Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][NH:17][CH2:16]2>>[ClH:1].[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH2:18][N:17]([C:2]1[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=1)[CH2:16]2
Reactant: Clc1ccnc2ccccc12
Reactant: Clc1ccc2c(c1)CNC2
Product: Cl
Product: Clc1ccc2c(c1)CN(c1ccnc3ccccc13)C2
Temperature: 145 °C
Yield: 24.2 %

Procedure:
A mixture of 4-chloroquinoline (0.245 g, 1.5 mmol) and 5-Chloro-2,3-dihydro-1H-isoindole (0.23 g, 1.5 mmol) was heated at 140-150° C. for 4 hours under Argon then cooled to room temperature. The crude product was recrystallized with methanol to provide 4-(5-Chloro-1,3-dihydro-isoindol-2-yl)-quinoline hydrochloride (0.115 g, 24%) as white solid, m.p. 270-275° C. and MS: m/e=280 (M+).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[S:13](=[O:17])(=[O:16])([OH:15])[OH:14]>C(O)(C)C>[S:13](=[O:15])(=[O:14])([OH:17])[O-:16].[OH:1][NH+:2]1[C:7]([CH3:8])([CH3:9])[CH2:6][CH:5]([OH:10])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: O=S(=O)(O)O
Reactant: CC1(C)CC(O)CC(C)(C)N1O
Solvent: CC(C)O
Product: CC1(C)CC(O)CC(C)(C)[NH+]1O
Product: O=S(=O)([O-])O
Yield: 38.1 %

Procedure:
5.0 g (0.029 mol) 1-hydroxy-2,2,6,6-tetramethyl-4-hydroxypiperidine and 3.0 g (0.031 mol) sulfuric acid are recrystallized from 50 mL of isopropanol, yielding 3.0 g of the desired hydroxylamine salt as a white crystalline solid, mp 238-241° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22](=[O:23])[C:21]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=3[C:19]2=[O:29])=[C:14]([CH3:30])[CH:13]=1.[C:31](Cl)(=[O:35])[C:32](Cl)=[O:33]>>[Cl:1][C:2]1[S:6][C:5]([S:7]([NH:10][C:31](=[O:35])[C:32]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:22](=[O:23])[C:21]4[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:20]=4[C:19]3=[O:29])=[C:14]([CH3:30])[CH:13]=2)=[O:33])(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)c1ccc(Cl)s1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Product: Cc1cc(NC(=O)C(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Reaction time: 1 h
Yield: 44 %

Procedure:
A 200 mg (1.0 mmol) of 5-chlorothiophenesulfonamide was slurried in 0.5 mL of oxalyl chloride and refluxed for 6 h. The solvent was removed in vacuo and 36 mg of the resulting solid was dissolved in 240 μl, acetonitrile and treated with 40 mg (0.14 mmol) 2-(4-amino-2-methylphenyl)-5-chlorobenzo[c]azoline-1,3-dione. After stirring for 1 h, the solvent was removed and the residue was purified by RP-HPLC to give 33 mg (44%) of the titled compound. ES-MS (M+H)+=538(2Cl).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:5]=2[S:4](=[O:14])(=[O:13])[N:3]=1.[CH3:15][CH:16]([NH2:22])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>>[Cl:12][C:10]1[CH:9]=[CH:8][C:6]2[NH:7][C:2]([NH:22][CH:16]([CH3:15])[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[N:3][S:4](=[O:14])(=[O:13])[C:5]=2[CH:11]=1
Reactant: CC(C)CCC(C)N
Reactant: O=S1(=O)N=C(Cl)Nc2ccc(Cl)cc21
Product: CC(C)CCC(C)NC1=NS(=O)(=O)c2cc(Cl)ccc2N1

Procedure:
Starting from 3,7-dichloro-4H-1,2,4-benzothiadiazine 1,1-dioxide (300 mg; 1.19 mmol) and 1,4-dimethylpentylamine (1.0 g; 8.68 mmol) with the use of same procedure as in example 21 210 mg (53.5%) of the title compound was prepared; m.p. >220° C.; 1H-NMR (DMSO-d6) ppm; 10.4 (s, 1H, NH), 7.7 (d, 1H, H-8), 7.6 (dd, 1H, H-5), 7.25 (d, 1H, H-7), 7.1 (br, 1H, NH), 3.88 (q, 1H, CH2), 1.55 (m, 3H), 1.21 (m, 2H), 1.1 (d, 3H, CH3), 0.9 (d, 6H, 2×CH3); MS:EI/70eV: 330 (M+), 258, 231, 190, 126, 69, 55, 44. Analysis: C10H12ClN3O2S requires C, 50.98; H, 6.11; N, 12.74; (found C, 51.14; H, 6.43; N, 12.64)
Reaction SMILES: [N:1]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)=[N:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C([O:20][CH2:21][CH3:22])(=O)C>ClCCl>[C:21]([NH:14][C:13]1[CH:15]=[CH:16][C:10]([N:1]=[N:2][C:3]2[CH:4]=[CH:5][C:6]([NH2:7])=[CH:8][CH:9]=2)=[CH:11][CH:12]=1)(=[O:20])[C:22]1[CH:8]=[CH:9][CH:3]=[CH:4][CH:5]=1
Reactant: CCOC(C)=O
Reactant: Nc1ccc(N=Nc2ccc(N)cc2)cc1
Solvent: ClCCl
Product: Nc1ccc(N=Nc2ccc(NC(=O)c3ccccc3)cc2)cc1
Yield: 54 %

Procedure:
Following the general monoacylation procedure, 4,4′-azodianiline (50 mg, 240 μmol) was treated with benzoyl choloride (26 μl, 240 μmol). Silica gel chromatography through a wide column (10% ethyl acetate in dichloromethane) provided S5 as an orange solid (44 mg, 130 μmol, 54% yield): 1H (DMSO, 400 MHz): 6.04 (s, 2H); 6.66 (d, 2H, J=8.4); 7.52-7.65 (m, 5H); 7.76 (d, 2H, J=8.8); 7.88-7.98 (m, 4H); 10.46 (s, 1H). 13C (DMSO, 100 MHz): 113.4, 120.5, 122.3, 124.9, 127.7, 128.4, 131.7, 134.8, 140.4, 142.9, 148.4, 152.5, 165.7. HRMS (ESI+): calc'd for C19H17N4O+—317.1397. found—317.1403 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.[NH2:22][C@H:23]([C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:26])[CH3:24].[BH3-]C#N.[Na+]>C(O)C>[CH2:14]([O:13][C:11]([CH:10]([NH:22][C@H:23]([C:25]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29]([OH:31])=[O:30])=[O:26])[CH3:24])[CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:12])[CH3:15]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1ccc(Cl)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(CCc1ccc(Cl)cc1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
A solution of ethyl 4-p-chlorophenyl-2-oxobutyrate (prepared from the acid by esterification with ethanol in refluxing CCl4) and L-alanyl-L-proline in ethanol can be treated with excess NaBH3CN and stirred at room temperature until reaction is complete. The ethanol can then be removed under vacuum and the product absorbed on strong acid ion-exchange resin. By elution with 2% pyridine in water, one can obtain N-(1-ethoxycarbonyl-3-p-chlorophenylpropyl)-L-alanyl-L-proline.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-:3])=[O:2].[C:15]1([OH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C.O>CC(C)=O>[C:15]1([O:21][S:11]([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)(=[O:12])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(S(=O)(=O)Oc2ccccc2)ccc1Cl
Temperature: 25 °C
Yield: 86.4 %

Procedure:
3-Nitro-4-Chloro-benzene-sulfonic acid-phenylester was obtained by mixing 51 g of 3-nitro-4-chloro-benzene-sulfonic acid-chloride with 18.8 g of phenol in 120 ml of acetone, and by adding 28 ml of triethylamine dropwise, while cooling, at a temperature not exceeding 10° C. The mixture was continued to be stirred for several hours at room temperature, and then water was added, in which process an oil was separated which was extracted with ether. After recrystallization of the residue from methanol, 54 g of 3-nitro-4-chloro-benzene-sulfonic acid-phenylester were obtained, which had a melting point of 71° C.
Reaction SMILES: N#N.[CH3:3][O:4][C:5]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:6]=1/[CH:7]=[CH:8]/[C:9](O)=[O:10].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C=O)C>[CH3:3][O:4][C:5]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:6]=1/[CH:7]=[CH:8]/[C:9]([Cl:23])=[O:10]
Reactant: COc1ccc(/C=C/C(=O)O)c(OC)c1OC
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(/C=C/C(=O)Cl)c(OC)c1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
(The following reaction is done in an anhydrous N2 atmosphere.) Dissolve trans-2,3,4-Trimethoxycinnamic acid (50) (200 mg, 0.84 mmol) in anhydrous DCM (4.4 mL) at it and add anhydrous DMF (3 drops, cat. amount). Then add slowly oxalyl chloride (96 μL, 1.09 mmol) stir the turbid mixture for additional 2 h at rt. Remove solvent and dry the residue in oil pump vacuum to obtain trans-2,3,4-Trimethoxycinnamic acid chloride (51) (ca. 0.84 mmol) as an yellow solid. Dissolve acid chloride (51) (108 mg, 0.42 mmol) in anhydrous DCM (4.0 mL) and add it to an ice cooled solution of Methyl 3-amino-4-methylbenzoate (52) (69 mg, 0.42 mmol) in anhydrous DCM (2.0 mL) and anhydrous pyridine (1.2 mL). Stir the resulting reaction mixture at rt overnight. Pour the reaction mixture into ice cooled 1M aqu. HCl, extract with EtOAc (3×), wash the combined organic layer with brine and dry it with Na2SO4. Purify the crude product by filtration through a short pad of silica gel with EtOAc and remove solvent to obtain 4-Methyl-3-[3-(2,3,4-trimethoxy-phenyl)-acryloylamino]-benzoic acid methyl ester (53) (99 mg, 61%) as a light yellow solid. 1H NMR (400 MHz, CDCl3): 2.35 (s, 3H); 3.87 (s, 3H); 3.88 (s, 6H); 3.91 (br.s, 3H); 6.59 (d, 1H, J=15.6 Hz); 6.68 (d, 1H, J=8.6 Hz); 7.08 (br.s, 1H); 7.20-7.29 (m, 2H); 7.77 (br.d, 1H, J=8.6 Hz); 7.90 (d, 1H, J=15.6 Hz); 8.55 (br.s 1H).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N)CN.C(O)(=[O:14])C(C)C.CCCCCCCCCCCCC[N+](CC1C=CC=CC=1)(C)C.[Cl-]>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:2]([OH:14])(=[O:3])[C:1]([OH:5])=[O:4]
Reactant: CC(C)C(=O)O
Reactant: O=C(O)CO
Agent: CCCCCCCCCCCCC[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Solvent: NCCN
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A 300-mL EZE-Seal stirred autoclave reactor equipped with Dispersimax Impeller (Autoclave Engineers) was charged with 100 mL of a solution containing glycolic acid (0.750M), ethylenediamine (0.863M), isobutyric acid (0.100M, HPLC internal standard), and flavin mononucleotide (0.01 mM), at pH 9.25, and the solution cooled to 5° C. To the reactor was then added 5.0 g of Pichia pastoris transformant strain GS115-MSP10 (423 IU glycolate oxidase and 869,000 IU catalase) which had been permeabilized by treatment with 0.1% benzalkonium chloride (Sigma), and the reactor purged with oxygen. The mixture was then stirred at 1000 rpm, which bubbled oxygen through the mixture via the action of the turbine impeller, and at 5° C. under 120 psig of oxygen. The reaction was monitored by taking a 0.4 mL aliquot of the reaction mixture at regular intervals, filtering the aliquot using a Millipore Ultrafree-MC 10,000 NMWL Filter Unit, and analyzing the filtrate by HPLC. After 1.0 h, the yields of glyoxylic acid, oxalic acid, and formic acid were 98.7%, 1.3%, and 0%, respectively, with no remaining glycolic acid. The recovered activities of permeabilized-cell glycolate oxidase and catalase were 87% and 84% of their initial values, respectively.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([SH:22])[N:3]=1.[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)(O)[O-].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:19]=[CH:18][C:13]3[O:14][CH2:15][CH2:16][O:17][C:12]=3[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:3]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1ccc2c(c1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(N)nc(SCc2ccccc2)c(C#N)c1-c1ccc2c(c1)OCCO2

Procedure:
100 mg (0.32 mol) of 2-amino-6-sulfanyl-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,5-pyridinedicarbonitrile [prepared analogously to Dyachenko et al., Russian Journal of Chemistry 33 (7), 1014–1017 (1997); 34 (4), 557–563 (1998)], 110 mg (0.64 mmol) of benzyl bromide and 108 mg (1.29 mmol) of sodium bicarbonate are stirred in 2 ml of DMF at room temperature for 5.5 h. Water is then added and the mixture is extracted three times with ethyl acetate. The combined organic phases are dried with magnesium sulfate and concentrated under reduced pressure. The residue is taken up in diethyl ether, giving, after reconcentration, a crystalline product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:9][CH2:10][CH2:11]C#N)[N:3]=1.[F:14][C:15]([F:21])([F:20])[CH2:16][N:17]=[C:18]=[S:19].[C:22](#[N:24])C>>[F:14][C:15]([F:21])([F:20])[CH2:16][NH:17][C:18](=[S:19])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH:9]([CH2:10][CH3:11])[C:22]#[N:24])[N:3]=1
Reactant: FC(F)(F)CN=C=S
Reactant: N#CCCCSc1cccc(N)n1
Reactant: CC#N
Product: CCC(C#N)Sc1cccc(NC(=S)NCC(F)(F)F)n1

Procedure:
A solution of 4-(2-aminopyrid-6-ylthio)butyronitrile (36 g.) and 2,2,2-trifluoroethylisothiocyanate (22 ml.) in acetonitrile (100 ml.) was left at room temperature for 18 hours. The crystalline precipitate was collected and washed with cold EtOH to give 4-[2-(3-[2,2,2-trifluoroethyl]thioureidopyrid-6-ylthio]butyronitrile, m.p. 131°-133°.
Reaction SMILES: [C:1]1([CH3:7])C=CC=CC=1.O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:17])=[CH:12][CH:11]=1.C1(C)C=CC(S(O)(=O)=[O:34])=CC=1>C(O)CO>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)[O:34][CH2:1][CH2:7][O:17]2)=[CH:14][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccccc1
Solvent: O
Solvent: OCCO
Product: O=[N+]([O-])c1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1
Yield: 91 %

Procedure:
Toluene (1900 ml) was stirred in a round-bottom flask (5 l) using a water separator. (4-Chlorophenyl)(4-nitrophenyl)methanone (250 g) was added portionwise. p-Toluene-sulfonic acid (54.5 g) was added portionwise. Ethylene glycol (237.5 g) was poured out into the mixture. The mixture was stirred and refluxed for 48 hours. The solvent was evaporated. The residue was dissolved into ethyl acetate (5 l) and washed twice with a K2CO310% solution. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was stirred in DIPE, filtered off and dried (vacuum, 40° C., 24 hours), yielding 265 g (91%) of 2-(4-chlorophenyl)-2-(4-nitrophenyl)-1,3-dioxolane (interm. 5-a).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][C:20]([F:22])=[CH:21][C:16]=4[C:15](=[O:23])[N:14]([CH3:24])[CH2:13][C:12]=23)[N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:35][C:36]1[C:37]([CH2:42]Br)=[CH:38][CH:39]=[CH:40][CH:41]=1.C(Cl)[Cl:45]>>[ClH:45].[F:22][C:20]1[CH:19]=[CH:18][C:17]2[N:11]3[CH:10]=[N:9][C:8]([C:5]4[N:4]=[C:3]([CH2:2][N:1]5[CH2:42][C:37]6[C:36](=[CH:41][CH:40]=[CH:39][CH:38]=6)[CH2:35]5)[O:7][N:6]=4)=[C:12]3[CH2:13][N:14]([CH3:24])[C:15](=[O:23])[C:16]=2[CH:21]=1
Reactant: CN1Cc2c(-c3noc(CN)n3)ncn2-c2ccc(F)cc2C1=O
Reactant: ClCCl
Reactant: BrCc1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Product: CN1Cc2c(-c3noc(CN4Cc5ccccc5C4)n3)ncn2-c2ccc(F)cc2C1=O
Product: Cl
Temperature: 25 °C
Reaction time: 7 h
Yield: 26 %

Procedure:
A suspension of 0.49 g (1.5 mmol) of 3-(5-aminomethyl-1,2,4-oxadiazol-3-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one in 8 ml of methylene chloride was treated under argon with 0.77 ml (4.5 mmol) of N-ethyldiisopropylamine and 0.475 g (1.8 mmol) of α,α'-dibromo-o-xylene and stirred at room temperature under argon for 7 hrs. The solution was washed once with 10 ml of water, dried with sodium sulfate, filtered and evaporated. The crude product was purified by chromatography on 40 g of silica gel (methylene chloride/acetone 4:1, then 22:1), whereupon the eluate was evaporated and the residue was taken up in 3 ml of methanol. The solution was acidified with ethereal hydrochloric acid and the solvent was removed in a vacuum. The residue was dissolved in 3 ml of methanol, whereupon the solution was cooled to about 0° and diluted dropwise with 3 ml of ether. Thereby, white crystals separated slowly and were filtered off. There were obtained 190 mg (26%) of 8-fluoro-3-(5-isoindolin-2-ylmethyl-1,2,4-oxadiazol-3-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one hydrochloride (22:3) of m.p. 177°-184° (dec.).
Reaction SMILES: [CH2:1]([C@@H:8]1CO[C:10](=O)[N:9]1[C:14](=[O:36])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:22][C:21]=1[Cl:35])[CH2:16]C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[NH:37]1C2CCCC(N)C=2C=[N:38]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:28]([O:27][C:23]1[CH:22]=[C:21]([Cl:35])[C:20]([CH2:19][C@@H:15]2[CH2:16][CH2:10][N:9]([CH:8]3[CH2:1][CH2:2][CH2:7][C:6]4[NH:38][N:37]=[CH:4][C:5]3=4)[C:14]2=[O:36])=[C:25]([Cl:26])[CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: NC1CCCc2[nH]ncc21
Reactant: O=CC[C@@H](Cc1c(Cl)cc(OCc2ccccc2)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1[C@H](Cc2c(Cl)cc(OCc3ccccc3)cc2Cl)CCN1C1CCCc2[nH]ncc21
Reaction time: 1 h

Procedure:
To a solution of (R)-4-((R)-4-Benzyl-2-oxo-oxazolidin-3-yl)-3-(4-benzyloxy-2,6-dichloro-benzyl)-4-oxo-butyraldehyde, Preparation 38, (2 g, 3.81 mmol) in DCE (75 mL) at room temperature, add 4,5,6,7-tetrahydro-1H-indazol-4-ylamine (0.66 g, 4.77 mmol) and sodium triacetoxy borohydride (2.42 g, 11.45 mmol). Stir the reaction at room temperature for 12 h and at 50° C. for 1 hour. Cool the reaction, dilute with dichloromethane and wash with water. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 50% ethyl acetate in hexane to 100% ethyl acetate to afford 1.32 g of the title compound. MS (m/z): 470 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6](=O)[CH3:7].CO[CH:16](OC)[N:17]([CH3:19])C.C[NH:23]N>C(O)(=O)C>[Cl:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][C:5]1[C:6]([CH3:7])=[N:23][N:17]([CH3:19])[CH:16]=1
Reactant: CNN
Reactant: COC(OC)N(C)C
Reactant: CC(=O)COc1ccc(F)cc1Cl
Solvent: CC(=O)O
Product: Cc1nn(C)cc1Oc1ccc(F)cc1Cl
Temperature: 90 °C
Reaction time: 15 h

Procedure:
A mixture of 1-(2-chloro-4-fluorophenoxy)-2-propanone (i.e. the product of Step A) (1.40 g, 6.93 mmol) and N,N-dimethylformamide dimethyl acetal (1.38 mL, 10.4 mmol) was heated to 90° C. for 3 h, and then concentrated under reduced pressure. The resulting material was diluted with ethanol (15 mL), and then methylhydrazine (0.49 mL, 9.0 mmol) and acetic acid (0.1 mL) were added. After 15 h, the reaction mixture was concentrated under reduced pressure and the resulting material was purified by silica gel column chromatography (5 to 40% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a brown yellow oil (680 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=C)=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4].I([O-])(=O)(=O)=[O:25].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:11]=[O:25])=[C:9]([NH2:13])[N:8]=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([O:21][CH3:22])[C:15]=2[F:23])[N:6]=1)=[O:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1c(N)nc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1C=O
Reaction time: 0.03 h
Yield: 96.2 %

Procedure:
6-Amino-2-(4-chloro-2-fluoro-3-methoxyphenyl)-5-vinyl-pyrimidine-4-carboxylic acid methyl ester (0.500 g, 1.5 mmol) was dissolved in THF (3 mL) and water (3 mL). Osmium tetroxide (4 mg, 0.015 mmol) was added and the reaction mixture was stirred for 2 min. Sodium periodate (0.63 g, 3 mmol) was then added over a period of 2 min. The reaction mixture was stirred for 16 h at ambient temperature then poured into water (150 mL) and extracted with dichloromethane thrice. The combined organic layers were dried, filtered and concentrated to afford the title compound (490 mg, 98% yield) in sufficient purity for subsequent reactions. An analytical sample was obtained by reverse phase chromatography: 1H NMR (CDCl3) δ 10.31 (s, 1H), 8.72 (br s, 1H), 7.77 (dd, 1H), 7.23 (m, 1H), 6.03 (br s, 1H), 4.06 (s, 3H), 4.01 (d, 3H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[F:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:34](O)=[O:35])=[CH:28]2>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:29]3[NH:30][C:31]4[C:27]([CH:28]=3)=[CH:26][C:25]([F:24])=[CH:33][CH:32]=4)=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cc4cc(F)ccc4[nH]3)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 5-fluoro-1H-indole-2-carboxylic acid. LC-MS (basic): tR=0.91 min; [M+H]+=493.1.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](O)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.P(Cl)(Cl)([Cl:24])=O.[OH-].[Na+]>>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([Cl:24])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: CN1CCN(c2ccc3nc(N)c(C#N)c(O)c3c2)CC1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CN1CCN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
The mixture of 2 g of 2-amino-3-cyano-4-hydroxy-6-(4-methylpiperazino)quinoline and 4 mL of phosphoryl chloride is stirred at 120° C. for 4 hours. The cooled reaction mixture is poured onto 40 g of ice, the pH of the mixture is adjusted to 8 with 10% NaOH solution, and the precipitated material is filtered off. After drying 1.5 g of the title compound is obtained, m.p.: 189° C.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][CH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([CH:48]=O)[CH2:44][CH2:43]2)[CH2:38][CH2:37]1.C(OCC)C>COC(C)(C)C>[O:29]1[CH2:33][CH2:32][O:31][CH:30]1[CH2:34][CH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C@H:42]2[CH2:47][CH2:46][C@H:45]([CH:48]=[CH:7][C:6]3[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=3)[CH2:44][CH2:43]2)[CH2:38][CH2:37]1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: [Br-]
Solvent: CCOCC
Solvent: COC(C)(C)C
Product: Fc1ccc(C=C[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Reaction time: 1.5 h

Procedure:
3 g of p-fluorobenzyl-triphenylphosphonium bromide (preparable from p-fluorobenzyl bromide and triphenylphosphine) are suspended in 50 ml of tert.butyl methyl ether. The suspension is treated at room temperature with 0.75 g of potassium tert.butylate and stirred for 1.5 hours. Subsequently, the mixture is treated dropwise at 0° C. within 5 minutes with a solution of 1.40 g of trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanecarboxaldehyde in 25 ml of tert.butyl methyl ether and stirred at room temperature for a further 24 hours. Thereafter, the reaction mixture is taken up diethyl ether, washed several times with water, dried over magnesium sulfate, filtered and concentrated. Chromatographic purification of the resulting crude product on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gives β-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]-4-fluorostyrene.