed with water and concentrated under reduced pressure to obtain 32.9 g (99% yield) of benzyl 4'-(1-hydroxyethyl)-4-biphenylcarboxylate (III-15).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH2:20](I)[CH3:21]>>[NH2:1][C:2]1[N:7]([CH2:20][CH3:21])[C:6](=[O:8])[C:5]([C:9]2[CH:10]=[CH:11][N:12]=[CH:13][CH:14]=2)=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: CCI
Reactant: Nc1nc(-c2ccco2)c(-c2ccncc2)c(=O)[nH]1
Product: CCn1c(N)nc(-c2ccco2)c(-c2ccncc2)c1=O

Procedure:
The title compound was synthesized in a manner similar to that described for Example 3 from 2-amino-6-(2-furyl)-5-(4-pyridyl)-3,4-dihydro-4-pyrimidinone and ethyl iodide.
Reaction SMILES: FC(F)(F)C1C=C(S([N:12]2[CH2:16][C@H:15]3[C@H:17]([NH2:20])[CH2:18][CH2:19][C@H:14]3[CH2:13]2)(=O)=O)C=CC=1.[CH:23](=O)[C:24]([CH3:27])(C)[CH3:25]>CC(C)=O>[CH2:25]([N:12]1[CH2:16][C@@H:15]2[C@@H:17]([NH:20][CH:18]([CH3:19])[CH3:17])[CH2:18][CH2:19][C@@H:14]2[CH2:13]1)[C:24]1[CH:27]=[CH:15][CH:14]=[CH:13][CH:23]=1
Reactant: CC(C)(C)C=O
Reactant: N[C@@H]1CC[C@H]2CN(S(=O)(=O)c3cccc(C(F)(F)F)c3)C[C@H]21
Solvent: CC(C)=O
Product: CC(C)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21

Procedure:
(3aR,4S,6aS)-2-Benzyl-N-isopropyloctahydrocyclopenta[c]pyrrol-4-amine was prepared by substituting (3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-amine from Example 33 Step A for (3aS,4R,6aR)-2-(3-(trifluoromethyl)phenylsulfonyl)octahydrocyclopenta[c]pyrrol-4-amine and acetone for pivalaldehyde in the procedure described in Example 281: 1H NMR (500 MHz, pyridine-d5) δ ppm 7.48 (d, J=7.5, 2H), 7.39 (t, J=7.5, 2H), 7.29 (t, J=7.3, 1H), 3.61-3.51 (m, 2H), 3.05 (dd, J=12.1, 5.4, 1H), 2.87-2.78 (m, 1H), 2.61-2.51 (m, 2H), 2.43-2.36 (m, 2H), 2.35-2.30 (m, 1H), 2.28-2.21 (m, 1H), 2.00-1.93 (m, 1H), 1.93-1.87 (m, 1H), 1.42-1.28 (m, 3H), 1.05-0.98 (m, 6H); MS (ESI+) m/z 259 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH3:18])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[N+:15]([O-])=O)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH3:18])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[C:9]=1[NH2:15])[CH3:2]
Reactant: CCOC(=O)[C@H](C)NCc1cccc(C)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)[C@H](C)NCc1cccc(C)c1N

Procedure:
A solution of 26.6 g of N-(3-methyl-2-nitrobenzyl)-L-alanine ethyl ester in 100 ml of absolute ethanol was hydrogenated in the presence of 2 g of 10% palladium/carbon. 6.7 liters of hydrogen were taken up in 5 hours. After completion of the hydrogenation, the catalyst was filtered off and the filtrate was evaporated to dryness. There was obtained N-(2-amino-3-methylbenzyl)-L-alanine ethyl ester in the form of a yellow oil; [α]D =-52.6° (c=1% in methanol).
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[C:9]([C:12]([OH:14])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][NH:21]1.O>C(Cl)Cl>[CH3:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]1[C:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[S:11][CH:10]=1)=[O:14]
Reactant: CC1CCCCN1
Reactant: O=C(O)c1csc(-c2ccccc2)c1
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CC1CCCCN1C(=O)c1csc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 5-phenyl-thiophene-3-carboxylic acid (1 eq.) in DCM (1 mL/100 mg SM) was added EDC (1.5 eq.). This mixture was stirred at room temperature for 5 minutes and then 2-methyl piperidine (1.2 eq.) was added and the mixture stirred for 18 hours. Water (1 mL/100 mg SM) was then added and the organic layer separated, dried and evaporated to give the crude product which was purified by column chromatography (EtOAc/iso-hexane). LCMS m/z 286 [M+H]+ R.T.=3.85 min (Analytical Method 3).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6](=[O:16])[C:5]=2[CH:4]=[CH:3][C:2]=1[C:17]([N:19]1[CH2:24][CH2:23][C:22]2[O:25][CH:26]=[CH:27][C:21]=2[CH2:20]1)=[O:18].[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C>[CH3:28][N:29]([CH2:31][C:26]1[O:25][C:22]2[CH2:23][CH2:24][N:19]([C:17]([C:2]3[CH:3]=[CH:4][C:5]4[C:6](=[O:16])[C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:13](=[O:15])[C:14]=4[CH:1]=3)=[O:18])[CH2:20][C:21]=2[CH:27]=1)[CH3:30]
Reactant: O=C1c2ccccc2C(=O)c2cc(C(=O)N3CCc4occc4C3)ccc21
Reactant: CNC
Reactant: C=O
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CCN(C(=O)c1ccc3c(c1)C(=O)c1ccccc1C3=O)C2
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.220 g (0.616 mmol) of 5-(anthraquinone-2-carbonyl)-4,5,6,7-tetrahydrofuro[3,2-c]pyridine in 20 ml of acetic acid, 0.083 ml (0.92 mmol) of 50% aqueous dimethylamine and 0.075 ml (0.75 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 30 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with 5% aqueous sodium hydrogen carbonate, and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (chloroform to chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[Mg+2].[CH2:19](O)[CH3:20]>>[C:1]([O:7][CH2:19][CH3:20])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCO
Reactant: CC(C)(C)C(=O)O
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CCOC(=O)C(C)(C)C
Yield: 77 %

Procedure:
Absolute ethanol (1035 ml) was added to 306 grams of neopentanoic acid (Exxon) in a flask fitted with a heating mantle and a reflux condenser. To this mixture was slowly added 65 ml of concentrated sulfuric acid (Mallinckrodt). The mixture was then heated under reflux for three hours. Heating was discontinued and the hot mixture was extracted with 4 liters of a 10% sodium carbonate solution. The organic layer which separated was collected and dried overnight with magnesium sulfate. It was then filtered and purified by distillation at atmospheric pressure. A low heat was first applied in order to collect a fraction at a temperature of 73° C. consisting principally of ethanol. When the head temperature began to drop, the heat was raised and a second fraction, consisting of ethyl pivalate was collected from 108°-111° C. This pure ethyl pivalate (yield about 77%) was then dried over magnesium sulfate.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[NH:29][C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=5)=[N:27][N:26]=4)[CH2:21][CH2:20]3)=[CH:14][CH:13]=1)=[N:7]2.[NH2:42][NH2:43]>O1CCOCC1>[C:36]1([C:5]2[C:6]([C:12]3[CH:13]=[CH:14][C:15]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[NH:29][C:28]([C:30]6[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=6)=[N:27][N:26]=5)[CH2:21][CH2:20]4)=[CH:16][CH:17]=3)=[N:7][C:8]3[C:3]([CH:4]=2)=[C:2]([NH:42][NH2:43])[N:11]=[CH:10][CH:9]=3)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Clc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Reactant: NN
Solvent: C1COCCO1
Product: NNc1nccc2nc(-c3ccc(CN4CCC(c5nnc(-c6ccccn6)[nH]5)CC4)cc3)c(-c3ccccc3)cc12
Temperature: 100 °C

Procedure:
A suspension of 8-8 (4.3 g, 7.7 mmol) in 30 mL 1,4-dioxane and hydrazine (7.4 g, 231.1 mmol) was heated in a microwave reactor at 100° C. for 5 mins. The mixture was cooled and concentrated to remove solvents. Toluene 40 mL (×3) was added and removed under vacuum to remove the residual hydrazine. The desired product 8-9 was obtained as a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:17])[CH:11]([N+:14]([O-:16])=[O:15])[CH2:12][OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].[C:25](Cl)(=[O:27])[CH3:26]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:17][C:25](=[O:27])[CH3:26])[CH:11]([N+:14]([O-:16])=[O:15])[CH2:12][O:13][C:18](=[O:20])[CH3:19])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)OC(C)=O
Reactant: O=[N+]([O-])c1ccc(C(O)C(CO)[N+](=O)[O-])cc1
Product: CC(=O)OCC(C(OC(C)=O)c1ccc([N+](=O)[O-])cc1)[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 211.7 %

Procedure:
A mixture of 8.5 g (0.035 moles) of 1-(4-nitrophenyl)-2-nitro-1,3-propanediol, 14 g (0.13 moles) of acetic anhydride and 1 g of acetyl chloride is stirred at 60° C. for 3 hours. The mixture is cooled, poured onto 60 g of ice and stirred thoroughly. Water is decanted, 10 ml of isopropanol are added to the waxy residue, and the substance is crystallized at 0° C. The separated crystalline product is filtered off, washed with isopropanol and dried at 20° C. 8.8 g (77%) of the title compound are obtained; m.p.: 63°-66° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][N:9]=1.[O:15]1[CH2:20][CH2:19][CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH2:16]1>O1CCOCC1.CCOC(C)=O.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>[Cl:14][C:13]1[C:8]([C:17]2[CH2:16][O:15][CH2:20][CH2:19][CH:18]=2)=[N:9][CH:10]=[CH:11][N:12]=1
Reactant: Clc1nccnc1Cl
Reactant: CC1(C)OB(C2=CCCOC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Clc1nccnc1C1=CCCOC1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Sodium carbonate (6.48 mL, 12.95 mmol, 2.0 M in water) was added to a stirred mixture of 2,3-dichloropyrazine (1.28 mL, 8.63 mmol), 2-(5,6-dihydro-2H-pyran-3-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.91 g, 4.32 mmol), and tetrakis(triphenylphosphine)palladium (0.50 g, 0.43 mmol) in dioxane (16 mL) under an argon atmosphere. The reaction mixture was stirred at 80° C. for 16 h before being cooled to room temperature and diluted with EtOAc. The mixture was washed with water, washed with sat. sodium chloride, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography to give 2-chloro-3-(5,6-dihydro-2H-pyran-3-yl)pyrazine. MS (ESI, pos. ion) m/z: 197.0 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=2)=[C:6]([CH:15]([O:29][CH2:30][CH2:31]OS(C)(=O)=O)[C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]2)[CH:5]=[CH:4][CH:3]=1.[N-:37]=[N+:38]=[N-:39].[Na+]>CN(C=O)C.CCOC(C)=O.O>[N:37]([CH2:31][CH2:30][O:29][CH:15]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:14])[CH:9]=1)[C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[CH2:17]1)=[N+:38]=[N-:39]
Reactant: Cc1cccc(-c2c(F)cccc2C(OCCOS(C)(=O)=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2c(F)cccc2C(OCCN=[N+]=[N-])[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
(3R)-tert-butyl 3-((6-fluoro-3′-methylbiphenyl-2-yl)(2-(methanesulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (1.1 g, 2 mmol) was dissolved in anhydrous DMF (15 mL), solid NaN3 (280 mg, 4 mmol) was added and the reaction mixture was heated to 80° C. for 5 h. The mixture was cooled to rt and diluted with EtOAc and water. The organic phase was separated, washed with water and dried over MgSO4. Removal of the solvent gave (3R)-tert-butyl 3-((2-azidoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)piperidine-1-carboxylate (0.89 g, yield 90%) which was used in the next step without purification.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[F:7][C:8]([F:23])([S:19](Cl)(=[O:21])=[O:20])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12].[F:24][C:25]([F:29])([F:28])[CH2:26][OH:27].C(N(CC)CC)C>ClCCl>[F:7][C:8]([F:23])([S:19]([O:27][CH2:26][C:25]([F:29])([F:28])[F:24])(=[O:21])=[O:20])[C:9]([F:18])([F:17])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12]
Reactant: OCC(F)(F)F
Reactant: O=S(=O)(Cl)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(OCC(F)(F)F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
The process according to claim 12, wherein the perfluorobutanesulphonate alkaline salts are solubilised in methanol and treated with gaseous hydrochloric acid to give the corresponding perfluorobutanesulphonic acid which, after treatment with PCl5 is transformed into the corresponding perfluorobutanesulphonyl chloride, the latter reacts with 2,2,2-trifluoroethanol and triethylamine in dichloromethane to give 2,2,2-trifluoroethanol perfluorobutanesulphonate, which is recycled in the reaction at phase a).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][N:12]=1.ClC1C=CC(C(NC2C=CC(I)=C(C)C=2)=O)=CN=1>>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:2]([CH3:1])[CH:3]=2)=[O:16])=[CH:13][N:12]=1
Reactant: Cc1ccc(N)cc1C
Reactant: O=C(Cl)c1ccc(Cl)nc1
Agent: Cc1cc(NC(=O)c2ccc(Cl)nc2)ccc1I
Product: Cc1ccc(NC(=O)c2ccc(Cl)nc2)cc1C

Procedure:
6-Chloro-N-(3,4-dimethyl-phenyl)-nicotinamide was prepared from 3,4-dimethyl aniline and 6-chloronicotinoyl chloride following a procedure similar to the one described in the synthesis of 6-chloro-N-(4-iodo-3-methyl-phenyl)-nicotinamide, above. The product was isolated after precipitation out of a small volume of CH2Cl2 with hexanes. HRMS m/z calcd for C14H13N2OCl [M+H]+: 261.0789. Found: 261.0788
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([Cl:15])([Cl:14])[Cl:13])[N:6]=[C:5]2Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH2:24][CH3:25])[CH2:19]1>CCOCC>[ClH:13].[CH2:24]([N:20]1[CH2:21][CH2:22][CH2:23][CH:18]([NH:17][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=3)[N:8]=[C:7]([C:12]([Cl:15])([Cl:14])[Cl:13])[N:6]=2)[CH2:19]1)[CH3:25]
Reactant: CCN1CCCC(N)C1
Reactant: Clc1nc(C(Cl)(Cl)Cl)nc2ccc(I)cc12
Solvent: CCOCC
Product: CCN1CCCC(Nc2nc(C(Cl)(Cl)Cl)nc3ccc(I)cc23)C1
Product: Cl
Temperature: 25 °C

Procedure:
6-iodo-4-chloro-2-trichloromethyl-quinazolin (8.14 g, 20 mmol) was dissolved in ether (anhydrous 200 mL) under stirring at rt. To this solution 3-amino-1-ethyl-piperidine (2.56 g, 20 mmol) in ether (anhydrous 30 mL) was added at 0° C. The reaction mixture was allowed to warm to rt overnight. Buff colored solid separated which was filtered, washed with ether (200 mL) and air dried. Crude yield: 5.1 g. The crude material was suspended in MeOH and stirred vigorously for 0.5 h and filtered. The solid was dried in vacuo (0.01 mm). Yield: 3.72 g, (34.7%). Mp 265°-266° C.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:22]([OH:24])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(C(C)C)CC)(C)C.C1[CH:42]=[CH:43][C:44]2N(O)N=[N:47][C:45]=2C=1.C(N)CCC>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:45]([NH:47][C:22](=[O:24])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:44][CH2:43][CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCN
Product: CCCCNC(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 127.7 %

Procedure:
Solid EDC.HCl (518 mg, 3.3 mmol) was added to a solution of (S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropanoic acid (405 mg, 1.5 mmol), diisopropylethylamine (2.5 mL, 14 mmol), HOBt (130 mg, 1.0 mmol), DMAP (18 mg, 0.15 mmol), butylamine (0.30 mL, 3 mmol), and anhydrous DMF (25 mL). The resulting clear light yellow solution was stirred at rt for 12 h. The solvent was removed (50° C., 150 Torr) and the residue was taken up in ether (100 mL) and washed with satd aq NaHCO3 (3×10 mL). Hexanes (30 mL) was added to the ether extract and this was washed with water (5×5 mL) and brine (3×5 mL), dried (Na2SO4), decanted, stripped and the crude material was purified using 40 g SiO2 with an eluent of hexanes to 30% MeOH in EA. Combining appropriate fractions and removal of solvent gave (S)-tert-butyl 1-(butylamino)-3-cyclohexyl-1-oxopropan-2-ylcarbamate (417 mg, 85%) as a white solid. 1H NMR (CDCl3) δ 0.80-1.80 (m 20H), 1.50 (s, 9H), 3.20 (m, 2H), 4.01 (d, 1H), 5.01 (d, 1H), 6.50 (bs, 1H). MS ESI +ve m/z 321 (M+Na).
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:12])[CH3:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:13]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][CH2:1][NH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:5]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: CC(=O)NCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)NCCc1ccc(C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 91.6 %

Procedure:
In a 500 ml flame-dried flask, N-phenethyl-acetamide (6.53 g, 40.0 mmol) was dissolved in methylene chloride (65 ml), and acetyl chloride (7.22 g, 92.0 mmol) was added in one portion. The resulting solution was cooled to about 0° C., and aluminum chloride (18.1 g, 136 mmol) was added in portions over about thirty minutes. The solution was stirred for about five minutes at about 0° C., and the ice bath was then removed and the mixture was heated to reflux for about thirty minutes. After cooling to room temperature, the reaction mixture was poured over ice water, stirred for about ten minutes, and then extracted with methylene chloride (2×100 ml). The combined organic extracts were then washed sequentially with water and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting white solid (7.52 g, 92% yield) was ascertained to be about 90% pure by NMR, and was employed directly without further purification. LRMS ([M+H]+)=206.2.
Reaction SMILES: [OH-].[Na+].O.C([O:6][C:7]([C:9]1([C:19]2[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=2)[CH2:18][CH2:17][C:12]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:11][CH2:10]1)=[O:8])C>CO.O1CCCC1>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([C:9]2([C:7]([OH:8])=[O:6])[CH2:10][CH2:11][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:17][CH2:18]2)=[N:20][CH:21]=1
Reactant: CCOC(=O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(c2ccc(Br)cn2)CCC2(CC1)OCCO2
Yield: 93.5 %

Procedure:
4N Aqueous solution of sodium hydroxide (5 ml) and water (5 ml) were added to a solution of 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid ethyl ester (1.0 g) described in Reference Example 81(2) in methanol (10 ml) and tetrahydrofuran (10 ml), and stirred at 80° C. for eight hours. After completion of the reaction, the organic solvent was evaporated and the aqueous layer was washed with diethyl ether. Concentrated hydrochloric acid was added to the aqueous layer under ice cooling, pH was adjusted to 4-5, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 8-(5-bromopyridin-2-yl)-1,4-dioxaspiro[4,5]decane-8-carboxylic acid (864 mg) as a colorless solid.
Reaction SMILES: [H-].[Na+].C(OC(=O)[NH:9][CH2:10][CH2:11][SH:12])(C)(C)C.[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=1>O1CCCC1.C(Cl)Cl>[F:14][C:15]1[N:16]=[C:17]([S:12][CH2:11][CH2:10][NH2:9])[CH:18]=[CH:19][CH:20]=1
Reactant: Fc1cccc(F)n1
Reactant: CC(C)(C)OC(=O)NCCS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: NCCSc1cccc(F)n1
Temperature: 0 °C
Yield: 127.6 %

Procedure:
Suspend sodium hydride (138 mg, 5.46 mmol) in tetrahydrofuran (6 mL) and cool to 0° C. in an ice bath. Add (2-mercaptoethyl)carbamic acid tert-butyl ester (0.461 mL, 2.73 mmol) dropwise over 5 minutes. Stir reaction for 30 minutes, add 2,6-difluoropyridine (0.495 mL, 0.546 mmol), remove ice bath and stir an additional hour. Re-cool reaction and quench with water. Extract with 1/1 hexanes/ethyl acetate. Dry organics over magnesium sulfate, filter and evaporate. Perform flash column chromatography (ethyl acetate/hexanes). Dissolve resulting orange oil in trifluoroacetic acid (3 mL) and stir for 15 minutes. Concentrate the reaction with a stream of dry nitrogen, re-dissolve in dry methylene chloride and evaporate to give 120 mg of the title compound as an orange oil. 1H NMR (d MeOH): 7.70 (m, 1H), 7.22 (m, 1H), 6.78 (m, 1H), 3.44 (m, 2H), 3.34 (m, 2H).
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[F:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[OH:24].C(=O)([O-])[O-].[K+].[K+].Cl>O>[N+:1]([C:4]1[C:9]([O:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Reactant: Oc1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)Cc1cccc(Oc2ccccc2F)c1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 5 h

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.), 2-fluorophenol (5.8 g.), anhydrous potassium carbonate (8.5 g.) and cupric oxide (1 g.) was stirred for 5 hours at 130° C. To the reaction mixture was added conc. hydrochloric acid and water, and the mixture was extracted with benzene. The extract was washed with water, dried over magnesium sulfate and then evaporated under reduced pressure to give oily 2-[2-nitro-3-(2-fluorophenoxy)phenyl]acetic acid.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH2:15][CH2:16][C:17]#N.Cl.CC[N:22]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O.C(N(CC)CC)C>[C:16]([CH2:17][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([OH:1])[C:3]([C:12]([NH2:22])=[O:14])=[CH:4][CH:5]=2)[N:10]=1)#[N:15]
Reactant: N#CCN
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc2cccnc2c1O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ccc2ccc(C(N)=O)c(O)c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
8-hydroxyquinoline-7-carboxylic acid (0.51 g), aminoacetonitrile.HCl (0.27 g), and triethylamine (0.38 mL) are dissolved in 10 mL dimethylformamide. EDC.HCl (0.54 g) and HOBt.H2O (0.38 g) are added and the reaction is stirred at room temperature for 2 days. The reaction is poured into 50 mL ice/H2O and stirred.