Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:11][CH2:12][C:13]([CH3:17])([NH:15][CH3:16])[CH3:14])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]1[O:35][C:34]2[CH:33]=[CH:32][C:28]([CH2:29][CH2:30]Br)=[CH:27][C:26]=2[O:25]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH2:11][CH2:12][C:13]([N:15]([CH2:30][CH2:29][C:28]2[CH:32]=[CH:33][C:34]3[O:35][CH2:24][O:25][C:26]=3[CH:27]=2)[CH3:16])([CH3:17])[CH3:14])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1
Reactant: BrCCc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1ccc2c(c1)OCO2)C(C)(C)CCC(C(N)=O)(c1ccccc1)c1ccccc1

Procedure:
A mixture containing 2,2-diphenyl-5-methyl-5-methylaminohexanamide (0.5 g-see Preparation 13), 3,4-methylenedioxyphenethyl bromide (0.38 g), anhydrous potassium carbonate (0.8 g) and acetonitrile (10 ml) was heated under reflux for 5.5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (3×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 6%). The product-containing fractions were combined and concentrated in vacuo to give an oil which solidified on standing. The solid was recrystallised from ethanol to give the title compound as colourless needles, yield 0.09 g, m.p. 165° (softens at 45°).
Reaction SMILES: [CH:1](=[O:4])[CH2:2][CH3:3].[CH:5](=[O:10])[CH2:6][CH:7]([CH3:9])[CH3:8].N1CCC[C@H]1C(O)=O>CN(C)C=O.C(OCC)C>[OH:10][C@@H:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[C@H:2]([CH3:3])[CH:1]=[O:4]
Reactant: CC(C)CC=O
Reactant: CCC=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C[C@H](O)[C@H](C)C=O
Reaction time: 16 h
Yield: 88 %

Procedure:
A solution of freshly distilled propionaldehyde (144 μL, 2.0 mmol) in 500 μL dimethylformamide pre-cooled to 4° C. was added slowly over the course of 2.5 h to a stirring suspension of isovaleraldehyde (107 μL, 1.0 mmol), L-proline (11.5 mg, 0.10 mmol) and 500 μL dimethylformamide at 4° C. After 16 h, the resulting solution was diluted with diethyl ether and washed successively with water and brine. The combined aqueous layers were back-extracted with 3 portions of dichloromethane. The organic layers were combined, dried over anhydrous MgSO4, and concentrated in vacuo. Flash chromatography (20:7 pentane:diethyl ether) afforded the title compound as a clear, colorless oil in 88% yield (126 mg, 0.88 mmol), 97% ee and 3:1 anti:syn. IR (film) 3419, 2958, 2935, 2872, 1719,1466, 1368, 1152, 1098, 1062,1025, 976.5 cm−1; 1H NMR (300 MHz, CDCl3) δ9.75 (d, J=1.5 Hz, 1H, CHO); 3.89 (ddd, 1H, J=9.9, 6.6, 2.7 Hz, 1H, CHOH); 2.44 (m, 1H, CHCH3); 1.83 (m, 1H, CH(CH3)2); 1.47 (m, 1H, CH2); 1.26 (m, 1H, CH2); 1.14 (d, 3H, J=7.2 Hz, CH3CHCHO); 0.97 (d, 3H, J=5.1 Hz, (CH3)2CH); 0.92 (d, 3H, J=6.6 Hz, (CH3)2CH); 13C NMR (75 MHz, CDCl3) δ205.5, 70.9, 52.8, 44.0, 34.5, 24.1, 21.8, 11.1; HRMS (CI) exact mass calcd for [M +H]+ (C8H17O2) requires m/z 145.1228, found m/z 145.1225; [α]D=−33.6 (c=1.0, CHCl3). The product ratios were determined by GLC analysis of the acetal derived from 2,2-dimethylpropane-1,3-diol (obtained by the method of Yamamoto, supra) using a Bodman Chiraldex β-DM (30 m×0.25 mm) column (100° C. isotherm, 23 psi); (2S, 3S) anti isomer tr=50.8 min, (2R, 3R) anti isomer tr=53.2 min, (2R, 3S) and (2S, 3R) syn isomers tr=45.5 min.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[H-].[Na+].[Cl:6][C:7]1[CH:12]=[C:11]([CH2:13]Cl)[CH:10]=[C:9]([Cl:15])[C:8]=1[C:16]1[NH:17][C:18]2[C:24]3[CH:25]=[CH:26][N:27]=[CH:28][C:23]=3[NH:22][C:21]3[N:29]=[CH:30][CH:31]=[CH:32][C:20]=3[C:19]=2[N:33]=1>CN(C)C=O.CO>[Cl:6][C:7]1[CH:12]=[C:11]([CH2:13][N:2]([CH3:3])[CH3:1])[CH:10]=[C:9]([Cl:15])[C:8]=1[C:16]1[NH:17][C:18]2[C:24]3[CH:25]=[CH:26][N:27]=[CH:28][C:23]=3[NH:22][C:21]3[N:29]=[CH:30][CH:31]=[CH:32][C:20]=3[C:19]=2[N:33]=1
Reactant: ClCc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Reactant: CNC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)Cc1cc(Cl)c(-c2nc3c([nH]2)-c2ccncc2Nc2ncccc2-3)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
A solution of dimethylamine (23 μL, 2.0 M in tetrahydrofuran) was dissolved in N,N-dimethylformamide (0.5 mL) and cooled to 0° C. Sodium hydride (1.1 mg, 0.05 mmol) was added and the mixture was stirred for 15 minutes. 2-[2,6-dichloro-4-(chloromethyl)phenyl]-3,8-dihydroimidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepine (10.0 mg, 0.02 mmol) was added and the mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with methanol and purified on preparative LCMS at pH 10 to give the desired product (3.2 mg, 31%). LC/MS: 437 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:15])[CH:8]=2)[N:3]=1.Br[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CC(C)=O>[CH2:13]([O:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:15])[CH:8]=2)[N:3]2[CH:17]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:1]=[C:2]2[CH:11]=1)[CH3:14]
Reactant: CCOc1cc(N)nc2ccc(F)cc12
Reactant: CCOC(=O)C(=O)CBr
Solvent: CC(C)=O
Product: CCOC(=O)c1cn2c(cc(OCC)c3cc(F)ccc32)n1
Temperature: 25 °C

Procedure:
In a single-necked flask were combined, 2.1 g. (0.010 mole) of 2-amino-4-ethoxy-6-fluoroquinoline, 2.1 g. (0.011 mole) ethyl bromopyruvate and 30 ml. of acetone. The mixture was refluxed for two hours, cooled to room temperature and the precipitated solid removed by filtration. The solid was partitioned between chloroform and 1N aqueous potassium hydroxide, the organic layer dried over magnesium sulfate and evaporated to dryness to yield 1.7 g. of crude product. This was dissolved in a small amount of chloroformethanol (95:5 v/v) and chromatographed on a column of 50 g. of 60-200 mesh silica gel (J. T. Baker Co.) eluting with the same solvent. Fractions of 50 ml. each were taken when ultraviolet light absorbing material began to come off the column. Fractions 1 through 8 were combined and evaporated to dryness in vacuo to afford 750 mg. of the title compound as a white solid, which upon crystallization from isopropanol melted at 213.5°-214.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][O:25]C)[N:14]([CH2:15][C:16]3([OH:22])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:23][CH2:24][OH:25])[N:14]([CH2:15][C:16]3([OH:22])[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCOCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1nc2ccccc2c2c1nc(CCO)n2CC1(O)CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
A suspension of 4-{[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol (0.95 g, 2.67 mmol) in dichloromethane (15 mL) was cooled to 0° C. Boron tribromide (8 mL, 8.00 mmol) was added and the reaction mixture was allowed to stir overnight while slowly warming to ambient temperature. The reaction mixture was concentrated. The residue was taken up in a mixture of methanol (15 mL) and 6M hydrochloric acid (10 mL) and refluxed for 2.5 hours. The reaction mixture was cooled to ambient temperature and the pH was adjusted to 8 with 2M sodium hydroxide. The mixture was extracted with chloroform (12×20 mL). The combined extracts were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide a yellow solid. This material purified by HPFC eluting with a gradient of 0 to 45% CMA in chloroform to provide an off white solid. The solid was triturated with acetonitrile, isolated by filtration, and dried in a vacuum oven at 140° C. to provide 0.536 g of 4-{[4-amino-2-(2-hydroxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}tetrahydro-2H-pyran-4-ol as a white solid, mp 237-238° C. MS (ESI) m/z 343 (M+H)+; Anal. calcd for C18H22N4O3: C, 63.14; H, 6.48; N, 16.36. Found: C, 63.04; H, 6.57; N, 16.19.
Reaction SMILES: Cl.[NH2:2][OH:3].[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:32]=O)[CH:17]=3)[C:12]2=[O:34])=[CH:7][CH:6]=1.C([O-])(=O)C.[Na+]>C(O)C.ClCCl>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([CH:32]=[N:2][OH:3])[CH:17]=3)[C:12]2=[O:34])=[CH:7][CH:6]=1
Reactant: NO
Reactant: CC(C)(C)OC(=O)CCCCc1cc2cc(C=O)ccc2c(=O)n1-c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCCCc1cc2cc(C=NO)ccc2c(=O)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
Hydroxylamine hydrochloride (314 mg, 4.52 mmol) was added to a stirred, room temperature mixture of tert-butyl 5-(2-(4-fluorophenyl)-6-formyl-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (638 mg, 1.507 mmol) and sodium acetate (742 mg, 9.04 mmol) in ethanol (10 mL), and the mixture was stirred at room temperature for 1 h. The mixture was diluted with dichloromethane (60 mL), washed with brine (saturated, 1×30 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give tert-butyl 5-(2-(4-fluorophenyl)-6-((hydroxyimino)methyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (658 mg, 1.501 mmol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[O:21]([C:28]1[CH:33]=[CH:32][C:31]([N:34]=[C:35]=[O:36])=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[O:21]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][C:35]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:36])=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: O=C=Nc1ccc(Oc2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(Oc5ccccc5)cc4)CC3)c2cc1OC
Yield: 44.2 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (20 mg, 0.0733 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 4-phenoxyphenyl isocyanate (23 mg, 0.109 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a brown solid (15.7 mg, 44%). 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.48 (m, 1H), 7.33 (m, 5H), 7.07 (m, 1H), 6.99 (m, 4H), 6.41 (br s, NH), 4.32-4.27 (m, 2H), 4.09 (s, 6H), 3.63 (m, 1H), 3.20 (m, 2H), 2.17 (m, 2H), 2.03-1.99 (m, 2H); LC/MS (ESI) calcd mass 484.2, found 485.3 [M+1]+.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:24][N:23](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:22][CH2:21][N:20](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:19][CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.[CH2:71](O)[CH3:72]>C(OCC)C>[NH:16]1[CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][NH:23][CH2:72][CH2:71][CH2:24][NH:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1
Reactant: CCO
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: C1CNCCNCCCNCCNCCNC1
Temperature: 100 °C
Reaction time: 72 h
Yield: 36 %

Procedure:
A mixture of 1,4,7,11,14-penta(p-toluenesulfonyl)-1,4,7,11,14-pentaazacyclopentadecane prepared as in Example 11C (26.3 g, 0.0258 mole) and concentrated H2SO4 (80 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 h. To the resulting brown solution, ethanol (160 mL) was added dropwise with stirring at 0° C. followed by ethyl ether (400 ml). The resulting tan solid was filtered and dried in vacuo over P2O5. The tarry solid was then dissolved by the addition of 10N NaOH and the salts were removed by filtration. The solution was then extracted with CHCl3 (6×200 ml). The extracts were combined, dried (Na2SO4) and the solvent was removed in vacuo to give an oil which crystallized on standing. The crude product was dissolved in hexane and insoluble impurities were removed by filtration. Upon cooling to -20° C., 2.28 g (36% yield) of the product was obtained as colorless needles: mp 49°-51° C.; 1H NMR (CDCl3) δ 1.69 (m, 4 H), 1.78 (br s, 5 H), 2.76 (m, 20 H). Exact mass: (M+H)+ : calcd., 244. 2501; Found: 244.2557 (C12H30N5).
Reaction SMILES: [C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[N:23]1([C:29]2[O:30][C:31]3[C:36]([N:37]=2)=[CH:35][CH:34]=[CH:33][N:32]=3)[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C(O)(C)C>[C:1]([O:6][C@@H:7]([C:9]1[N:14]=[C:13]([N:26]2[CH2:25][CH2:24][N:23]([C:29]3[O:30][C:31]4[C:36]([N:37]=3)=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:28][CH2:27]2)[CH:12]=[CH:11][N:10]=1)[CH3:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O[C@H](C)c1nccc(Cl)n1
Reactant: c1cnc2oc(N3CCNCC3)nc2c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H](C)c1nccc(N2CCN(c3nc4cccnc4o3)CC2)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of (R)-1-(4-chloro-pyrimidin-2-yl)-ethyl butyrate (prepared according to the method of Preparation Seven, 6.8 g, 29.9 mmol) and triethylamine (12.5 mL, 89.6 mmol) in isopropanol (100 mL) was added 2-(1-piperazinyl)oxazolo[5,4-b]pyridine (prepared according to the method of Example 9, Step A, 6.1 g, 29.9 mmol). This mixture was stirred at reflux overnight, cooled to room temperature, and evaporated. The residue was diluted with saturated, aqueous sodium bicarbonate and extracted with chloroform (3×). The combined organic extracts were dried over sodium sulfate, filtered, evaporated, and purified by flash column chromatography (1.5→2% methanol/chloroform) to give 11.1 g (94%) of the title compound of Example 9, Step B as a yellow oil which solidified upon standing. 1H NMR (CDCl3, 250 MHz) δ 8.28 (d, 1H), 7.97 (dd, 1H), 7.60 (dd, 1H), 7.25 (dd, 1H), 6.44 (d, 1H), 5.70 (q, 1H), 3.85 (app s, 8H), 2.42 (t, 2H), 1.78-1.61 (c, 2H), 1.60 (d, 3H), 0.98 (t, 3H); MS (APCI) 397 (MH+).
Reaction SMILES: [CH:1]1[C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]([C:5]=23)=[CH:3][CH:2]=1.[H-].[Na+].[CH2:16](Br)[C:17]#[CH:18]>CN(C)C=O>[CH2:18]([C:3]1[CH:2]=[CH:1][C:13]2[O:12][N:11]=[C:6]3[N:7]=[CH:8][CH2:9][O:10][C:4]=1[C:5]=23)[C:17]#[CH:16]
Reactant: C1=Nc2noc3cccc(c23)OC1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCc1ccc2onc3c2c1OCC=N3
Temperature: 80 °C
Yield: 53 %

Procedure:
A solution of 4,5-dihydroisoxazolo[3,4,5-ef][1,4]benzoxazepine of Example 7(b ) (3.9 g; 22.1 mmoles) in 120 ml dimethylformamide was added to a suspension of sodium hydride (1.4 g; 27.7 mmoles). This was followed by a solution of propargyl bromide (2.7 ml of 80% solution; 24.4 mmoles). The reaction was heated at 80° C. for 1.5 hours and then quenched into water (400 ml). The resulting precipitate was filtered, rinsed and dried, then passed through a column of florisil (ethyl acetate/dichloromethane). This gave 3.5 g of a solid, mp 100°-104° C., which was recrystallized from isopropanol to give 2.5 g (53%) of 4,5-dihydro-3-(2-propynyl)isoxazolo[3,4,5-ef][1,4]benzoxazepine, mp 104°-106° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([NH:8][NH2:9])=O)([O-:3])=[O:2].[CH3:14][C:15]1[O:16][C:17](=[O:25])[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.CN1CCCC1=O>O>[CH3:14][C:15]1[N:20]([C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[C:17]([OH:25])=[O:16])[C:6]([C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]=2[N+:1]([O-:3])=[O:2])=[N:8][N:9]=1
Reactant: Cc1nc2ccccc2c(=O)o1
Reactant: NNC(=O)c1ccccc1[N+](=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1nnc(-c2ccccc2[N+](=O)[O-])n1-c1ccccc1C(=O)O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture consisting of 1.8 g of 2-nitrobenzoic hydrazide, 1.6 g of 2-methylbenzo[d][1,3]oxazin-4-one and 5 ml of N-methylpyrrolidone was heated to 80° C. with stirring for 2 hours. After cooling, the mixture was admixed with water to slight cloudiness and stirred for a further 1 hour, during which time a solid precipitated out which was filtered off with suction, recrystallized from ethanol and dried under reduced pressure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH:16][C:17]2[CH:18]=[N:19][NH:20][CH:21]=2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:28])(=[O:27])[N:25]([CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:24](=[O:35])[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:38]([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH:16][C:17]2[CH:21]=[N:20][N:19]([CH3:38])[CH:18]=2)[CH:12]=[CH:11][C:10]=1[N:22]1[S:26](=[O:27])(=[O:28])[N:25]([CH2:29][CH2:30][Si:31]([CH3:33])([CH3:32])[CH3:34])[C:24](=[O:35])[CH2:23]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C=Cc3cn[nH]c3)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: Cn1cc(C=Cc2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-{2-benzyloxy-4-[2-(1H-pyrazol-4-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (example 40, step C) (114 mg, 0.224 mmol), MeI (0.05 mL, 0.80 mmol) and K2CO3 (60 mg, 0.43 mmol) in CH3CN (3 mL) is stirred at RT for 2 days. The mixture is partitioned between EtOAc and aq. NaHCO3. The organic phase is dried over MgSO4 and concentrated to afford the crude product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Cl)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:17]([O-:20])([O-:19])=[O:18].[Na+:21].[Na+].COC(C)(C)C>O>[Na+:21].[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][S:17]([O-:20])(=[O:19])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Product: O=S(=O)([O-])Cc1ccc(OCc2ccccc2)cc1
Temperature: 75 °C
Reaction time: 21 h
Yield: 18.8 %

Procedure:
A mixture of 25.51 g of 4-benzyloxybenzyl chloride and 28.78 g of sodium sulfite in 96 ml of water was stirred at 75° C. for 21 hours. After cooling to room temperature, the reaction solution was stirred with 100 ml of tert-butyl methyl ether, and the solids were filtered off with suction, washed twice with 20 ml of tert-butyl methyl ether, once with 20 ml of ice-water, twice with 20 ml of acetone and twice with 20 ml of dichloromethane. The precipitate was dried in a vacuum drying cabinet at 40° C. overnight. This gave the product (6.20 g) with a molecular weight of 300.3 g/mol (C14H13O4S.Na); MS (ESI): m/e=301 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH:10]([CH2:20][NH2:21])[N:9]=1.[NH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[C:31](Cl)=[O:32].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[O:19])[CH:10]([CH2:20][NH:21][C:31]([C:23]2[NH:22][C:30]3[C:25]([CH:24]=2)=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:32])[N:9]=1
Reactant: NCC1N=C(c2ccccc2F)c2ccccc2NC1=O
Reactant: O=C(Cl)c1cc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCC1N=C(c2ccccc2F)c2ccccc2NC1=O)c1cc2ccccc2[nH]1
Reaction time: 0.08 h
Yield: 32.4 %

Procedure:
1,3-Dihydro-5-(2-fluorophenyl)-3(RS)-aminomethyl-2H-1,4-benzodiazepin-2-one (80 mg, 0.282 mmole) and indole-2-carbonyl chloride (53 mg, 0.30 mmol) were mixed in 5 ml of methylene chloride at room temperature. The homogeneous reaction mixture was protected from moisture and treated with 42 l (0.30 mmole) of triethylamine. Within five min., triethylamine hydrochloride precipitated. The reaction mixture was stirred at room temperatre overnight and then partitioned between methylene chloride and saturated sodium bicarbonate solution. The resulting solid was collected, washed with water and dried over P2O5 at 70° C. In this way, 39 mg of the analytical product was obtained, m.p.: 315°-317° (d).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13](=O)[CH2:14]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=[S:20])([S-:19])[NH2:18].[NH4+]>CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][S:11][CH2:12][C:13]1[N:18]=[C:17]([SH:20])[S:19][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCSCC(=O)CCl
Reactant: NC(=S)[S-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCSCc1csc(S)n1

Procedure:
To a stirred solution of 1-(2-t-butyloxycarbonylaminoethylthio)-3-chloropropan-2-one (11.47 g, 42.8 mmol) in methanol (50 mL) was added ammonium dithiocarbamate (4.73 g, 42.9 mmol) at room temperature. After 50 hours the reaction mixture was partitioned between ethyl acetate and water.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]([C:8]2([OH:20])[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([F:21])=[C:4]([C:8]2([OH:20])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cccc(Cl)c2F)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2cccc(Cl)c2F)CCNC1
Reaction time: 1 h

Procedure:
Preparation according to Preparation 2: tert-Butyl 3-(3-chloro-2-fluorophenyl)-3-hydroxypyrrolidin-1-carboxylate (4.42 g, 14 mmol), dichloromethane (100 mL), trifluoroacetic acid (10 mL). Stirred for 1 h. Yield: 2.24 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[C:3]=1[N:9]=[C:14]([C:13]1[CH:17]=[CH:18][CH:19]=[C:11]([Cl:10])[CH:12]=1)[NH:8]2
Reactant: Nc1ncnc(Cl)c1N
Reactant: O=C(O)c1cccc(Cl)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1cccc(-c2nc3c(Cl)ncnc3[nH]2)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a mixture of 6-Chloro-4,5-diaminopyrimidine (0.70 g, 4.84 mmol) and 3-chlorobenzoic acid (0.76 g, 4.84 mmol) in the flask was added phosphoryl chloride (40.0 mL), and the resulting mixture was stirred for 16 h at 100° C. The reaction mixture was evaporated to remove excess phosphoryl chloride, and the residue was added to water (20 mL). The precipitate was filtered and purified by flash chromatography (0 to 5% Methanol/DCM) to afford the title compound (1.28 g, 31%) as a yellow solid. LC/MS: Rt=1.59 min, ES+ 265.0 (FA standard).
Reaction SMILES: [CH3:1][CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([NH:18]/[C:8](/[CH3:10])=[C:2](/[CH3:1])\[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C(/C)NCc1ccccc1
Reaction time: 6 h
Yield: 104.8 %

Procedure:
A solution of ethyl 2-methylacetoaceate (1-004-01) (115.34 g) and benzylamine (85.73 g) in toluene (1.6 L) was azeotropically dehydrated in an oil bath at 145° C. for 8 h under nitrogen atmosphere. Benzylamine was added to the reaction mixture and the reaction mixture was dehydrated again. After 6 h, the reaction mixture was distilled under atmospheric pressure to remove about 600 mL of the solvent, and evaporated under reduced pressure to give ethyl 3-benzylamino-2-methylcrotonate (1-004-02) (195.66 g).