Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C@@H:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12])(C)(C)C.Cl>O1CCOCC1>[NH2:7][CH2:8][CH2:9][C@@H:10]([OH:15])[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)[C@H](O)CCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To a stirred solution of N-[(3R)-3-hydroxy-4,4-dimethyl-pentyl]-carbamic acid tert-butyl ester (1.2 g, 5.19 mmol) in dioxane (5 ml) is added 4N hydrochloric acid in dioxane (12 ml) at 0° C. and the mixture is stirred for 1 h at room temperature. The reaction mixture is concentrated in vacuo and solid is triturated with pentane yielding (3R)-1-amino-4,4-dimethyl-pentan-3-ol (0.5 g, 2.98 mmol, 57%).
Reaction SMILES: [CH3:1][C:2]1([O:5][CH2:4]1)[CH3:3].[CH3:6][C:7]1([CH3:19])[C:11]([CH3:13])([CH3:12])[O:10][B:9]([C:14]2[CH:15]=[N:16][NH:17][CH:18]=2)[O:8]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)C>[CH3:3][C:2]([OH:5])([CH3:1])[CH2:4][N:17]1[CH:18]=[C:14]([B:9]2[O:8][C:7]([CH3:19])([CH3:6])[C:11]([CH3:13])([CH3:12])[O:10]2)[CH:15]=[N:16]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 16 h
Yield: 30.1 %

Procedure:
Isobutylene oxide (101 μL, 1.13 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg, 1.03 mmol) and cesium carbonate (403 mg, 1.24 mmol) stirring in N,N-dimethylformamide (3.4 mL). The mixture was stirred at 80° C. for 16 h, cooled to room temperature, diluted with diethyl ether, washed with water (3×) and brine, dried over sodium sulfate, filtered, and concentrated to give 2-methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-2-ol (84 mg, 0.31 mmol, 31% yield) as a yellow solid. ESI: [M+H]+ m/z 267.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:27][C:28]2[CH:32]=[C:31]([CH:33]3[CH2:35][CH2:34]3)[NH:30][N:29]=2)=[N:4][C:5]([C:8]2[S:12][C:11]([S:13]([NH:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)(=[O:15])=[O:14])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.Cl.CC1C=CC(COC(NNC(C2C=NC=CN=2)=O)=O)=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[NH2:19][CH2:18][CH2:17][NH:16][S:13]([C:11]1[S:12][C:8]([C:5]2[N:4]=[C:3]([NH:27][C:28]3[CH:32]=[C:31]([CH:33]4[CH2:34][CH2:35]4)[NH:30][N:29]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:9][CH:10]=1)(=[O:15])=[O:14]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Agent: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: NCCNS(=O)(=O)c1ccc(-c2ncc(Cl)c(Nc3cc(C4CC4)[nH]n3)n2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.7 %

Procedure:
tert-Butyl 2-(5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamido)ethylcarbamate (Compound 78) (70 mg, 12.96 mmol, 1 equiv.) was added into HCl in MeOH and the resulting mixture was stirred at room temperature for 2 h. The mixture was adjusted pH10 with Na2CO3, and extracted with EA (50 mL×3). The organic phase was combined and washed with brine, dried (Na2SO4), evaporated to afford N-(2-aminoethyl)-5-(5-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (Compound 75) (38.3 mg, 67%). LC-MS (m/z)=440 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.81-0.82 (m, 2H), 1.03-1.05 (m, 2H), 2.01-2.03 (m, 1H), 2.90 (q, J=5.6 Hz, 2H), 3.15 (q, J=6.0 Hz, 2H), 6.43 (s, 1H), 7.71 (d, J=4.0 Hz, 1H), 7.85 (d, J=3.6 Hz, 1H), 8.18 (s, 1H), 8.48 (d, J=5.6 Hz, 1H), 8.55 (s, 1H), 9.83 (d, J=20.8 Hz, 1H)
Reaction SMILES: [NH2:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>>[O:12]=[C:11]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:4][CH:3]=[C:2]1[NH:1][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1coc2ccccc2c1=O
Product: CCOC(=O)C(=CNc1coc2ccccc2c1=O)C(=O)OCC
Temperature: 140 °C
Yield: 62.2 %

Procedure:
A mixture of 3-aminochromone (8.0 g, 0.05 mole) and diethyl ethoxymethylenemalonate (17.3 g, 0.08 mole) was heated under nitrogen at 140° C. for 2.5 hrs. The reaction mixture was cooled. The product, which crystallized out was filtered off and triturated with petroleum ether. Recrystallization from ethyl acetate - absolute ethanol gave white crystals (10.3 g, 62.5%), m.p. 155°-157° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(=O)O[C@H:25]1[CH2:29][C@@H:28]([N:30]2[CH:38]=[N:37][C:36]3[C:31]2=[N:32][C:33]([Cl:40])=[N:34][C:35]=3[Cl:39])[CH:27]=[CH:26]1)C.[CH2:42]([C:44]1[CH:48]=[N:47][NH:46][N:45]=1)[CH3:43]>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:40][C:33]1[N:32]=[C:31]2[C:36]([N:37]=[CH:38][N:30]2[C@@H:28]2[CH2:29][C@H:25]([N:47]3[CH:48]=[C:44]([CH2:42][CH3:43])[N:45]=[N:46]3)[CH:26]=[CH:27]2)=[C:35]([Cl:39])[N:34]=1
Reactant: CCc1cn[nH]n1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCc1cn([C@@H]2C=C[C@H](n3cnc4c(Cl)nc(Cl)nc43)C2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture comprising triphenylphosphine (0.299 g, 0.874 mmol) and Pd2(dba)3 (0.267 g, 0.291 mmol) in dry THF (5 mL) under an inert atmosphere of argon is stirred at RT for 10 minutes. This mixture is then added to a pre-stirring mixture of carbonic acid (1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl ester ethyl ester (Intermediate AA2) (2.00 g, 5.83 mmol) and 4-ethyl-2H-[1,2,3]triazole (0.594 g, 6.12 mmol) in THF (15 mL). The resulting mixture is stirred at RT overnight and then concentrated in vacuo. The crude product is purified by chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title compound as a white solid. (MH+ 350).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[Cl-].[OH:30][CH:31]1[CH2:34][NH2+:33][CH2:32]1>>[CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:24][CH2:25][CH2:26][CH2:27]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][N:33]4[CH2:34][CH:31]([OH:30])[CH2:32]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Reactant: OC1C[NH2+]C1
Agent: [Cl-]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CC(O)C4)cn3)nc2n1C1CCCC1
Yield: 47 %

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide and 3-hydroxy-azetidinium chloride (73 mg, 0.667 mmol) gave 7-cyclopentyl-2-[5-(3-hydroxy-azetidin-1-ylmethyl)-pyridin-2-ylamino]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide as a light yellow solid (0.131 g, 47%) [following SiO2 chromatography, eluting with 0-5% (2M NH3 in MeOH)/DCM). MS(ESI) m/z 436.2 (M+H)+ (method B).
Reaction SMILES: [N:1]1[CH:2]=[C:3]([NH2:10])[N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CN(C=O)C.CCOC(C)=O>[C:21]1([O:20][C:18](=[O:19])[NH:10][C:3]2[N:4]3[N:5]=[CH:6][CH:7]=[CH:8][C:9]3=[N:1][CH:2]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cnc2cccnn12
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Nc1cnc2cccnn12)Oc1ccccc1
Reaction time: 3 h
Yield: 71.9 %

Procedure:
To a solution of imidazo[1,2-b]pyridazin-3-ylamine (209 mg, 1.56 mmol) in dry DMF (5.0 mL) was added pyridine (382 μL, 4.68 mmol) and phenyl chloroformate (244 mg, 1.56 mmol). After 3 h at rt, the mixture was diluted with EtOAc (100 mL) and washed with saturated aqueous NaHCO3 (50 mL). The organic layer was dried (MgSO4) and concentrated. The residue was purified (FCC) to give imidazo[1,2-b]pyridazin-3-yl-carbamic acid phenyl ester (285 mg, 72%). MS (ESI+): calcd for C13H10N4O2 m/z 254.08. found 255.3 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:6][N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[O:16])[CH2:8]1.[CH3:28][NH2:29]>CN(C)C=O>[Cl:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:6][N:7]1[CH2:12][CH2:11][O:10][C@@H:9]([CH2:13][NH:14][C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]([NH:29][CH3:28])=[O:23])=[O:16])[CH2:8]1
Reactant: CN
Reactant: O=C(O)CCCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)CCCNC(=O)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 22 °C
Reaction time: 0.67 h

Procedure:
N,N′-carbonyldiimidazole (0.0132 g) was added to a stirred solution of Intermediate 26 (0.030 g) in N,N-dimethylformamide (2 ml), and the mixture stirred at 22° C. under nitrogen for 40 min. Methylamine (2.0M solution in tetrahydrofuran, 0.102 ml) was added, and stirring was continued at 22° C. for 17 h. The mixture was applied directly to a sulphonic acid ion exchange cartridge (2 g Isolute SCX), and eluted with methanol followed by 10% 0.880 ammonia in methanol to give a gum (0.042 g). Purification by chromatography on silica gel (1 g Varian Bond Elut cartridge), eluting with chloroform, ether, ethyl acetate, acetone, and methanol, gave a gum (0.025 g), which was further purified by mass directed preparative HPLC to give the title compound as a colourless gum (7.2 mg).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:6][CH2:5]1)(=O)C>CO.[OH-].[Na+]>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][O:10][CH:7]2[CH2:6][CH2:5][NH:4][CH2:9][CH2:8]2)=[CH:13][CH:14]=1
Reactant: CC(=O)N1CCC(OCc2ccc(Cl)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(COC2CCNCC2)cc1
Yield: 62.5 %

Procedure:
1-acetyl-4-{[(4-chlorophenyl)methyl]oxy}piperidine (Preparation 99, 11 g, 41.1 mmol) in methanol (50 ml) and sodium hydroxide solution (5 M, 30 ml) were refluxed on a steam bath for 10 h. After cooling, methanol was removed and the remaining solution was extracted with petroleum ether (40-60, 3×30 ml). The organic extracts were dried (Na2SO4) and concentrated in vacuo to give an white solid (5.8 g, 62%). A portion was recrystallised from petroleum ether to give needle crystals (3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9].Cl.[OH-].[Na+].[CH:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21](Cl)=[O:22])=[CH:15][CH:14]=1>O>[CH2:19]([O:20][C:21](=[O:22])[NH:1][C:2]1[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][C:3]=1[OH:9])[C:16]1[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(O)cc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Nc1ccc(O)cc1O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a cooled solution (0° C.) of 4-amino resorcinol.HCl (1.0 g, 6.18 mmol) in H2O (10 mL) was added dropwise aq. NaOH (0.49 g, 12.3 mmol) in H2O (15 mL). To this mixture were added slowly Cbz-Cl (Carbobenzoxy chloride, 1.06 mL, 7.43 mmol) and NaOH (0.25 g) in H2O (5 mL). After stirring for 1 h at room temperature, the mixture was extracted with EtOAc (2×50 mL). The organic layer was dried over MgSO4 (10 g), filtrated and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc:hexane=1:5) to give (2,4-dihydroxyphenyl)-carbamic acid benzyl ester (KCBG02. 1.28 g, 80%).
Reaction SMILES: O[C:2]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH2:23][C:24]([CH3:26])=[CH2:25])[CH2:3][CH2:4][N:5]([C:19]([O:21]C)=[O:20])[C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.[H-].[Na+]>C1COCC1.CCOCC>[CH3:26][C:24](=[CH2:25])[CH2:23][C@@:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:20][C:19](=[O:21])[N:5]([C@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]2)[CH2:4][CH2:3]1
Reactant: C=C(C)CC(O)(CCN(C(=O)OC)[C@H]1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C(C)C[C@]1(c2ccccc2)CCN([C@H]2CCCN(C(=O)OC(C)(C)C)C2)C(=O)O1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
To a solution of (3S)-tert-butyl 3-((3-hydroxy-5-methyl-3-phenylhex-5-enyl)(methoxycarbonyl)amino)piperidine-1-carboxylate (5.80 g, 13 mmol) in dry THF (200 mL) was added NaH (60% in mineral oil, 1.04 g, 2 equiv). The mixture was heated to reflux for 2 h. After being cooled down to rt, the mixture was diluted with ether (200 mL), quenched with satd aq NH4Cl solution (25 mL), washed with 1% HCl solution (50 mL), brine (35 mL), and dried over Na2SO4. After filtration and concentration, the residue was purified by chromatography on a 120 g silica gel column, eluted with a 40-70% EtOAc in hexanes gradient to afford (5)-tert-butyl 3-((R)-6-(2-methylallyI)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)piperidine-1-carboxylate (2.98 g, 55% yield). LC-MS Method 1 tR=1.92 min., m/z 437 (M+Na).
Reaction SMILES: I[C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[NH2:11].[Cu][C:13]#[N:14].[NH4+].[OH-].C(Cl)Cl>CN(C=O)C>[NH2:11][C:3]1[CH:4]=[C:5]2[C:9]([CH2:8][CH2:7][CH2:6]2)=[CH:10][C:2]=1[C:13]#[N:14]
Reactant: Nc1cc2c(cc1I)CCC2
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1cc2c(cc1N)CCC2
Temperature: 160 °C

Procedure:
To a solution of 6-iodoindan-5-amine (135 mg, 0.52 mmol) in DMF (2 mL), was added copper (I) cyanide (93 mg, 1.04 mmol). The mixture was heated at 160° C. for 1.5 h. The reaction mixture was poured into 10% NH4OH. An equal amount of CH2Cl2 was added and resulting mixture was filtered. The filtrate was partitioned between two layers. The aqueous layer was extracted with CH2Cl2 (1×). The combined organic layers were concentrated in vacuo. The residue was dissolved in Et2O. The Et2O layer was washed with aqueous Na2S2O3, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) yielding 6-aminoindane-5-carbonitrile. LCMS calc.=159.1; found=159.1 (M+1)+. 1H NMR (500 MHz, CDCl3) δ 7.22 (s, 1H), 6.64 (s, 1H), 4.25 (br, s, 2H), 2.85 (t, J=7.4 Hz, 2H), 2.80 (t, J=7.4 Hz, 2H), 2.09-2.03 (m, 2H).
Reaction SMILES: C1(N2C=NC3C2=NC(OCC)=NC=3N)CCCC=C1.[CH:20]1([N:26]2[CH:34]=[N:33][C:32]3[C:27]2=[N:28][C:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[N:30][C:31]=3[NH2:35])[CH2:25][CH2:24][CH2:23][CH:22]=[CH:21]1>>[CH2:37]([O:36][C:29]1[N:28]=[C:27]2[C:32]([N:33]=[CH:34][N:26]2[CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:31]([NH2:35])[N:30]=1)[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Agent: CCOc1nc(N)c2ncn(C3C=CCCC3)c2n1
Product: CCCCCOc1nc(N)c2ncn(C3CCCCC3)c2n1
Yield: 90 %

Procedure:
The procedure of Example 8 was repeated except that the 9-(2-cyclohexenyl)-2-ethoxy-9H-adenine used therein was replaced by an equivalent weight of 9-(2-cyclohexenyl)-2-n-pentyloxy-9H-adenine. There was produced the title product in 90% yield; m.p. 64°-68° C. IR(neat): 3500, 3320, 1635, 1590, 1460, 1395, 1340, 1325, 1265 cm-1. UV: λmaxEtOH 253 nm(ε10900), 269 nm(ε16800). NMR(CDCl3): 1.50(19H, m), 4.20(1H, m), 4.26(2H, t, J=6.5 Hz), 6.25(2H, s), 7.56(1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:15](Cl)(=[O:17])[CH3:16]>C(OCC)(=O)C.O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:15]([CH3:16])=[O:17])=[CH:3][CH:4]=1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C)cc1
Reaction time: 2 h
Yield: 77801.2 %

Procedure:
100 g (933.3 mmol) of p-toluidine and 154.8 g (1.120 mmol) of potassium carbonate were dissolved in a mixed solvent of 1,000 ml of ethyl acetate and 500 ml of water. Thereinto was dropped 87.9 g (1.120 mmol) of acetyl chloride with ice-cooling, followed by stirring for 2 hours. Extraction with ethyl acetate was carried out. The organic phase obtained was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The crude crystal obtained was washed with hexane to obtain 130 g (yield: 93%) of p-acetotoluidine.
Reaction SMILES: [CH2:1]([CH:8]([C:19](=[O:28])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9](=[O:18])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCC>[Pd].C(OCC)(=O)C>[CH2:1]([CH:8]([C:9](=[O:18])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(C=Cc1ccccc1)C(Cc1ccccc1)C(=O)C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=C(CCc1ccccc1)C(Cc1ccccc1)C(=O)CCc1ccccc1
Yield: 69.4 %

Procedure:
4-Benzyl-1,7-diphenyl-1,6-heptadiene-3, 5-dione (9b, 0.26 g, 0.7 mmol) and palladium on activated carbon (0.25 g, 10%) were combined in ethyl acetate (50 ml). The mixture was placed under a hydrogen atmosphere (60 psi) on a Parr apparatus for 2 hr at room temperature. The resulting mixture was filtered through celite and the filtrate was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford an oil. Hexane was added to the crude oil and the resulting precipitate was filtered. The crude solid was recrystallized twice from hexane to give 0.18 g (69%) of white needles: mp 74-75° C.; 1H NMR: δ enol form: 2.61 (m, 10H), 7.14 (m, 15H); keto form: 2.61 (m, 8H), 3.07 (d, 2H, J=7.2 Hz), 3.90 (t, 1H, J=7.6 Hz), 7.14 (m, 15H); 13C NMR: δ 29.3, 34.3, 44.3, 69.2, 126.1, 126.7, 128.3, 128.4, 128.6, 128.7, 137.9, 140.4, 204.3; Exact mass calcd for C26H26O2: 370.1933, observed (M+H) 371.2014.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]([CH3:14])=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[O:15].[C:16]1(=O)[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH2:17]1.C(N=C=NCCCN(C)C)C>C(#N)C>[CH3:1][N:2]1[C:6]2[C:7]([CH3:14])=[C:8]([C:11]([O:13][C:16]3[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH:17]=3)=[O:12])[CH:9]=[CH:10][C:5]=2[S:4][C:3]1=[O:15]
Reactant: O=C1CCCC(=O)C1
Reactant: Cc1c(C(=O)O)ccc2sc(=O)n(C)c12
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: Cc1c(C(=O)OC2=CC(=O)CCC2)ccc2sc(=O)n(C)c12
Temperature: 50 °C
Reaction time: 4 h
Yield: 48 %

Procedure:
1.1 g (5 mmol) of 3,4-dimethylbenzothiazol-2-one-5-carboxylic acid, 0.58 g of 1,3-cyclohexanedione and 1.25 g of ethyl(3′-dimethylaminopropyl)carbodiimide were dissolved in 40 ml of acetonitrile, and the solution was stirred at 50° C. for 4 hours. After the reaction had ended, the precipitate was filtered off and the solution was concentrated. The residue was taken up in water and extracted with methylene chloride. The organic phase was washed and dried and the solvent was then removed. Chromatography of the residue on silica gel (mobile phase: cyclohexane/ethyl acetate, gradient from 100:0 to 50:50) gave 0.77 g (2.4 mmol, 48% yield) of cyclohexenone-3-yl 3,4-dimethylbenzothiazol-2-one-5-carboxylate of m.p. 144° C.-146° C.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[CH3:42][N:43]([CH3:50])[CH2:44][C:45]([CH3:49])([CH3:48])[CH2:46][NH2:47]>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH2:44][N:43]([CH3:50])[CH3:42])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)CC(C)(C)CN
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NCC(C)(C)CN(C)C)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a mixture of 0.10 g (0.22 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-100), 0.12 mL (0.66 mmole) of ethyldiisopropyl amine and 0.039 mL (0.25 mmole) of N,N,-2,2-tetramethyl-propane-1,3-diamine in 2.0 mL of dimethylformamide was added 0.11 g (0.25 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The resulting solid was collected by filtration, washed with saturated sodium carbonate and water, and dried under vacuum. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.080 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-benzamide (I-60) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:16]1([NH:22][C:23](=[S:24])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[CH:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccc(NNC(=O)C(F)(F)F)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CCO
Product: O=C(NNc1ccc(NC(=S)Nc2ccccc2)cc1)C(F)(F)F

Procedure:
2-(4-Aminophenyl)-1-trifluoroacetylhydrazine (2.0 g, 0.0091 mole) and phenyl isothiocyanate (1.2 g, 0.0091 mole) were mixed together in ethanol (25 ml) and the mixture was heated to reflux for 20 minutes. A white solid precipitated out of the mixture during the heating. The mixture was chilled in ice and the solid was filtered off, washed with ethanol, and dried. Spectral data on this material indicated that it was not the desired product. The filtrate from above was diluted with water and a second solid material formed. This material was filtered off, washed with water and dried to give a white crystalline powder. Yield 0.80 g (25%), m.p. 172°-174° C. Spectral evidence verified that this substance was the desired product.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:14][CH3:15])=[CH:7][C:8]([CH2:11][CH:12]=[CH2:13])=[CH:9][CH:10]=1)(=O)C.C(OC1C(OC)=CC(CC=C)=CC=1)(=[O:34])CCCCCCC/C=C\CCCCCCCC>>[CH3:15][O:14][C:6]1[CH:7]=[C:8](/[CH:11]=[CH:12]/[CH:13]=[O:34])[CH:9]=[CH:10][C:5]=1[OH:4]
Reactant: C=CCc1ccc(OC(C)=O)c(OC)c1
Reactant: C=CCc1ccc(OC(=O)CCCCCCC/C=C\CCCCCCCC)c(OC)c1
Product: COc1cc(/C=C/C=O)ccc1O
Yield: 58 %

Procedure:
If the procedure of Example 1 is followed, but 25 ppm of eugenol acetate are employed as inductor in place of eugenol oleate, and if the fungus Fusarium moniliforme DSM 764 is used, 252 mg of coniferyl aldehyde (58% of theory) are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][NH:13]C(OC(C)(C)C)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].O1CCOCC1.[ClH:27]>>[ClH:27].[CH2:1]([O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][NH2:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](NNC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CC[C@H](NN)CC1

Procedure:
A solution of trans-4-(N′-tert-butoxycarbonyl-hydrazino)-cyclohexanecarboxylic acid ethyl ester (0.625 g, 2.18 mmol) in 4 M hydrogen chloride solution in 1,4-dioxane (5.5 ml, 22 mmol) was stirred at room temperature for 3 days. The precipitate was collected by filtration, washed with tert-butyl methyl ether and dried in vacuo to give the title compound as white solid in quantitative yield. MS m/e: 187 ([M+H]+).