Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[C:18]([O:23][CH2:24][CH:25]1[O:27][CH2:26]1)(=[O:22])[C:19]([CH3:21])=[CH2:20].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)C>[Cl-].C[N+](C)(C)C>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[C:15]([O:17][CH2:26][CH:25]([OH:27])[CH2:24][O:23][C:18](=[O:22])[C:19]([CH3:21])=[CH2:20])=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1c2ccccc2cc2ccccc12
Reactant: C=C(C)C(=O)OCC1CO1
Agent: C[N+](C)(C)C
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: [Cl-]
Product: C=C(C)C(=O)OCC(O)COC(=O)c1c2ccccc2cc2ccccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Anthracene-9-carboxylic acid (50 g) was added over 30 minutes with stirring to glycidyl methacrylate (33.9 g, epoxide content 6.6 equiv./kg) containing 0.13 g of 2,6-di-tert.butyl-p-cresol and 0.25 g of tetramethylammonium chloride and heated to 100° C. Heating at 100° C. was continued for a further 4 hours, by which time the epoxide content of the mixture had fallen to a negligibly low value. The resultant product was a brown, glassy solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.[H-].[Na+].[CH2:20](I)[CH3:21].O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:17])[C:7](=[O:8])[N:6]([CH2:20][CH3:21])[C:5]2[CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CCI
Reactant: COC(=O)c1ccc2c(c1)NC(=O)C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN1C(=O)C(C)(C)Oc2ccc(C(=O)OC)cc21
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To a solution of 2,2-dimethyl-6-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine [prepared in Preparation 6(1)] (1.50 g) in dimethylformamide (20 ml) were added 60% sodium hydride (in oil) (0.3 g) and ethyl iodide (1.1 g) and the mixture was stirred at 50° C. for 1 hour. Water was added to the reaction solution and extraction with ethyl acetate was conducted. The solvent was distilled off under reduced pressure and the resulting residue was subjected to purification by column chromatography using ethyl acetate/hexane [1:4 (v/v)] to give 2,2-dimethyl-4-ethyl-6-methoxycarbonyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine (1.6 g).
Reaction SMILES: [O:1]1[CH2:5][CH:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][CH:8]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.I[C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[N:29]([C@H:37]2[CH2:42][CH2:41][C@@H:40]([N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)[CH2:39][CH2:38]2)[N:28]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[O:1]1[CH2:5][CH:4]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([C:27]3[C:35]4[C:30](=[N:31][CH:32]=[N:33][C:34]=4[NH2:36])[N:29]([C@H:37]4[CH2:38][CH2:39][C@@H:40]([N:43]5[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]5)[CH2:41][CH2:42]4)[N:28]=3)=[CH:11][CH:12]=2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: CC1(C)OB(c2ccc(NC3COc4ccccc43)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(NC5COc6ccccc65)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 20.2 %

Procedure:
A mixture of N-(2,3-dihydrobenzo[b]furan-3-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.080 g, 0.000237 mol), cis-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.087 g, 0.000198 mol), tetrakis-(triphenylphosphine)palladium (0.014 g, 0.000012 mol) and sodium carbonate monohydrate (0.061 g, 0.000495 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1 M ammonium acetate over 25 min, 21 mL/min). Subsequently, the crude product was dissolved in dichloromethane, loaded onto Trikonex column (7 cm) and eluted with dichloromethane (5 mL). The desired band was cut, the product was extracted with a mixture of dichloromethane/methanol/triethylamine in a ratio of 90:5:5 (10 mL) and the solvents were removed under reduced pressure. The residue was triturated in diethyl ether and the precipitate was collected by filtration and dried to yield cis-3-[4-(2,3-dihydrobenzo[b]furan-3-ylamino)phenyl]1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.021 g, 0.00004 mol) as a white solid.
Reaction SMILES: F[C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[F:12][C:13]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:14]=1[C:15]([NH2:17])=[NH:16].C(N(C(C)C)CC)(C)C>C(#N)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:13]([F:12])=[C:14]([C:15]2[N:17]=[C:4]([OH:5])[C:3]3[CH:7]=[CH:8][C:9]([F:11])=[N:10][C:2]=3[N:16]=2)[CH:18]=1
Reactant: O=C(Cl)c1ccc(F)nc1F
Reactant: N=C(N)c1cc(Cl)ccc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Oc1nc(-c2cc(Cl)ccc2F)nc2nc(F)ccc12
Temperature: 25 °C

Procedure:
To a mixture of 2,6-difluoronicotinic acid chloride (6.4 g), dissolved in acetonitrile (200 mL) was added 2-fluoro-5-chlorobenzamidine (6.73 g) and diisopropyl ethyl amine (24 mL). The mixture was heated to reflux for 2 h and cooled to room temperature. The mixture was concentrated under reduced pressure. The precipitate was filtered and washed with ether and dried under reduced pressure to afford the 2-(5-chloro-2-fluoro-phenyl)-7-fluoro-pyrido[2,3-d]pyrimidin-4-ol that was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:30]#[N:31].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[C:30]([CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: [C-]#N
Reactant: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 38.6 %

Procedure:
A suspension of 350 mg of 4-chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole, prepared in step a) in Example 2, in 7 ml of DMF was cooled in ice, and 94 mg of sodium cyanide was added to the cooled suspension under an argon atmosphere. The mixture was stirred at room temperature for 2.5 hr, and brine was then added to the reaction solution. The mixture was extracted twice with ethyl acetate, and the organic layers were combined, followed by washing with brine. The washed organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give 132 mg of the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([OH:16])=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.O[C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1.C1COCC1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[O:20][CH3:21])[C:14]([O:16][C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)=[O:15])[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: COc1ccc(C(=O)O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: NS(=O)(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Oc2ccc(S(N)(=O)=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.3 %

Procedure:
Into a round bottom flask, there are introduced 2.86 g (10 mmoles) of 3-(1-adamantyl)-4-methoxybenzoic acid, 1.73 g (10 mmoles) of 4-hydroxybenzenesulfonamide and 50 ml of THF. There are added, successively, 2.1 g (10 mmoles) of 1,3-dicyclohexylcarbodiimide and then 1.22 (10 mmoles) of 4-dimethylaminopyridine. The medium is stirred at ambient temperature for 4 hours. The reaction medium is poured into water and extracted with ethyl ether. The organic phase is decanted, washed with water, dried on magnesium sulfate and evaporated. The resulting solid is purified by chromatography on a silica column eluted by a 60:40 mixture of ethyl ether and hexane. After evaporation of the solvents, 2 g (46% yield) of 4-[3-(1-adamantyl)-4-methoxybenzoyloxy] benzenesulfonamide having a melting point of 223°-224° C. are recovered.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[O:18][CH2:19][C:20](O)=[O:21])=[O:14])[CH3:11]>ClCCCl>[Cl:3][C:20](=[O:21])[CH2:19][O:18][C:17]1[CH:16]=[C:15]([CH:25]=[CH:24][CH:23]=1)[C:13]([O:12][CH2:10][CH3:11])=[O:14]
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)c1cccc(OCC(=O)O)c1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCC(=O)Cl)c1

Procedure:
32.5 ml (0.45 mol) of thionyl chloride and 10 μl of N,N-dimethylformamide are added to a solution of 20.0 g (89.2 mmol) of [3-(ethoxycarbonyl)phenoxy]acetic acid (A. Banerjee, M. M. Adak, S. Das, S. Banerjee, S. Sengupta, Indian Chem. Soc., 1987, 64, 1, 34-37) in 200 ml of 1,2-dichloroethane. The mixture is refluxed for 1 hour and is then concentrated to dryness and dried under vacuum at 50° C. overnight and used as it is in the subsequent stage.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C@@H:8]1[C:12]2[NH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][C:11]=2[C:10](=[O:25])[NH:9]1.Br[C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:36]=1[N:35]=[C:34]([NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[N:33]([CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:48])[CH3:47])[C:32]2=[O:53]>O1CCOCC1.O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C>[C:38]([NH:37][C:34]1[N:33]([CH2:42][CH2:43][CH2:44][O:45][Si:46]([C:49]([CH3:52])([CH3:51])[CH3:50])([CH3:47])[CH3:48])[C:32](=[O:53])[C:31]2[C:36](=[C:27]([C:14]3[NH:13][C:12]4[C@@H:8]([CH3:7])[NH:9][C:10](=[O:25])[C:11]=4[CH:15]=3)[CH:28]=[CH:29][CH:30]=2)[N:35]=1)([CH3:39])([CH3:41])[CH3:40]
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2c(=O)n1CCCO[Si](C)(C)C(C)(C)C
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 80 °C
Yield: 54.9 %

Procedure:
Potassium carbonate (Mallinkrodt; 0.091 g, 0.657 mmol), 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(ii) chloride (Aldrich; 5.82 mg, 8.22 μmol), (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705; 0.086 g, 0.329 mmol), 8-bromo-2-(tert-butylamino)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)quinazolin-4(3H)-one (500b; 0.077 g, 0.164 mmol) were combined in 2 mL dioxane and 0.4 mL water. Argon was bubbled into the reaction for 1 min. The reaction was sealed and heated to 80° C. for 1 h. The reaction was adsorbed onto 1 g silica gel and The material was and purified by silica gel chromatography (12 g column) using 0-100% EtOAc/hexanes. The product-containing fractions were concentrated to afford (R)-2-(tert-butylamino)-3-(3-((tert-butyldimethylsilyl)oxy)propyl)-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (0.047 g, 0.090 mmol, 54.6% yield) as a light-yellow solid: 1H NMR (400 MHz, CDCl3) δ ppm 12.52 (1H, br. s.), 7.88-8.23 (2H, m), 7.22 (1H, t, J=7.7 Hz), 6.84 (1H, d, J=1.2 Hz), 5.89 (1H, br. s.), 5.31 (1H, s), 4.68 (1H, q, J=6.7 Hz), 4.18 (2H, t, J=7.1 Hz), 3.79 (2H, t, J=5.3 Hz), 1.92-2.02 (2H, m), 1.65 (9H, s), 1.54 (3H, d, J=6.8 Hz), 0.96 (9H, s), 0.15 (6H, s). m/z (ESI, +ve ion) 524.2 (M+H)+.
Reaction SMILES: [C:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:19](Cl)(=O)[CH2:20]CCCCCC.[CH2:29](O)[CH2:30]O.N1C=CN=C1>>[C:1]([O:8][CH2:9][CH2:10][O:11][C:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:29][CH3:30])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:19][CH3:20]
Reactant: OCCO
Reactant: CCCCCC(=O)OCCOC(=O)CCCCC
Reactant: CCCCCCCC(=O)Cl
Agent: c1c[nH]cn1
Product: CCCCCCCC(=O)OCCOC(=O)CCCCCCC

Procedure:
Ethylene glycol di-n-octanoate was prepared as described for ethylene glycol di-n-hexanoate (except that heating was conducted at 140°- 150° C.) from octanoyl chloride (483 ml, 2.83 mol), anhydrous ethylene glycol (78 ml, 1.40 mol) and imidazole (193 g, 2.84 mol). Obtained 381.3 g (86.7% purified yield) of clear, colorless, mobile oil (bp 145°°148° C./<1 mm Hg).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CC(=O)CC>[Cl:23][CH2:22][CH2:21][CH2:20][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])=[CH:11][CH:10]=1
Reactant: ClCCCBr
Reactant: O=C(c1ccc(O)cc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(c1ccc(OCCCCl)cc1)C1CC1
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of Example 1A (10 g, 61.7 mmol), K2CO3 (12.7 g, 91.9 mmol), and 1-bromo-3-chloropropane (10.74 g, 68.2 mmol) in 2-butanone (100 mL) was refluxed for 24 hours, cooled to room temperature, filtered, and concentrated. The concentrate was heated to 40° C. under vacuum for three hours to afford 13.256 g (90%) of the desired product of sufficient purity for subsequent use without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]4[C:19]([C:20]5[C:21]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:22][O:23][C:24]=5[CH3:25])=[N:18][N:17]=[C:14]43)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:32][NH2:33]>O>[CH3:32][NH:33][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][N:13]4[C:19]([C:20]5[C:21]([C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=6)=[N:22][O:23][C:24]=5[CH3:25])=[N:18][N:17]=[C:14]43)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc2n1Cc1ccc(-c3ccc(Cl)nn3)cc1-2
Reactant: CN
Solvent: O
Product: CNc1ccc(-c2ccc3c(c2)-c2nnc(-c4c(-c5ccccc5)noc4C)n2C3)nn1

Procedure:
8-(6-Chloropyridazin-3-yl)-3-(5-methyl-3-phenylisoxazol-4-yl)-5H-[1,2,4]triazolo[3,4-α]isoindole was heated in a sealed tube with methylamine (3 ml of 40% solution in water) for 16 h. The reaction mixture was cooled, poured into H2O and extracted into CH2Cl2, dried (MgSO4), and concentrated under reduced pressure.
Reaction SMILES: C([OH:4])C=C.[Cl:5][CH2:6][CH2:7][C:8](Cl)=[O:9].[C:11]1([CH3:17])C=CC=C[CH:12]=1>>[Cl:5][CH2:6][CH2:7][C:8]([O:9][CH2:17][CH:11]=[CH2:12])=[O:4]
Reactant: Cc1ccccc1
Reactant: C=CCO
Reactant: O=C(Cl)CCCl
Product: C=CCOC(=O)CCCl
Yield: 71 %

Procedure:
58.08 g (1.0 mol) of allyl alcohol were dissolved in 200 ml of toluene, and 190.46 g (1.5 mol) of 3-chloropropionyl chloride were added dropwise at 90° C. The reaction solution was refluxed for a further 1.5 hours. The organic phase was washed with 10% strength NaOH solution and twice with H2O, and the solvent was evaporated. The product was subsequently distilled at 74° C. and 20 mbar, giving 104.3 g of allyl 3-chloropropionate (71% of theory).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][C:9]=1[CH2:29][CH3:30]>C1COCC1>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([NH:20][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[C:9]([CH2:29][CH3:30])[CH:10]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:26][CH:25]=1)#[N:28]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(N)c(CC)c1
Reactant: CC(C)N=C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1ccc(NC(=O)NC(C)C)c(CC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A solution of isopropyl isocyanate (130 mg, 1.55 mmol) in THF (2 ml) was added to a solution of the ethyl (RS)-(4-amino-3-ethyl-phenyl)-(4-cyano-phenylamino)-acetate (500 mg, 1.55 mmol) described in Example 186.1 in THF (10 ml). The mixture was stirred overnight at room temperature. Thereafter, further isopropyl isocyanate (260 mg, 3.1 mmol) was added and the mixture was stirred overnight at 50° C. The reaction mixture was concentrated. The residue was suspended in CH2Cl2/MeOH (98:2) and the colorless solid was filtered off. The solid was washed with EtOH and dried under a high vacuum. Ethyl (RS)-(4-cyano-phenylamino)-[3-ethyl-4-(3-isopropyl-ureido)-phenyl]-acetate (395 mg, 62%) was obtained as a colorless solid; MS: 409 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH:4]=O.Cl.[CH3:9][C@@H:10]([NH2:14])[CH2:11][CH2:12][CH3:13].C(N(CC)CC)C>CO.[Pd]>[CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH:14][C@@H:10]([CH2:11][CH2:12][CH3:13])[CH3:9]
Reactant: CCC[C@@H](C)N
Reactant: COC(C=O)OC
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC[C@@H](C)NCC(OC)OC
Reaction time: 2 h

Procedure:
2,2-Dimethoxyacetaldehyde (0.59 mL) was added to a solution of (R)-pentan-2-amine hydrochloride (0.48 g) and triethylamine (0.54 mL) in methanol (4 mL) and the mixture stirred for 2 h. A slurry of palladium on carbon (10%, 20 mg) in methanol (1 mL) was added and the mixture hydrogenated at 5 bar for 20 h. The mixture was then filtered and in vacuo. The resulting residue was triturated with diethyl ether (5 mL) and the resulting white solid extracted with further diethyl ether (2×5 mL). The combined ether fractions were concentrated in vacuo to afford (R)—N-(2,2-dimethoxyethyl)pentan-2-amine (0.745 g) as an oil. 1H NMR (400 MHz, CDCl3) δ 4.92 (t, J=5.4 Hz, 1H), 3.47 (s, 3H), 3.47 (s, 3H), 3.25-3.15 (m, 1H), 2.99 (ddd, J=27.9, 12.7, 5.5 Hz, 2H), 1.86-1.77 (m, 1H), 1.64-1.54 (m, 1H), 1.49-1.32 (m, 5H), 0.95 (t, J=7.3 Hz, 3H)
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH2:7][CH2:6]2)=O.[NH2:12][C@@H:13]([C:18]([OH:20])=[O:19])[C:14]([SH:17])([CH3:16])[CH3:15]>CO>[CH3:15][C:14]1([CH3:16])[S:17][CH:1]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][CH2:7][CH2:6]3)[NH:12][C@H:13]1[C:18]([OH:20])=[O:19]
Reactant: O=Cc1ccc2c(c1)CCC2
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: CO
Product: CC1(C)SC(c2ccc3c(c2)CCC3)N[C@H]1C(=O)O
Reaction time: 48 h

Procedure:
1.44 g (10 mmoles) of 5-formylindane are portionwise added to a solution containing 1.5 g of D-penicillamine in 100 ml of methanol at room temperature while stirring. After 48 hours, the mixture is evaporated to dryness. The residue is dissolved in ether with boiling, treated with activated carbon and filtered. The crude product is precipitated by adding petroleum ether. The thus-obtained product is dissolved in hot ethanol, clarified with carbon, filtered, then water is added up to a beginning opalescence. On cooling, the title compound precipitates in a crystalline form in a yield of 1.57 g (57.1%), m.p. 140°-142° C., [α]D20 =+18° (c=0.551, dimethylsulphoxide).
Reaction SMILES: [CH3:1][S:2][CH3:3].[S:4]([O:9]C)([O:7][CH3:8])(=[O:6])=[O:5]>CCOCC>[CH3:8][O:7][S:4]([O-:9])(=[O:6])=[O:5].[CH3:1][S+:2]([CH3:8])[CH3:3]
Reactant: CSC
Reactant: COS(=O)(=O)OC
Solvent: CCOCC
Product: COS(=O)(=O)[O-]
Product: C[S+](C)C
Temperature: 0 °C

Procedure:
Dimethyl sulfide (25.0 mL) is cooled to 0° C., and dimethyl sulfate (25.0 mL) is added. The liquid is stirred at 0° C. and allowed to warm slowly as the ice in the cooling bath melts. The following day, ether is added and the solid mass crushed with a stirring rod. The solid is filtered, washed well with ether, and dried in vacuo to provide 48.0 g of the salt as a white crystalline solid.
Reaction SMILES: C[N:2](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=O)=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36].C(N(CC)CC)C.N[C:46]1[CH:47]=[C:48]([CH3:55])[C:49](C)([CH3:53])[NH:50][C:51]=1C>CN(C=O)C>[NH2:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([NH:2][C:51]2[CH:46]=[CH:47][C:48]([CH3:55])=[C:49]([CH3:53])[N:50]=2)=[O:32])=[CH:28][C:27]=1[N+:35]([O-:37])=[O:36]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC1=CC(N)=C(C)NC1(C)C
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2ccc(N)c([N+](=O)[O-])c2)nc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To DMF (20 mL) were added HATU (2.87 g, 7.55 mmol), 4-amino-3-nitrobenzoic acid (916 mg, 5.03 mmol), triethylamine (1.05 mL, 762 mmol) and 5-amino-2,3-dimethyllutidine (615 mg, 5.03 mmol) [J. Het. Chem. 31, 1641 (1994)]. The mixture was stirred at ambient temperature for 1 h, then at 80° C. for 18 h. The solution was decanted into ethyl acetate and extracted once with water and five times with brine, then dried, filtered, and the solvent was removed under reduced pressure. The residue was purified by chromatography using a gradient of 80-100% heptane/ethyl acetate to give 4-amino-N-(5,6-dimethylpyridin-2-yl)-3-nitrobenzamide. MS (m/z) 287.0 (M+1).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)([CH3:6])[CH3:5].C1N2CN3CN(C2)C[N:17]1C3>C(Cl)Cl>[BrH:1].[NH2:17][CH2:2][C:3](=[O:15])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)([CH3:6])[CH3:5]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: CC(C)(C(=O)CBr)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: Br
Product: CC(C)(C(=O)CN)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 158.8 %

Procedure:
A mixture of 1-bromo-3-(3,4-dichlorophenyl)-3-methylbutan-2-one (4.0 g, 13 mmol) and HMTA (hexamethylenetetramine, 2.0 g, 14 mmol) in DCM (25 mL) was stirred 48 h at room temperature. The volatiles were evaporated in vacuo. The crude material was dissolved in EtOH (80 mL) and combined with conc HCl (40 mL). The resulting mixture was heated at reflux 2 h, cooled to room temperature, and concentrated in vacuo to give 1-amino-3-(3,4-dichlorophenyl)-3-methylbutan-2-one hydrobromide (6.75 g), which was used in the next reaction without purification. 1H NMR (400 MHz, DMSO-d6) δ 8.00 (bs, 3H), 7.61 (d, 1H), 7.52 (d, 1H), 7.29 (dd, 1H), 3.94 (m, 2H), 1.47 (s, 6H).