Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(N(C(=O)[C@H](CC1C=CC=CC=1)N)N)(=O)=[O:3].[Cl:18][C:19]1[CH:36]=[CH:35][C:22]2[O:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=3[CH2:26][N:27]([C:28](Cl)=[O:29])[C:21]=2[CH:20]=1>>[Cl:18][C:19]1[CH:36]=[CH:35][C:22]2[O:23][C:24]3[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=3[CH2:26][N:27]([C:28]([OH:3])=[O:29])[C:21]=2[CH:20]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: CS(=O)(=O)N(N)C(=O)[C@@H](N)Cc1ccccc1
Product: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2,[2-[(methylsulfonyl)amino]-1-oxo-3-phenyl]hydrazide (15) was prepared in the manner described above in Example 5 on a 0.51 mmol scale starting with N-(methylsulfonyl)-L-phenylalanine, hydrazide (14), prepared as described above in Example 14, and 8-chlorodibenz[b,f][1,4]-oxazepine-10(11H)-carbonyl chloride (2), prepared as described above in Example 2, to yield 0.11 g (42%) of product. Analysis calculated for C24H23N4O5SCl (M.W. 514.98): C, 55.98; H, 4.50; N, 10.88; Cl, 6.88. Found: C, 55.81 H, 4.46; N, 10.66; Cl, 6.96.
Reaction SMILES: C([N:4]1[CH:9]([CH2:10][C:11]#[N:12])[C:8](=[O:13])[NH:7][C:6](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]1=[O:21])(=O)C.O.NN>CN(C)C=O>[CH:14](=[C:6]1[NH:7][C:8](=[O:13])[CH:9]([CH2:10][C:11]#[N:12])[NH:4][C:5]1=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)N1C(=O)C(=Cc2ccccc2)NC(=O)C1CC#N
Agent: NN
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC1NC(=O)C(=Cc2ccccc2)NC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
100 ml of dimethylformamide was added to the syrup of 1-acetyl-3-benzylidene-6-cyanomethyl-2,5-dioxopiperazine and dissolved, followed by addition of 8.89 g (0.1776 mol) of hydrazine monohydrate. The solution was stirred at room temperature for 3 hours, concentrated, and the residue washed with water to obtain 4.91 g of 3-benzylidene-6-cyanomethyl-2,5-dioxopiperazine. Yield (based on N,N'-diacetyl-3-cyanomethyl-2,5-dioxopiperazine): 45.8%.
Reaction SMILES: Cl.[OH:2][N:3]1[CH:7]=[CH:6][N:5]=[C:4]1[S:8][CH3:9].[CH3:10][N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:12](Cl)=[O:13]>>[CH3:9][S:8][C:4]1[N:3]([O:2][C:12](=[O:13])[N:11]([CH3:10])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CSc1nccn1O
Agent: Cl
Product: CSc1nccn1OC(=O)N(C)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-2-methylsulfanyl-imidazole hydrochloride and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (97%, oil).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.CO.[Cl-].[NH4+]>[Zn].C(OCC)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOCC
Solvent: CO
Product: CN1CCN(Cc2ccc(N)cc2)CC1
Yield: 77.3 %

Procedure:
1-methyl-4-(4-nitrobenzyl)-piperazine (F652-01, 4.67 g, 19.9 mmol), methanol (100 mL), zinc powder (6.5 g, 99.3 mmol) and ammonium chloride (4.3 g, 79.5 mmol) were placed in a reaction vessel and heated for 2 hours under reflux. After returning to room temperature, the reaction mixture was filtered through Celite. The solvent of the filtrate was distilled off under reduced pressure to obtain a solid. Diethyl ether was added to the solid, and insoluble components were removed by filtration. 4-(4-methylpiperazin-1-ylmethyl)phenylamine (F652-02, white solid, 3.16 g, 77%) was obtained by removing the solvent of the filtrate by distillation.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>O1CCCC1.C(OCC)C>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:9]([C:10]#[N:11])([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:28]
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(CC#N)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccc(OC)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Combine 4-methoxyphenylacetonitrile (200 g, 1.36 mol) and tetrahydrofuran (500 mL). Cool to about −5° C. Add dropwise a solution of sodium bis(trimethylsilyl)amide (2900 mL, 1 M in tetrahydrofuran, 2.90 mol). When the addition is complete warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution via cannula into a cooled (−12° C.) solution of ethyl bromoacetate (459.9 g) in tetrahydrofuran (1800 mL) at such a rate that the temperature of the reaction mixture does not rise above about 15° C. Allow to stir at ambient temperature. After 18 hours, dilute with diethyl ether and extract with water, 10% hydrochloric acid solution, and saturated aqueous solution of sodium bicarbonate. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. Distill the residue by bulb-to-bulb distillation to give the title compound: bp; 175-185° C. at 1.0 mm Hg.
Reaction SMILES: CS(O[C@H:6]1[CH2:9][C@H:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.O>[C:14]([O:13][C:11](=[O:12])[NH:10][C@H:8]1[CH2:9][C@@H:6]([N:18]=[N+:19]=[N-:20])[CH2:7]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](OS(C)(=O)=O)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N=[N+]=[N-])C1
Temperature: 85 °C
Reaction time: 18 h
Yield: 95.4 %

Procedure:
To a solution of trans-3-((tert-butoxycarbonyl)amino)cyclobutyl methanesulfonate (29 g, 109 mmol) in DMF (100 mL) was added sodium azide (5.68 mL, 162 mmol, Sigma-Aldrich Chemical Company, Inc.) portionwise and the mixture stirred at 85° C. for 18 h. The reaction was diluted with water (200 mL) after cooling and extracted with EtOAc (3×100 mL). The combined organic was washed with water (2×100 mL) and brine, dried over Na2SO4 and evaporated in vacuo to give product tert-butyl(cis-3-azidocyclobutyl)carbamate (22 g, 104 mmol, 95% yield) that was used in the next step without further purification.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:26][CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:3]([C:5]2[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:28][CH2:29]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)nn1C
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 41 %

Procedure:
As described for example 48c, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.29 mmol) was converted, using 4-aminotetrahydropyran instead of N,N-dimethylhydrazine, to the title compound (40 mg, 41%) which was obtained as a colorless oil. MS: m/e=415.3 [M+H]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[O:13][C:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:11]([C:21]1[CH:26]=[CH:25][C:24]([C:27]3([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:29][CH2:28]3)=[CH:23][CH:22]=1)[C:10]2=[O:39])=[O:4].[OH-].[Li+]>C1COCC1.CCOC(C)=O>[C:35]([O:34][C:32]([NH:31][C:27]1([C:24]2[CH:23]=[CH:22][C:21]([C:11]3[C:10](=[O:39])[C:9]4[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][CH:8]=4)[O:13][C:12]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:26][CH:25]=2)[CH2:28][CH2:29][CH2:30]1)=[O:33])([CH3:38])([CH3:36])[CH3:37]
Reactant: COC(=O)c1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C(=O)O)cccc4c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.4 %

Procedure:
To a solution of 3-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-4-oxo-2-phenyl-4H-chromene-8-carboxylic acid methyl ester (31 mg, 0.059 mmol) in THF (2 mL) was added a solution of 2 M aqueous lithium hydroxide (2 mL) and the reaction stirred at RT for 18 h. The reaction mixture was diluted with EtOAc, washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound as an off-white solid (30 mg, 100%). LCMS (Method G): RT=3.81 min, [M+H]+=512.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:28]=[C:29]1[NH:33][C@H:32]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[CH2:31][O:30]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:4]=[CH:3][C:2]([N:33]5[C@H:32]([CH2:34][OH:35])[CH2:31][O:30][C:29]5=[O:28])=[N:7][CH:6]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Product: O=C(c1ccc(N2C(=O)OC[C@H]2CO)nc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 53.4 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using (6-bromopyridin-3-yl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (880 mg) described in Preparation Example 112 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (650 mg), the title compound (510 mg) was obtained.
Reaction SMILES: [C:1]([C:3]([NH2:8])([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2].[CH2:9]([O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]=1[F:22])[C:10]#[CH:11]>>[C:1]([C:3]([NH:8][C:17](=[O:18])[C:16]1[CH:20]=[CH:21][C:13]([O:12][CH2:9][C:10]#[CH:11])=[C:14]([F:22])[CH:15]=1)([CH3:7])[CH:4]([CH3:6])[CH3:5])#[N:2]
Reactant: CC(C)C(C)(N)C#N
Reactant: C#CCOc1ccc(C(=O)Cl)cc1F
Product: C#CCOc1ccc(C(=O)NC(C)(C#N)C(C)C)cc1F

Procedure:
According to the same method as that of Production Example 1, 1-cyano-1,2-dimethylpropylamine was used in place of 2,2-dimethylpropylamine, and 4-(2-propynyloxy)-3-fluorobenzoyl chloride was used in place of 4-(2-propynyloxy)-3-methoxybenzoyl chloride to obtain N-(1-cyano-1,2-dimethylpropyl)-3-fluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 27 of the present invention) represented by the formula:
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[NH:10][N:9]=1)=[O:7])C>CO>[C:16]1([CH:14]([CH3:15])[CH2:13][C:11]2[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cc(CC(C)c2ccccc2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1cc(C(=O)O)n[nH]1)c1ccccc1

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 1.01 mmol) was added to a stirring, room temperature solution of 61 (0.0523 g, 0.2024 mmol) in MeOH (0.51 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (9 min): The reaction was concentrated, redissolved in H2O, and extracted with EtOAc. 10% aq. HCl was added dropwise to the aqueous layer until the pH=2. When a white solid did not precipitate as expected, EtOAc was added, and the organic layer was removed, dried with Na2SO4, filtered, and concentrated to provide pure 62. 1H (CD3OD, 400 MHz): δ 7.24-7.18 (2H, m), 7.17-7.05 (3H, m), 6.56 (1H, s), 3.17 (1H, app sex, J=7.3 Hz), 2.96 (1H, dd, J=13.6, 7.3 Hz), 2.80 (1H, dd, J=13.7, 7.8 Hz), 1.25 (3H, d, J=6.8 Hz) ppm. 13C (CD3OD, 100 MHz): δ 164.88, 153.40, 142.91, 140.97, 130.09, 129.25, 127.21, 106.11, 44.41, 34.96, 20.35 ppm. DEPT (CD3OD, 100 MHz): CH3 carbon: 20.35; CH2 carbon: 44.41; CH carbons: 130.09, 129.25, 127.21, 106.11, 34.96 ppm. HPLC: 8.849 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18]>>[F:1][C:2]1[C:3]([N+:17]([O-:19])=[O:18])=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1nc2cc(F)ccc2o1
Agent: O=S(=O)(O)O
Product: Cc1nc2cc(F)c([N+](=O)[O-])cc2o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Fluoro-2-methyl-benzoxazole (5.20 g, 0.0344 mol) was added to ice cooled Sulfuric acid (15.0 mL) such as to maintain the temperature below 25° C. After complete addition, a mixture of Sulfuric acid (2.75 mL) and Nitric acid (2.50 mL, 0.0536 mol) was added dropwise, maintaining the temperature below 18° C. After the addition was complete, the cooling bath was removed and the mixture was stirred at ambient temperature for 3 h, then was poured onto 100 mL ice with stirring. The solids were collected and washed with water (3×100 mL) and dried to give 5-Fluoro-2-methyl-6-nitro-benzoxazole as yellow solids. 1H-NMR (DMSO): 8.64 (d, 1H, J=5.4 Hz), 7.97 (d, 1H, J=10.8 Hz), 2.71 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([I:11])[S:10][C:3]=12.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:18][C:19]1[N:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([O:25][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([I:11])[S:10][C:3]=23)=[CH:21][CH:20]=1
Reactant: Oc1ccc(Cl)nc1
Reactant: Clc1ccnc2cc(I)sc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Clc1ccc(Oc2ccnc3cc(I)sc23)cn1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 32 %

Procedure:
Related methodology was described in WO 2005/121125. A stirred mixture of 7-chloro-2-iodothieno[3,2-b]pyridine (1.48 g, 5.00 mmol, prepared according to Ragan, J. A. Org. Proc. Res. 2003, 7, 676), cesium carbonate (2.44 g, 7.50 mmol), and DMF (50 mL) was heated to 135° C. under nitrogen with an attached reflux condenser. Next a solution of 6-chloropyridin-3-ol (0.972 g, 7.50 mmol) in DMF (20 mL) was added dropwise by syringe (2 mL approx every 5 min over a period of 50 minutes). The reaction was heated for 4 hours more after addition was complete. The reaction was left stirring at room temperature for 18 hours for convenience. The dark mixture was partitioned between EtOAc (100 mL) and water (100 mL). The phases were separated, and the aqueous phase was re-extracted with EtOAc (50 mL). The combined organic phases were washed with water (3×200 mL), brine (200 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude was purified by Biotage Flash 40M, eluting with 20% EtOAc/hexanes (1 L) followed by 1:1 EtOAc/hexanes (1 L). The product was obtained as a beige solid (628 mg, 32%). 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=6 Hz, 1H), 8.33 (d, J=2 Hz, 1H), 7.80 (s, 1H), 7.48 (m, 1H), 7.43 (d, J=9 Hz, 1H), 6.54 (d, J=6 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Reactant: OB(O)c1ccccn1
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one and pyridine-2-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.905 min, m/z=435.2; 1H NMR (CDCl3) 1.22-1.37 (m, 1H), 1.49 (d, 3H), 1.60-1.70 (m, 2H), 1.80-1.97 (m, 2H), 2.07-2.31 (m, 3H), 2.85 (m, 1H), 3.50 (m, 2H), 5.65 (m, 1H), 6.97 (m, 4H), 7.20 (m, 3H), 7.57-7.70 (m, 4H), 8.60 (m, 1H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[O:27][C@H:26]([CH2:28][O:29]C(=O)C2C=CC=CC=2)[C@@H:16]([O:17]C(=O)C2C=CC=CC=2)[C@H:6]1[O:7]C(=O)C1C=CC=CC=1)(=O)[CH3:2].OC1C=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][CH:40]=1.B(F)(F)F>ClCCl>[O:4]([C:1]1[CH:2]=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][CH:40]=1)[C@@H:5]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:16]([OH:17])[C@H:6]1[OH:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: FB(F)F
Solvent: ClCCl
Product: O=Cc1ccc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 1-O-acetyl-2,3,5-tri-O-benzoyl β-D-ribofuranose (1 g, 2.0 mmol), p-hydroxybenzaldehyde (0.5 g, 4.1 mmol), and boron trifluoride diethyletherate (0.12 ml, 1 mmol) in 20 ml of dry dichloromethane was stirred overnight at room temperature. The solvent was removed in vacuo and the residue extracted with ethyl acetate and brine. The organic layer was dried with sodium sulfate, filtered and the solvents were removed in vacuo. The residue was not purified further, but suspended in methanol and the pH adjusted to 11 with 1.0 N aqueous NaOH. This was stirred and with occasional readjustment of the pH until t.l.c. on silica gel (eluant 1:1 ethyl acetate/hexanes) indicated only material at the solvent front or baseline. Silica gel was added directly to the reaction material and the solvent removed in vacuo. The powder was added to a column of silica gel and purified by flash chromatography with 100% ethyl acetate as eluant. The title compound was obtained as a colourless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[C:12]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)=[O:31])=[CH:26][CH:25]=3)[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([N+:20]([O-])=O)[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H][H]>C(O)(=O)C.[Ni]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[C:12]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)=[O:31])=[CH:28][CH:29]=3)[C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: CN1CCN(C(=O)c2ccc(NC(=C3C(=O)Nc4cc(Cl)ccc43)c3ccc(N)c([N+](=O)[O-])c3)cc2)CC1
Reactant: [H][H]
Agent: [Ni]
Solvent: CC(=O)O
Product: CN1CCN(C(=O)c2ccc(NC(=C3C(=O)Nc4cc(Cl)ccc43)c3ccc(N)c(N)c3)cc2)CC1
Reaction time: 4 h

Procedure:
0.746 g of 6-chloro-3-{1-[4-(4-methyl-1-piperazinyl-carbonyl)phenylamino]-1-(4-amino-3-nitrophenyl)methylene}-2-indolinone are hydrogenated in 30 ml acetic acid with the addition of 0.60 g Raney nickel under 50 psi of hydrogen pressure for 4 hours. After the addition of another 0.30 g of Raney nickel hydrogenation is continued under the same conditions for a further 4 hours, then the catalyst is removed by suction filtering. The residue obtained from the filtrate by distilling off the solvent is dissolved in water, the solution is made alkaline with soda solution. The crude product precipitated is suction filtered, washed with water, dried, dissolved in 70 ml of dichloromethane/methanol/ammonia solution=70:30:3 and filtered through a layer of silica gel. The filtrate is concentrated by evaporation, the residue is stirred with 5 ml of ethyl acetate, suction filtered and dried at 80° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[N:11]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C@H:5]([OH:6])[C:10]#[N:11]
Reactant: C#N
Reactant: O=Cc1cccc(O)c1
Product: N#C[C@@H](O)c1cccc(O)c1
Reaction time: 0.58 h

Procedure:
61 mg (0.5 mmol) of meta-hydroxybenzaldehyde were reacted at pH 3.25 with 450 μl of 4.2M aqueous HCN solution in accordance with Example 14. The reaction was complete after 30 to 40 minutes. The (S)-3-hydroxymandelonitrile was isolated as described in Example 14.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[C:11]1[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=3[S:8][CH2:7][C:6]2=1.Cl.N1C=CC=CC=1>>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:12]1[C:11]2[C:10]3[CH:21]=[CH:22][CH:23]=[CH:24][C:9]=3[S:8][CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([OH:2])[CH:4]=2
Reactant: COc1ccc2c(c1)c1c(n2CCN(C)C)-c2ccccc2SC1
Agent: Cl
Solvent: c1ccncc1
Product: CN(C)CCn1c2c(c3cc(O)ccc31)CSc1ccccc1-2
Temperature: 210 °C

Procedure:
A mixture of [2-(8-methoxy-6H-5-thia-11-aza-benzo[a]fluoren-11-yl)-ethyl]-dimethyl-amine (800 mg, 2.39 mmol) and Pyridine HCl (3.01 g, 23.7 mmol, 10 eq.) was heated to 210° C. for 30 minutes. The reaction mixture was then partitioned between EtOAc and saturated NaHCO3 aqueous solution. The aqueous layer was extracted three times with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a crude material. The crude material was purified by silica gel (EtOAc to CH2Cl2: MeOH 5:1) to yield the title compound as a brown solid.
Reaction SMILES: C(OC([N:8]1[C:12](=[O:13])/[C:11](=[CH:14]\N(C)C)/[CH:10]2[CH2:18][C:19]3[C:24]([CH:9]12)=[CH:23][CH:22]=[CH:21][CH:20]=3)=O)(C)(C)C.Cl.[O:26]1CCOCC1>O>[OH:26]/[CH:14]=[C:11]1/[CH:10]2[CH2:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:9]2[NH:8][C:12]/1=[O:13]
Reactant: C1COCCO1
Reactant: CN(C)/C=C1\C(=O)N(C(=O)OC(C)(C)C)C2c3ccccc3CC12
Agent: Cl
Solvent: O
Product: O=C1NC2c3ccccc3CC2/C1=C/O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-[1-dimethylamino-meth-(Z)-ylidene]-2-oxo-3,3a,4,8b-tetrahydro-2H-indeno[1,2-b]pyrrole-1-carboxylic acid tert-butyl ester D1 (1.68 g, 4.63 mmol) in dioxane (50 mL) was added HCl (37%, 8.37 mL). The solution was stirred overnight at room temperature and was then diluted with water, extracted with ethyl acetate, washed with brine, dried and concentrated to give 3-[1-Hydroxy-meth-(Z)-ylidene]-3,3a,4,8b-tetrahydro-1H-indeno[1,2-b]pyrrol-2-one C1 identical to method A (0.85 g, 78%).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH3:13])[C:8]2=[NH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15]OS(F)(=O)=O>C(Cl)Cl>[C:1]1([N:7]2[CH2:11][C:10](=[O:12])[N:9]([CH3:13])[C:8]2=[N:14][CH3:15])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COS(=O)(=O)F
Reactant: CN1C(=N)N(c2ccccc2)CC1=O
Solvent: ClCCl
Product: CN=C1N(C)C(=O)CN1c1ccccc1

Procedure:
3.78 g. of 1-phenyl-2-imino-3-methyl-4-oxoimidazolidine, 40 ml. dry methylene chloride and 6 ml. of methylfluorosulfonate are mixed and stirred in a flash equipped with a drying tube at room temperature. After 20 hours the solid was filtered and the filtrate was stripped to dryness. The residue was treated with 30 ml. of water and extracted once with ether. The aqueous layer was separated and added slowly to 12 ml. of 5N NaOH with cooling and stirring. The white precipitate was filtered, washed with water and dried. Thin-layer chromatography showed a single spot (Rf 0.6, 5% EtOH. CH2Cl2). The yield was 2.75 g. (68%), m.p. 116°-118° C.