Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[S:11][C:10]([C:12]#[N:13])=[CH:9][C:8]=2[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH3:24])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[S:11][C:10]([C:12]3[NH:29][N:28]=[N:27][N:13]=3)=[CH:9][C:8]=2[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([CH3:24])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cc(C#N)sc2Cc2ccc(Cl)cc2)c2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Product: Cc1ccc(-c2cc(-c3nnn[nH]3)sc2Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 110 °C
Yield: 85.8 %

Procedure:
A round-bottomed flask was charged with 5-(4-chlorobenzyl)-4-(4-methylnaphthalen-1-yl)thiophene-2-carbonitrile (170 mg, 0.45 mmol), zinc bromide (338 mg, 1.50 mmol) and sodium azide (97.5 mg, 1.50 mmol). After degassed, DMF (3 mL) was added. The reaction mixture was heated to 110° C. and stirred at this temperature until complete. The reaction was cooled to rt and 30 mL of 0.1 N aqueous HCl was added. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc:AcOH=30:10:1). 161 mg (85%) of product was obtained as a white solid, 1H NMR (CDCl3, 500 MHz) δ 8.05 (d, J=8.46 Hz, 1H), 7.73 (s, 1H), 7.63 (d, J=8.36 Hz, 1H), 7.53 (t, J=7.58 Hz, 1H), 7.42 (t, J=7.53 Hz, 1H), 7.33 (d, J=7.11 Hz, 1H), 7.23 (d, J=7.08 Hz, 1H), 7.14 (d, J=8.25 Hz, 2H), 6.92 (d, J=8.14 Hz, 2H), 3.86 (ABq, 2H, ΔδAB=0.06, JAB=15.90 Hz), 2.70 (s, 3H); 13C NMR (CDCl3, 125 MHz) δ 152.61, 145.54, 139.59, 137.96, 135.22, 132.97, 132.76, 132.69, 132.27, 131.09, 130.05, 128.81, 127.55, 126.33, 126.25, 126.20, 126.16, 124.75, 122.29, 34.24, 19.77.
Reaction SMILES: C(N)CCCCCCCCCCCCCCCCC.Cl.[C:21]1(C(O)=O)[C:38]2=[C:39]3[C:28]([C:29]4[C:40]5[C:33](=[CH:34][CH:35]=[CH:36][C:37]2=5)[CH:32]=[CH:31][CH:30]=4)=[CH:27][CH:26]=[C:25](C(O)=O)[C:24]3=[C:23](C(O)=O)[C:22]=1C(O)=O.C(O)(=O)CCCCCCCCCCCCCCCCC>C(O)(C)C>[CH:36]1[C:37]2=[C:40]3[C:29]([C:28]4[C:39]5[C:24](=[CH:23][CH:22]=[CH:21][C:38]2=5)[CH:25]=[CH:26][CH:27]=4)=[CH:30][CH:31]=[CH:32][C:33]3=[CH:34][CH:35]=1
Reactant: O=C(O)c1c(C(=O)O)c2c(C(=O)O)ccc3c4cccc5cccc(c(c1C(=O)O)c23)c54
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCN
Agent: Cl
Solvent: CC(C)O
Product: c1cc2cccc3c4cccc5cccc(c(c1)c23)c54

Procedure:
0.7 part of stearylamine are dissolved warm in 60 ml of isopropanol and to this solution are added 35 parts by volume of about 37% aqueous hydrochloric acid. With stirring, the alkaline perylenetetracarboxylic acid/stearic acid solution is added dropwise to this mixture in the course of 15 minutes at 60° C. The formation of the anhydride imide is brought to completion by stirring the acid suspension for 31/2 hours at reflux temperature. The red pigment suspension is then filtered at about 70° C. The filter cake is washed neutral with water and dried in a vacuum cabinet at 80° C., affording 29.8 parts of a perylene pigment which produces strong red colourations of excellent fastness properties when it is incorporated in alkylmelamine stoving lacquers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](=[N:17][OH:18])[NH2:16])=[C:10]3[CH2:9][N:8]([CH3:19])[C:7](=[O:20])[C:6]=2[CH:21]=1.[Cl:22][CH2:23][C:24](OC(=O)CCl)=O>CN(C)C=O>[Cl:22][CH2:23][C:24]1[O:18][N:17]=[C:15]([C:14]2[N:13]=[CH:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:21][C:6]=4[C:7](=[O:20])[N:8]([CH3:19])[CH2:9][C:10]=23)[N:16]=1
Reactant: CN1Cc2c(C(N)=NO)ncn2-c2ccc(F)cc2C1=O
Reactant: O=C(CCl)OC(=O)CCl
Solvent: CN(C)C=O
Product: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2ccc(F)cc2C1=O
Reaction time: 2 h
Yield: 58.2 %

Procedure:
A suspension of 5.8 g (0.020 mol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamidoxime in 60 ml of dimethylformamide was treated with 3.9 g (0.023 mol) of chloroacetic anhydride. The yellow solution obtained was stirred at 100° for 11/2 hr. and then completely freed from solvents. The oily product crystallized from acetonitrile and was filtered off. The mother liquor was concentrated, the residue was chromatographed over silica gel with dichloromethane/methanol 97:3 as the eluent and the additional portion of product obtained was recrystallized from acetonitrile. There were obtained a total of 4.05 g (59%) of 3-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 245°-247°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11](O)=[O:12].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>O1CCCC1.C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[CH:11]=[O:12]
Reactant: O=C(O)C=Cc1ccc(Cl)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C/C=C/c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.7 %

Procedure:
3-(2,4-Dichlorophenyl)acrylic acid (900 mg, 4.15 mmol) is dissolved in tetrahydrofuran (50 mL) and the resulting solution is cooled to 0° C. before triethylamine (0.692 mL, 4.98 mmol) and isobutyl chloroformate (0.647 mL, 4.98 mmol) are added. The reaction mixture is stirred for 30 min and the precipitate formed is filtered off. The filtrate is then cooled to 0° C. and water (1 mL) is added followed by sodium borohydride (314 mg, 8.29 mmol). The resulting mixture is stirred for 30 min until complete conversion is observed. The solution is diluted with ethyl acetate (100 mL) and the organic layer is washed with aqueous 1M hydrochloride (30 mL) and with brine (30 mL), is dried over sodium sulphate and is concentrated under reduced pressure after filtration. The residue obtained is dissolved in dichloromethane (20 mL) and Dess-Martin periodinane (2638 mg, 6.22 mmol) is added. The solution is stirred at room temperature for 3 h until full conversion of the starting material is observed. The reaction mixture is washed with a 1 to 1 solution of aqueous 10% sodium thiosulphate and of aqueous saturated sodium hydrogen carbonate (10 mL) and with brine (10 mL). The organic layer is dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product isolated is finally purified by flash column chromatography on silica gel (dichloromethane as eluent) to give the desired product (624 mg, 3.10 mmol, 75% yield).
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][O:15][N:16]=[C:17]([C:34](=[O:37])[CH2:35][Br:36])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[CH:24]([C:29]([OH:31])=[O:30])[CH:25](O)[CH2:26][S:27][C@H:22]12)=[O:19].C(N(CC)CC)C.Cl>C(OCC)(=O)C>[CH3:14][O:15][N:16]=[C:17]([C:34](=[O:37])[CH2:35][Br:36])[C:18]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH2:26][S:27][C@H:22]12)=[O:19]
Reactant: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: Cl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON=C(C(=O)CBr)C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.5 %

Procedure:
Trifluoroacetic anhydride (0.5 ml.) was added to a solution of 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 180 mg.) in dry tetrafuran (10 ml.) and stirred at room temperature for 10 minutes. Triethylamine (0.2 ml.) was added to the resultant solution and stirred at room temperature for 10 minutes. Ethyl acetate was added to the solution and adjusted to pH 2.0 with 6N hydrochloric acid. The solution was washed with water and a sodium chloride saturated aqueous solution successively and dried over magnesium sulfate. After the solution was concentrated in vacuo, the residue was pulverized with diisopropyl ether to give 7-(2-methoxyimino-3-oxo-4-bromobutyramido)-3-cephem-4-carboxylic acid (syn isomer, 171.5 mg.).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][Si:5]([CH:10]=[CH2:11])([CH:8]=[CH2:9])[CH:6]=[CH2:7].[C-:12]#[N:13].[Na+]>CN(C)C=O>[C:12]([CH2:2][CH2:3][CH2:4][Si:5]([CH:10]=[CH2:11])([CH:8]=[CH2:9])[CH:6]=[CH2:7])#[N:13]
Reactant: C=C[Si](C=C)(C=C)CCCCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C[Si](C=C)(C=C)CCCC#N
Temperature: 70 °C
Yield: 86.2 %

Procedure:
Compound 3-chloropropyltrivinylsilane (1000 mg, 5.35 mmol) and sodium cyanide (525 mg, 10.70 mmol) were dissolved in 18 ml of dimethylformamide, and the mixture was heated at 70° C. for 4 hours. After the reaction, the organic layer was extracted after addition of distilled water and ether, and then purified by column chromatography (n-Hex:EA=10:1, Rf=0.42), to give 818 mg (86% yield) of pure 3-cyanopropyltrivinylsilane.
Reaction SMILES: [C:1]([CH:3]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4]1)#[N:2].[Cl:12][CH2:13][C:14]([N:16]=[C:17]=[O:18])=[O:15]>C(OCC)C>[Cl:12][CH2:13][C:14]([NH:16][C:17]([N:4]1[CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:3]1[C:1]#[N:2])=[O:18])=[O:15]
Reactant: O=C=NC(=O)CCl
Reactant: N#CC1NC1c1ccccc1
Solvent: CCOCC
Product: N#CC1C(c2ccccc2)N1C(=O)NC(=O)CCl

Procedure:
1 g. Crude 2-cyano-3-phenyl-aziridine is dissolved in 25 ml. anhydrous diethyl ether. A solution of 0.83 g. chloroacetyl isocyanate in 3.5 ml. diethyl ether is added thereto dropwise, while stirring, and the reaction mixture is further stirred for 1 hour at ambient temperature. The precipitate obtained is then filtered off with suction, washed with diethyl ether and dried in a vacuum. There is thus obtained 1.24 g. 1-(N-chloroacetyl-carbamoyl)-2-cyano3-phenyl-aziridine; m.p. 153°-158°-165° C. According to the NMR spectrum, the product is an isomeric mixture containing about 30% of the trans form and about 70% of the cis form.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]1[CH3:13])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:18](Cl)(=[O:20])[CH3:19]>C(=S)=S>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:18](=[O:20])[CH3:19])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccccc2CC1C
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)CC(C)N2C(C)=O
Temperature: 50 °C
Yield: 96.9 %

Procedure:
To a mixture of the compound from Step 1 (2.0 g, 11.4 mmol) and aluminum chloride (7.0 g, 52 mmol) in carbon disulfide (20 mL) is added acetyl chloride (1.2 mL, 17.1 mmol). The mixture is heated at 50° C. for 72 h, cooled, quenched with ice water then diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate, filtered, concentrated, and chromatographed on silica gel eluting with 40-50% ethyl acetate in heptane to give 2.4 g (97%) of the title compound as a off-white solid. MS (ESI+) m/z 217.1 (M+H). Anal. Calcd for C13H15NO2: C, 71.87; H, 6.96; N, 6.45. Found: C, 71.78; H, 6.98; N, 6.43.
Reaction SMILES: F[B-](F)(F)F.C[N+:7](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.[C:23]([C:25]1[CH:30]=[CH:29][C:28]([CH:31]2[N:36]([CH2:37][C:38](O)=[O:39])[C:35](=[O:41])[N:34]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:51])([F:50])[F:49])[CH:43]=3)[C:33]3[CH2:52][CH2:53][C:54](=[O:55])[C:32]2=3)=[CH:27][CH:26]=1)#[N:24].C(N(CC)C(C)C)(C)C.N>CN(C)C=O>[C:23]([C:25]1[CH:26]=[CH:27][C:28]([CH:31]2[N:36]([CH2:37][C:38]([NH2:7])=[O:39])[C:35](=[O:41])[N:34]([C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([C:48]([F:49])([F:51])[F:50])[CH:43]=3)[C:33]3[CH2:52][CH2:53][C:54](=[O:55])[C:32]2=3)=[CH:29][CH:30]=1)#[N:24]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(=O)O)cc1
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: N#Cc1ccc(C2C3=C(CCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N,N,N′,N′-Tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (43 mg, 0.13 mmol) is added to a solution of 2-(4-(4-cyanophenyl)-2,5-dioxo-1-(3-(trifluoro-methyl)phenyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidin-3(2H,4H,5H)-yl)acetic acid (example 4, 60 mg, 0.13 mmol) and N,N-diisopropylethylamine (50 μL, 0.29 mmol) in N,N-dimethylformamide (0.5 mL). After 20 min aqueous ammonia (32%, 8 μL, 0.13 mmol) added and the mixture is stirred at room temperature for 1 h. The mixture is purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 36 mg; ESI mass spectrum [M+H]+=455; Retention time HPLC: 0.50 min (X012_S01).
Reaction SMILES: [C:1]1(/[C:7](=[N:41]/[O:42][CH3:43])/[C:8]([NH:10][CH:11]2[C:39](=[O:40])[N:13]3[C:14]([C:23]([O:25]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:24])=[C:15]([CH:19]=[N:20][O:21][CH3:22])[C@@H:16]([CH3:18])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>[C:1]1(/[C:7](=[N:41]/[O:42][CH3:43])/[C:8]([NH:10][CH:11]2[C:39](=[O:40])[N:13]3[C:14]([C:23]([OH:25])=[O:24])=[C:15]([CH:19]=[N:20][O:21][CH3:22])[C@@H:16]([CH3:18])[S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CON=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3ccccc3)[C@H]2S[C@@H]1C
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CON=CC1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3ccccc3)[C@H]2S[C@@H]1C
Yield: 53.7 %

Procedure:
A solution of 294 mg of diphenylmethyl 7-[2-phenyl-(Z)-2-methoxyiminoacetamido]-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylate in 0.3 ml of anisole and 10 ml of CF3COOH was stirred at room temperature for 20 minutes. After distilling off the CF3COOH under reduced pressure, the residue was dissolved in AcOEt and then transferred into 5% aqueous NaHCO3. The water layer was adjusted to pH 2.0 with 5% H3PO4 added, and extracted again with AcOEt. The AcOEt layer was washed with H2O and saturated aqueous NaCl solution, successively, and dried over Na2SO4, followed by distilling off the AcOEt under reduced pressure. The residue was treated with Et2O, thus yielding 114 mg (54%) of 7-[2-phenyl-(Z)-2-methoxyiminoacetamido]-2α-methyl-3-methoxyiminomethylceph-3-em-4-carboxylic acid as crystals.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:26][C:27]1[CH:28]=[CH:29][C:30]([CH3:36])=[C:31](B(O)O)[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]1([S:7]([N:10]2[CH2:14][CH:13]([C:15]3[CH:16]=[C:17]([C:29]4[CH:28]=[C:27]([Cl:26])[CH:32]=[CH:31][C:30]=4[CH3:36])[CH:18]=[CH:19][CH:20]=3)[N:12]([CH:22]([CH3:24])[CH3:23])[C:11]2=[O:25])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N1C(=O)N(S(=O)(=O)c2ccccc2)CC1c1cccc(Br)c1
Reactant: Cc1ccc(Cl)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1-c1cccc(C2CN(S(=O)(=O)c3ccccc3)C(=O)N2C(C)C)c1

Procedure:
In analogy to example 1, step 3,1-benzenesulfonyl-4-(3-bromo-phenyl)-3-isopropyl-imidazolidin-2-one (example 12, step 1) was reacted with 5-chloro-2-methylphenylboronic acid in the presence of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct and sodium carbonate in dioxane/water to give 1-benzenesulfonyl-4-(5′-chloro-2′-methyl-biphenyl-3-yl)-3-isopropyl-imidazolidin-2-one as a light yellow oil. MS: 469.1 ([M+H]+)
Reaction SMILES: [CH2:1]([C:4]1([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.C1C[O:37]CC1.O>CCOC(C)=O.O=[Os](=O)(=O)=O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]2[CH2:6][CH2:5][C:4]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([CH2:1][CH2:2][OH:37])[O:9][C:8]2=[O:10])[CH3:12])=[CH:14][CH:15]=1
Reactant: C1CCOC1
Reactant: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CCC(CCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-allyl-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (obtained as described in Example 111) in THF-H2O (1:1, 20 mL) were added NaIO4 (1.0148 g, 4.74 mmol, 5 equiv) and OsO4 (2.5 wt. % solution in t-BuOH, 0.1708 g, 0.0167 mmol, 0.018 equiv), and the mixture was stirred at rt for 2 h. The mixture was diluted with EtOAc, dried over Na2SO4, and concentrated under reduced pressure. The residue was dissolved in MeOH (10 mL) and NaBH4 (0.200 g) was added. After the mixture was stirred for 1 h at rt, acetone was added. The solvents were removed in vacuo, the residue was treated with saturated brine, extracted with CH2Cl2, and dried over Na2SO4. After the solvents were evaporated, the residue was purified by chromatography on silica gel eluted with hexanes/EtOAc to afford the two diastereomers of 3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one.
Reaction SMILES: C[O:2][C:3](=[O:44])[C@@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[C:31](=[O:37])[NH:32][CH:33]2[CH2:36][CH2:35][CH2:34]2)=[O:25])[N:19]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:18]=1)=[O:16])[CH2:5][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[Li+].[OH-]>C1COCC1>[C:10]([O:9][C:7](=[O:8])[CH2:6][CH2:5][C@H:4]([NH:14][C:15]([C:17]1[CH:21]=[C:20]([O:22][CH2:23][C:24]([N:26]2[CH2:30][CH2:29][CH2:28][C@H:27]2[C:31](=[O:37])[NH:32][CH:33]2[CH2:36][CH2:35][CH2:34]2)=[O:25])[N:19]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:18]=1)=[O:16])[C:3]([OH:44])=[O:2])([CH3:13])([CH3:11])[CH3:12]
Reactant: COC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NC2CCC2)n(-c2ccccc2)n1)C(=O)O
Reaction time: 2 h

Procedure:
To a solution of 1.88 g (S)-2-({5-[2-((S)-2-cyclobutylcarbamoyl-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester 1-methyl ester in 12 ml THF were added 73 mg LiOH (as solution in 4 ml water). After 2 h the reaction mixture was neutralized with Amberlite IR-120, filtrated and washed with methanol.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1>>[CH3:3][C:2]([CH3:5])([CH3:4])[CH:1]=[N:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1
Reactant: CC(C)(C)C=O
Reactant: NC1CCNC1
Product: CC(C)(C)C=NC1CCNC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.1 g (0.1 mol) of 71% strength pivalaldehyde, initially introduced into the reaction vessel and 8.6 g (0.1 mol) of 3-aminopyrrolidine are added dropwise at 20° C. to 30° C., while cooling in a water bath. The mixture is subsequently stirred at room temperature for 1 hour and is then distilled. Yield: 13.5 g (85% of theory), boiling point: 63° C.-65° C./10 to 12 mbar; content: 97%.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.C(O)(C(F)(F)F)=O.[CH3:26][C:27]([CH3:29])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(O)(=O)C>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][N:10]([CH:27]([CH3:29])[CH3:26])[CH2:9][C:7]=2[N:8]=1
Reactant: CC(C)=O
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 6) as a TFA salt (820 mg, 2.0 mmol) in anhydrous THF (5 ml) was added anhydrous acetone (500 μl) and glacial acetic acid (four drops). The reaction was stirred at RT for 30 minutes after which time sodium triacetoxyborohydride (848 mg, 4.0 mmols) was added. After stirring for a further 30 minutes at RT, the reaction was partitioned between water and DCM. The aqueous phase was extracted into DCM and the organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo to afford the title compound as a brown oil, which was used without further purification.
Reaction SMILES: C(N)CN.[Na].[H][H].[CH3:8][C:9]1[CH2:14][CH2:13][CH:12]([C:15]([CH3:17])=[CH2:16])[CH2:11][CH:10]=1>O>[C:12]1([CH:15]([CH3:17])[CH3:16])[CH:13]=[CH:14][C:9]([CH3:8])=[CH:10][CH:11]=1
Reactant: [H][H]
Reactant: C=C(C)C1CC=C(C)CC1
Agent: [Na]
Solvent: O
Solvent: NCCN
Product: Cc1ccc(C(C)C)cc1
Temperature: 50 °C
Yield: 99 %

Procedure:
To mixture of ethylenediamine (525 mmol, 31.6 g, 35.2 ml), anhydrous FeCl3 (0,964 mmol, 0.16 g) and sodium (145 mmol, 3.34 g) was heated to about 50° C. under N2. After sodium dissolution had started, as evidenced by hydrogen evolution and formation of a dark solution, α-limonene (742 mmol, 101 g, 120 ml), certified as derived from biomass (obtained from Sigma-Aldrich (St. Louis, Mo.), was added dropwise into the mixture and the mixture heated to 100° C. The mixture was heated at 100° C. for 8 h. The mixture was then cooled down and diluted with water (300 ml) and extracted two times with dichloro methane (DCM) (300 ml). The organic layers were dried over magnesium sulfate and concentrated using a rotary evaporator obtaining the crude para-cymene product. Yield: 99% (purity 99%)
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4].[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([N:29]([CH2:30][CH3:31])[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:18]3[CH:19]=[C:20]4[O:25][CH2:24][O:23][C:21]4=[CH:22][C:17]=3[CH2:16][C:15]([CH3:26])=[N:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4])[CH3:28]
Reactant: CCNCC
Reactant: CC1=NN=C(c2ccc(NC(=O)CCl)cc2)c2cc3c(cc2C1)OCO3
Product: CCN(CC)CC(=O)Nc1ccc(C2=NN=C(C)Cc3cc4c(cc32)OCO4)cc1

Procedure:
It was prepared from 1-(4-chloroacetylaminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine by using the process of Example 102, except that diethylamine was used instead of pyrrolidine, m.p.: 157°-158° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:5][CH:4]([N:6]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:17]=[N:18][C:19]([NH:31][C:32]([NH:34][CH2:35][CH2:36][CH3:37])=[O:33])=[CH:20][C:21]=4[C:22]4[S:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[N:26]=4)=[CH:13][CH:14]=3)[C:9](=[O:38])[C:8]([C:39]([O:41]CC)=[O:40])=[CH:7]2)[CH2:3]1.[OH-].[Li+]>O1CCCC1>[CH3:5][N:2]([CH3:1])[CH2:3][CH2:4][N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[CH:17]=[N:18][C:19]([NH:31][C:32]([NH:34][CH2:35][CH2:36][CH3:37])=[O:33])=[CH:20][C:21]=3[C:22]3[S:23][CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[N:26]=3)=[CH:13][CH:14]=2)[C:9](=[O:38])[C:8]([C:39]([OH:41])=[O:40])=[CH:7]1
Reactant: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C2CN(C)C2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CCN(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of ethyl 1-(2-(dimethylamino)ethyl)-4-oxo-6-(6-(3-propylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1,4-dihydroquinoline-3-carboxylate (Example 150, 100 mg, 0.16 mmol) in tetrahydrofuran (2 mL) was added lithium hydroxide (1 M, 650 μL) and the mixture was stirred for 1 h at room temperature. The organics were removed under a stream of nitrogen and the precipitate that formed was isolated by filtration, washed with water (1 mL), and dried in a vacuum oven overnight at 40° C. to give 70 mg of yellowish solid.