Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[NH2:50][CH:51]([CH2:62][CH3:63])[C@@H:52]([C:54]1[O:55][C:56]([CH:59]2[CH2:61][CH2:60]2)=[N:57][N:58]=1)[OH:53].[F:64][C:65]([F:83])([CH2:80][CH2:81][CH3:82])[CH2:66][C@H:67]([NH:71][C:72]([N:74]1[CH2:79][CH2:78][O:77][CH2:76][CH2:75]1)=[O:73])[C:68](O)=[O:69]>C(Cl)Cl>[CH:59]1([C:56]2[O:55][C:54]([CH:52]([OH:53])[C@@H:51]([NH:50][C:68]([C@@H:67]([NH:71][C:72]([N:74]3[CH2:79][CH2:78][O:77][CH2:76][CH2:75]3)=[O:73])[CH2:66][C:65]([F:83])([F:64])[CH2:80][CH2:81][CH3:82])=[O:69])[CH2:62][CH3:63])=[N:58][N:57]=2)[CH2:61][CH2:60]1
Reactant: CCC(N)[C@H](O)c1nnc(C2CC2)o1
Reactant: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCC(F)(F)C[C@H](NC(=O)N1CCOCC1)C(=O)N[C@@H](CC)C(O)c1nnc(C2CC2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
PyBOP (171.73 mg, 0.33 mmol), diisopropylethylamine (0.0575 mL, 0.33 mmol) and (S)-2-amino-1-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-butan-1-ol; compound with trifluoro-acetic acid (0.30 mmol) are added to a solution of (S)-4,4-Difluoro-2-[(morpholine-4-carbonyl)-amino]-heptanoic acid (88.29 mg, 0.30 mmol) in dry methylene chloride (4 mL) and the reaction mixture is stirred overnight at room temperature. The reaction is quenched with aqueous sodium bicarbonate, extracted twice with methylene chloride, the organic extracts are dried over sodium sulfate and evaporated under reduced pressure. Column chromatography on silica eluting with a mixture of methylene chloride and ethyl acetate gives morpholine-4-carboxylic acid ((S)-1-{(S)-1-[(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-hydroxy-methyl]-propylcarbamoyl-}3,3-difluoro-hexyl)-amide as a solid (87 mg). LC/MS 97%, 474 (M+1).
Reaction SMILES: CS[C:3]([NH:8][CH2:9][C:10]#[CH:11])=[CH:4][N+:5]([O-:7])=[O:6].[NH:12]([C:16]1[S:17][CH:18]=[C:19]([CH2:21][S:22][CH2:23][CH2:24][NH2:25])[N:20]=1)[C:13]([NH2:15])=[NH:14]>>[N+:5]([CH:4]=[C:3]([NH:8][CH2:9][C:10]#[CH:11])[NH:25][CH2:24][CH2:23][S:22][CH2:21][C:19]1[N:20]=[C:16]([NH:12][C:13]([NH2:15])=[NH:14])[S:17][CH:18]=1)([O-:7])=[O:6]
Reactant: C#CCNC(=C[N+](=O)[O-])SC
Reactant: N=C(N)Nc1nc(CSCCN)cs1
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1csc(NC(=N)N)n1

Procedure:
1-Methylthio-1-(2-propynylamino)-2-nitroethylene (prepared in Example 2, Step A, above) is reacted in an inert solvent with about an equimolar amount of 2-[(2-guanidinothiazol-4-yl)methylthio]ethylamine to produce, after workup, the title product.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6].[Br:15]Br>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(C)c1
Reactant: BrBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc([N+](=O)[O-])c(CBr)c1
Temperature: 25 °C
Yield: 81.6 %

Procedure:
In a 5-liter three-necked round-bottomed flask equipped with a reflux condenser, overhead stirrer, addition funnel and nitrogen inlet, was placed 220 g of methyl 3-methyl-4-nitrobenzoate, 2 l of anhydrous carbon tetrachloride and 4 g of benzoyl peroxide. To the resulting solution, irradiated with a 275 watt UV light, was added 198 g of bromine dropwise over a period of 2 hours at reflux. After the addition was complete the reaction mixture was refluxed for an additional 60 hours. The reaction mixture was cooled to room temperature. The solid which formed was separated by suction filtration. This solid (159.1 g) consisted of the expected methyl 3-bromomethyl-4-nitrobenzoate with minor amounts of the starting material. The mother liquors together with another 220 g of methyl 3-methyl-4-nitrobenzoate and 4 g of benzoyl peroxide were returned to the flask and treated with 198 g of bromine as described above. After the addition was complete the reaction mixture was refluxed another 96 hours, cooled to room temperature and the resulting solid separated by filtration yielding another 252 g of methyl 3-bromomethyl-4-nitrobenzoate. The solids were combined yielding a total of 411.1 g of methyl 3-bromomethyl-4-nitrobenzoate with minor amounts of the starting methyl 3-methyl-4-nitrobenzoate and methyl 3-dibromomethyl-4-nitrobenzoate. This solid was used as such in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH:11]1[C:16]([OH:17])=[CH:15][CH:14]=[C:13]([CH3:18])[CH:12]=1.CCC(COC(C([N:41](CC[NH+](C)C)C)=O)(C1C=CC=CC=1)C1C=CC=CC=1)CC.[Cl-].N(OS(=O)(=O)O)=O>O.S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[N:6]=[N:41][C:11]1[CH:12]=[C:13]([CH3:18])[CH:14]=[CH:15][C:16]=1[OH:17])([O-:3])=[O:2]
Reactant: CCC(CC)COC(C(=O)N(C)CC[NH+](C)C)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(O)cc1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: O=NOS(=O)(=O)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(O)c(N=Nc2ccccc2[N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 0.25 h

Procedure:
A mixture of 2-nitroaniline (27.63 g, 0.2 mol), para-cresol (10.81 g, 0.10 mol), Hostapur® SAS93 (1.55), Triton X-100® [polyethylene(10) isooctylphenyl ether] (2.45 g) and water (100 mL) is heated to 50° C. The reaction mixture is rapidly stirred at this temperature for 15 minutes and then the rapidly stirred resultant suspension is allowed to cool to room temperature. The reaction mixture is cooled to 11° C. and a solution of sulfuric acid (11.99 g, 0.12 mol), Hostapur® SAS93 (0.51), and Triton X-100® [polyethylene(10) isooctylphenyl ether] (0.73 g) in 20 mL of water is added dropwise. To the resultant suspension is added dropwise at 9–11° C. nitrosylsulfuric acid (25.40 g, 0.2 mol, 63.51 grams of a 40% solution of nirosylsulfuric acid in sulfuric acid). Upon completion of the reaction, the aqueous phase is separated and the resultant crude product washed by decantation with water (300 mL). An analytical sample is prepared by dry-column flash chromatography (1:1 toluene:heptane eluent)(dry-column flash chromatography method reference: Leonard, J.; Lygro, B.; Procter., G. Advanced Practical Organic Chemistry 2 Ed.; Blackie Academic: London, 1995, pp 215–216).
Reaction SMILES: [Li]CCCC.[CH:6]([C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)([CH3:8])[CH3:7].[NH2:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:18]=1[C:19]#N.[OH2:29]>CCOCC.CCOCC.C1COCC1>[NH2:16][C:17]1[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[CH:21][C:18]=1[C:19]([C:12]1[CH:13]=[CH:14][C:9]([CH:6]([CH3:8])[CH3:7])=[CH:10][CH:11]=1)=[O:29]
Reactant: O
Reactant: COc1cc(N)c(C#N)cc1OC
Reactant: CC(C)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cc(N)c(C(=O)c2ccc(C(C)C)cc2)cc1OC
Temperature: -5 °C
Reaction time: 0.25 h

Procedure:
18.8 ml (30 mmol) of BuLi (1.6 M in hexane) is added dropwise to a cooled (−5° C.) solution of 6 g (30 mmol) 4-isopropyl-1-bromobenzene in 25 ml ether. The reaction mixture is stirred for 15 min at −5° C. and one additional hour at rt. After that time the solution is cooled to −5° C. and a solution 1.8 g (10 mmol) 2-amino-4,5-dimethoxybenzonitrile in 20 ml ether/THF (1:1) is added dropwise. After 30 min the reaction mixture is poured slowly into water and extracted with ethyl acetate. The organic layer is dried and evaporated. The crude material is dissolved in 200 ml ether and stirred with 100 ml 2N HCl for one hour. After chromatography (DCM/MeOH 15:1) the product is obtained as yellow oil.
Reaction SMILES: CO.C1COCC1.[OH:8][CH:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30]/[C:31](=[N:38]\[O:39][CH3:40])/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:25][CH:24]=2)=[CH:17][CH:16]=1)[CH2:10][C:11]([O:13]C)=[O:12].[OH-].[Na+]>O>[OH:8][CH:9]([C:15]1[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30]/[C:31](=[N:38]\[O:39][CH3:40])/[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[CH:25][CH:24]=2)=[CH:19][CH:20]=1)[CH2:10][C:11]([OH:13])=[O:12]
Reactant: CO/N=C(\COc1ccc(COc2ccc(C(O)CC(=O)OC)cc2)cc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CO/N=C(\COc1ccc(COc2ccc(C(O)CC(=O)O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 52.6 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged 2 mL of Methanol and 2 mL of THF. To the stirred solvent was added methyl 3-hydroxy-3-{4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenyl}propanoate (0.04 g, 0.08 mmol) and NaOH was added followed by water (0.5 mL). Then it was stirred at RT for 12 h, after completion of the reaction (reaction monitored by TLC), reaction mixture was evaporated completely and the crude was washed with ether, and diluted with water and then neutralized with 1N HCl, then extracted with ethyl acetate, organic layer was washed with water and brine, dried over Na2SO4. The organic layer was evaporated on rotavapor under reduced pressure to give the product as a white colour solid. (0.02 g, yield: 52.6%); Purity: 45.3% and 43.6%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[CH:32]=[CH:31][C:14]([CH2:15][NH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)=[O:18])=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>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(OCC)(=O)C.C1(C)C=CC=CC=1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:11]2[CH:32]=[CH:31][C:14]([CH2:15][NH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)=[O:18])=[CH:13][CH:12]=2)[CH:2]=1
Reactant: OB(O)c1cccnc1
Reactant: O=C(NCc1ccc(Br)cc1)c1ccc(-c2ccccc2)cc1
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: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C(NCc1ccc(-c2cccnc2)cc1)c1ccc(-c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a sealed tube was added pyridin-3-ylboronic acid 10-4 (25 mg, 0.21 mmol), N-(4-bromobenzyl)biphenyl-4-carboxamide 10−3 (50 mg, 0.14 mmol), Pd(PPh3)4 (16 mg, 0.014 mmol), saturated Na2CO3 (2.1 mL), ethanol (0.7 mL) and toluene (0.7 mL). The reaction was heated to 110° C. and stirred for 2 hours. After cooling to room temperature, the reaction was diluted into ethyl acetate, washed with brine. The organic phase was taken to dryness by rotary evaporation. The residue was purified by HPLC to give N-(4-(pyridin-3-yl)benzyl)biphenyl-4-carboxamide 10 as off-white solid. MS m/z 385.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ 9.18 (t, 1H), 8.89 (s, 1H), 8.57 (d, 1H), 8.08 (m, 3H), 7.81 (d, 2H), 7.75-7.70 (m, 4H), 7.52-7.42 (m, 6H), 4.57 (d, 2H).
Reaction SMILES: N1([CH:7]2[N:12](C(OCC)=O)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[CH:9]=[C:8]2[C:28]([O:30][CH2:31][CH3:32])=[O:29])CCOCC1.O>CN(C=O)C>[CH2:31]([O:30][C:28]([C:8]1[CH:9]=[C:10]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[N:11]=[N:12][CH:7]=1)=[O:29])[CH3:32]
Reactant: CCOC(=O)C1=CC(c2cccc(C(F)(F)F)c2)=NN(C(=O)OCC)C1N1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnnc(-c2cccc(C(F)(F)F)c2)c1
Yield: 47 %

Procedure:
6-(4-morpholinyl)-3-[3-(trifluoromethyl)phenyl]-1,5(6H)-pyridazindicarboxylic acid, diethyl ester (10.73 g, 0.024 mole) was refluxed in DMF (150 mL) for 30 min. The mixture was poured into water and extracted 3×100 mL with ethyl acetate. The organic layer was dried (MgSO4), filtered through silica gel, and evaporated in vacuo to give a crude solid which was recrystallized from cyclohexane/ethyl acetate to give 6-[3-(trifluoromethyl)phenyl]-4-pyridazinecarboxylic acid ethyl ester (3.34 g, 47% yield, Compound No. 1) as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[C:3]1=[CH2:13].[BH4-].[Na+].O>CO.C(OCC)C>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13]
Reactant: C=C1N(C)c2ccccc2C1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CC1N(C)c2ccccc2C1(C)C

Procedure:
To a stirred solution of 3.46 g of 1,3,3-trimethyl-2-methyleneindoline (VIII, R2 =R8 =R9 =Me) in 50 ml methanol was added at room temperature in three portions at about five-minute intervals a total of 1.14 g of sodium borohydride (conveniently, as three 7/16-inch pellets, a commercially available form). The initial deep red color of the solution gradually changed to a light orange during the reaction. The mixture was then diluted first with 20 ml of ethyl ether, and then with 50 ml of water. The ether layer was separated, and the lower aqueous layer was again extracted with ether. The combined ether layers were washed with 10% aqueous sodium hydroxide solution and then water, and dried over anhydrous magnesium sulfate. Removal of solvent from the filtered extracts left 3.10 g (88.6%) of an orange oil. This oil was distilled in vacuum to give 2.52 g (72.0% of the theoretical amount of 3.50 g) of pale yellow oil boiling at 80°-81° C. at 2.3 mm Hg pressure.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.N1([C:16]([N:18]2[CH:22]=[CH:21]N=C2)=[O:17])C=CN=C1.Br.NCC([C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1)=O>>[NH:6]1[C:5]2[CH:9]=[CH:10][C:2]([N:1]3[CH:21]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=4)[CH2:22][NH:18][C:16]3=[O:17])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: Nc1ccc2nc[nH]c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCC(=O)c1ccc(Cl)c(Cl)c1
Agent: Br
Product: O=C1NCC(c2ccc(Cl)c(Cl)c2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized as hydrochloride salt starting from 5-aminobenzimidazole (1.18 g, 8.87 mmol), di(1H-imidazol-1-yl)methanone (1.58 g, 9.76 mmol), TEA (3.71, 26.61 mmol), aminomethyl-(3,4-dichlorophenyl)ketone hydrobromide (2.528 g, 8.87 mmol), TEA (2.47 mL, 17.72 mmol), PdC (10%, 0.02 g) as described in method 1.
Reaction SMILES: [NH2:1][C:2]1[CH:6]([CH3:7])[CH2:5][N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[CH3:14][I:15]>>[I-:15].[NH2:1][C:2]1[CH:6]([CH3:7])[CH2:5][N+:4]([CH3:14])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: CC1CN(c2ccccc2)N=C1N
Reactant: CI
Product: CC1C[N+](C)(c2ccccc2)N=C1N
Product: [I-]

Procedure:
A 6.0 g. amount of 3-amino-4-methyl-1-phenyl-2-pyrazoline (Example 4) and 12.0 ml. of methyl iodide is heated at reflux for 2 hours. The reaction mixture is cooled and filtered to collect 11.2 g. of crude product. The material is dissolved in water and recrystallized from 95% ethanol to give 4.5 g. of the product of the Example as colorless needles, m.p. 168.5°-170° C.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)[CH2:3]C1.F[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1.C(=O)([O-])[O-].[Li+].[Li+]>>[CH2:9]([C@H:5]1[C@@:4]([CH2:1][CH3:3])([OH:12])[CH2:8][CH2:7][N:6]1[C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH3:11]
Reactant: COc1cc(F)ccc1C#N
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(OC)c2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-diethylpyrrolidin-3-ol 0.5 oxalate (201 mg), 4-fluoro-2-methoxybenzonitrile (250 mg) and lithium carbonate (180 mg), the title compound was obtained as a colorless solid (yield: 158 mg, yield: 54%).
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][C:16](=[O:18])[CH:15]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([OH:14])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH3:28][O:29][CH2:30]Cl>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][C:16](=[O:18])[CH:15]=[C:6]1[C:7]1[CH:8]=[CH:9][C:10]([O:14][CH2:28][O:29][CH3:30])=[CH:11][C:12]=1[CH2:13]2)[CH2:2][CH2:3][CH3:4]
Reactant: COCCl
Reactant: CCCCC12CC(=O)C=C1c1ccc(O)cc1C2
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC12CC(=O)C=C1c1ccc(OCOC)cc1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 8a-butyl-6-hydroxy-8,8a-dihydrocyclopenta[a]inden-2(1H)-one (300 mg, 1.2 mmol) in anhydrous DMF (3 mL) was placed under a N2 atmosphere and stirred at room temperature while N,N-diisopropylethylamine (0.63=L, 3.6 mmol) and chloromethyl methyl ether (0.183 mL, 2.4 mmol) were added successively. After stirring at room temperature overnight, the mixture was diluted with EtOAc (100 mL) and washed with 1N HCl. The acid wash was back-extracted with EtOAc. The combined organics were washed with 5% NaHCO3, water and brine, dried over MgSO4, filtered, and concentrated under vacuum to a brown oil. The crude product was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4×7 cm) silica gel column, eluting with 5:1 hexane-EtOAc, to provide 8a-butyl-6-(methoxymethoxy)-8,8a-dihydrocyclopenta[a]inden-2(1H)-one as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([C:15]([N:17]([CH:31]([CH3:33])[CH3:32])[C@@H:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)=[O:16])[C:12]([CH3:14])=[CH:13][C:8]=2[O:7][C:6]([CH3:35])([CH3:34])[C:5]1=[O:36].ClC(Cl)(O[C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[CH2:49]([N:51](CC)CC)C>C(Cl)(Cl)Cl>[CH:31]([N:17]([C:15]([C:11]1[C:12]([CH3:14])=[CH:13][C:8]2[O:7][C:6]([CH3:34])([CH3:35])[C:5](=[O:36])[N:4]([CH2:3][CH2:2][NH:1][C:41]([NH:51][CH3:49])=[O:47])[C:9]=2[CH:10]=1)=[O:16])[C@@H:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:19]1)([CH3:32])[CH3:33]
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCN)C(=O)C(C)(C)O2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CNC(=O)NCCN1C(=O)C(C)(C)Oc2cc(C)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To tert-butyl (3R)-3-[{[4-(2-aminoethyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (200 mg) were added triphosgene (47 mg), triethylamine (0.12 ml) and chloroform (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated, and thereto were added methylamine (0.17 ml) and chloroform (5 ml) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform /methanol=9/1) to give the title compound (70 mg) as colorless amorphous.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:31]=[CH:30][C:13]2[S:14][CH:15]=[C:16]([CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[O:28][CH3:29])[C:12]=2[CH:11]=1.CN1CCOCC1.O>ClCCl>[C:1]([NH:9][C:10]1[CH:31]=[CH:30][C:13]2[S:14][CH:15]=[C:16]([CH2:17][C:18]3[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=3[O:28][CH3:29])[C:12]=2[CH:11]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(Cc2csc3ccc(N)cc23)c(OC)c1
Solvent: O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2scc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 1 h
Yield: 65.9 %

Procedure:
Hexanoyl chloride (0.024 g.) was added to a stirred solution of methyl 4-(5-aminobenzo[b]thien-3-ylmethyl)-3-methoxybenzoate (H) (0.06 g.), and N-methylmorpholine (0.1 ml.) in dichloromethane (3 ml.). The mixture was stirred for 1 hour and then poured into water (20 ml.). The aqueous mixture was extracted with dichloromethane (2×20 ml.). The combined extracts were dried (MgSO4), and evaporated. The mixture was recrystallized from a mixture of ethyl acetate and hexane to give the title compound (0.05 g., 75%) as a colorless solid; NMR (250 MHz, DMSO-d6): 0.87(t,3H, CH2CH3), 1.28(m,4H, CH2.CH2.CH3), 1.59 (quintet,2H, CH2CH2CON), 2.29(t,2H, CH2CON), 3.84(s, 3H, OCH3), 3.91(s,3H, OCH3), 4.11(s,2H, CH2 --Ar), 7.14 (d,1H), 7.34(s, 1H), 7.49(m,3H), 7.86(d,1H), 8.11(d, 1H), 9.95(s,1H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[C@@H:8]([CH3:12])[C:9]([OH:11])=O.[C:13]([O:17][C:18](=[O:26])[CH2:19][CH:20]([NH2:25])[CH:21]([OH:24])[CH2:22][F:23])([CH3:16])([CH3:15])[CH3:14].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C1C=CN=CC=1)C.C1COCC1>[C:13]([O:17][C:18](=[O:26])[CH2:19][CH:20]([NH:25][C:9](=[O:11])[C@@H:8]([N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]1=[O:1])[CH3:12])[CH:21]([OH:24])[CH2:22][F:23])([CH3:16])([CH3:14])[CH3:15]
Reactant: C[C@@H](C(=O)O)n1ccccc1=O
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Agent: CN(C)c1ccncc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: C1CCOC1
Product: C[C@@H](C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF)n1ccccc1=O
Temperature: 0 °C
Yield: 91.5 %

Procedure:
A stirred mixture of (S)-2-(2-Oxo-2H-pyridin-1-yl)-propionic acid (70 mg, 0.42 mmol), 3-Amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (91 mg, 0.44 mmol), HOAt (63 mg, 0.46 mmol) and DMAP (59 mg, 0.48 mmol) and anhydrous THF (5 ml) was cooled to 0° C. then EDC (88 mg, 0.46 mmol) was added. The mixture was allowed to warm to room temperature during 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (3% methanol in ethyl acetate) to afford the title compound as a white foam (137 mg, 92%): 1H NMR (400 MHz, CDCl3) δ 1.3-1.5 9H, 2×s), 2.5-2.7 2H, m), 3.4-3.7 1H, m), 3.9-4.6 4H, m), 5.4-5.6 1H, m), 6.2-6.3 1H, m), 6.5-6.6 1H, m), 7.1-7.6 3H, m); 19F NMR (376 MHz, CDCl3) δ −230.14, −230.14, −230.17, −230.95, −231.07.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])[CH2:10][OH:11].C(O)(=O)C.[CH:23](=O)[C:24]([CH3:27])([CH3:26])[CH3:25].C([BH3-])#N.[Na+]>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:3]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])[CH2:10][OH:11])[CH:4]=1
Reactant: CC(C)(C)C=O
Reactant: Nc1ccc(Cl)cc1C(CO)c1ccccc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)CNc1ccc(Cl)cc1C(CO)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of 2-(2-amino-5-chlorophenyl)-2-(2-chlorophenyl)ethanol (4.44 g) in methanol (50 ml) were added acetic acid (1.4 ml) and pivalaldehyde (2.0 g). The mixture was stirred for 30 minutes at room temperature. To the solution was added sodium cyano borohydride (1.5 g), and the mixture was stirred for one hour at room temperature. The reaction mixture was then processed in substantially the same manner as in Example 52-(7) to give 5.5 g of an oily compound.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[CH2:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][N:7]1[CH2:12][CH3:13].[C:18](Cl)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:12]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[CH2:5][CH2:4][C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:18](=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:13]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CCN1CCCCC1CCc1ccccc1N
Product: CCN1CCCCC1CCc1ccccc1NC(=O)C=Cc1ccccc1

Procedure:
Reaction of 2-(2-aminophenethyl)-1-ethylpiperidine with cinnamoyl chloride according to the procedure of Example 25 provides 2'-[2-(1-ethyl-2-piperidyl)ethyl]cinnamanilide, m.p. 119.5° - 121.5° C. (corr.), from ethyl acetate and then acetonitrile.