Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][NH:13][S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:16])=[O:15])[CH3:10])=[CH:4][CH:3]=1.[N:29]1([CH2:35][CH2:36]O)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:11][CH2:12][N:13]([CH2:36][CH2:35][N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[S:14]([C:17]2[C:18]3[CH:19]=[CH:20][N:21]=[CH:22][C:23]=3[CH:24]=[CH:25][CH:26]=2)(=[O:15])=[O:16])[CH3:10])=[CH:27][CH:28]=1
Reactant: CN(CC=Cc1ccc(Cl)cc1)CCNS(=O)(=O)c1cccc2cnccc12
Reactant: OCCN1CCCCC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(CC=Cc1ccc(Cl)cc1)CCN(CCN1CCCCC1)S(=O)(=O)c1cccc2cnccc12
Yield: 74.9 %

Procedure:
To a solution of 0.39 g of the amorphous compound obtained in Example 190, 0.145 g of 1-piperidinethanol and 0.369 g of triphenylphosphine in 5 ml of tetrahydrofuran, was added dropwise a solution of 0.245 g of diethyl azodicarboxylate in 2 ml of tetrahydrofuran with stirring under ice cooling. The mixture was stirred for 2 hours and evaporated to remove the solvent under a reduced pressure, and resulting residue dissolved in 30 ml of ethyl acetate and extracted three times with 10 ml of 1N hydrochloric acid. The aqueous layer was alkallized with sodium bicarbonate and extracted three times with 10 ml of ehtyl acetate, and the organic extract was dried over magnesium sulfate and evaporated to remove the solvent at a reduced pressure. The resulting residue was applied to a silica gel column and eluted with 2% methanol in chloroform, to obtain 0.37 g of the title compound as a colorless oil.
Reaction SMILES: CO[C:3]([C:5]1([CH2:15][CH:16]=O)[CH2:10][CH2:9][CH:8]([C:11]([O:13][CH3:14])=[O:12])[CH2:7][CH2:6]1)=[O:4].[CH3:18][CH:19]1[CH2:23][CH2:22][CH2:21][N:20]1[CH:24]1[CH2:28][CH2:27][C@H:26]([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:25]1>>[CH3:14][O:13][C:11]([CH:8]1[CH2:7][CH2:6][C:5]2([C:3](=[O:4])[N:35]([C:32]3[CH:33]=[CH:34][C:29]([CH:26]4[CH2:27][CH2:28][CH:24]([N:20]5[CH2:21][CH2:22][CH2:23][CH:19]5[CH3:18])[CH2:25]4)=[CH:30][CH:31]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=[O:12]
Reactant: CC1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Reactant: COC(=O)C1CCC(CC=O)(C(=O)OC)CC1
Product: COC(=O)C1CCC2(CC1)CCN(c1ccc(C3CCC(N4CCCC4C)C3)cc1)C2=O

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 1 by condensing 1-(2-oxo-ethyl)-cyclohexane-1,4-dicarboxylic acid dimethyl ester (Intermediate 5) with 4-[(S)-3-(2-methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 15), and subsequently cyclization.
Reaction SMILES: [CH2:1]([O:3][O:4][P:5]([C:11]([F:33])([F:32])[C:12]1[CH:31]=[CH:30][C:15]([CH2:16][CH:17]([C:26]([O:28]C)=[O:27])[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][CH:13]=1)([O:7][O:8][CH2:9][CH3:10])=[O:6])[CH3:2].[Li+].[OH-]>C1COCC1>[CH2:1]([O:3][O:4][P:5]([C:11]([F:33])([F:32])[C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH:17]([C:26]([OH:28])=[O:27])[NH:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[CH:30][CH:31]=1)([O:7][O:8][CH2:9][CH3:10])=[O:6])[CH3:2]
Reactant: CCOOP(=O)(OOCC)C(F)(F)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOOP(=O)(OOCC)C(F)(F)c1ccc(CC(NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 0 °C
Yield: 89.9 %

Procedure:
To a solution of 42 (536 mg, 1.15 mmol) in THF (10 mL) at 0° C. was added 0.2 N LiOH (6.3 mL, 1.3 mmol, 1.1 equivalents) at 0° C. dropwise over 15 minutes. The reaction was then stirred at 0° C. and monitored by TLC with four additions of 576 μL (0.115 mmol, 0.1 equivalents) 0.2 N LiOH over a 2 hour period. The reaction mixture was then partitioned between ice-cold 0.2 N HCl/brine and EtOAc (3×75 mL); dried (MgSO4) and solvent removed by rotovap (20° C.) to yield 33 as a foam (500 mg, 96%). 1H NMR (250 MHz, CDCl3 +D2O) δ:7.46 (d, 2H, J=8.1 Hz, aromatic), 7.21 (d, 2H, J=8.1 Hz, aromatic), 4.57 (m, 1H, Hα), 4.10 (m, 4H, OCH2), 3.11 (m, 2H, Hβ), 1.36 (s, 9H, C(CH3)3), 1.23 (2 t, 6H, J=7.1 Hz, CH3); FABMS m/z 452.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N:5]=[C:4]([NH2:9])[N:3]=1.[C:10]([O:14][C:15]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C([O-])([O-])=O.[Na+].[Na+]>>[NH2:9][C:4]1[N:3]=[C:2]([C:21]2[CH:22]=[C:17]([CH:18]=[CH:19][CH:20]=2)[C:15]([O:14][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:16])[C:7]([CH3:8])=[CH:6][N:5]=1
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
Reactant: Cc1cnc(N)nc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cnc(N)nc1-c1cccc(C(=O)OC(C)(C)C)c1
Temperature: 120 °C
Yield: 49.9 %

Procedure:
To 4-chloro-5-methylpyrimidin-2-amine (150 mg, 1.04 mmol), tetrakistriphenylphosphine Palladium (0) (60 mg, 0.052 mmol) and 3-(tert-butoxycarbonyl)phenylboronic acid (347 mg, 1.56 mmol), 1,2-DME (3 mL) and Na2CO3 (1.04 mL, 2 M, 2.08 mmol) were added and heated to 120° C. in a microwave reactor for 30 minutes. The reaction mixture was filtered using EtOAc and the filtrate was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield tert-butyl 3-(2-amino-5-methylpyrimidin-4-yl)benzoate (148 mg, 50%). ESI-MS m/z calc. 285.1, found 286.5 (M+1)+. Retention time 1.33 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([Cl:14])=[CH:9][C:8]=2[Cl:15])[N:5]=[C:4]([S:16][CH3:17])[C:3]=1[C:18]([NH2:20])=[O:19].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH2:29][C:30](Cl)=O)[CH:26]=[CH:27][CH:28]=1.[O-]CC.[Na+]>C(O)C>[Cl:13][C:12]1[CH:11]=[C:10]([Cl:14])[CH:9]=[C:8]([Cl:15])[C:7]=1[N:6]1[C:2]2=[N:1][C:30]([CH2:29][C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([O:22][CH3:21])[CH:24]=3)=[N:20][C:18](=[O:19])[C:3]2=[C:4]([S:16][CH3:17])[NH:5]1
Reactant: CSc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(N)=O
Reactant: COc1cccc(CC(=O)Cl)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(SC)c-3c(=O)n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
To a stirred solution of 176 mg (0.5 mmol) of 5-amino-3-(methylthio)-1-(2,4,6-trichlorophenyl)pyrazole-4-carboxamide in 6 mL of absolute ethanol was added 550 mg (3.0 mmol) of 3-methoxyphenylacetyl chloride followed by 2.3 mL (6.0 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux, and the heating mantle was then removed. The reaction was treated with 5 mL of 10% aq. HOAc, cooled to ambient temperature, and filtered. The filtrate was washed with 6 mL of 1:1 water-methanol then 6 mL of 1:1 ether-hexanes. The off-white solid was briefly air-dried to give 220 mg (92%) of 1-(2,4,6-trichlorophenyl)-3-(methylthio)-6-(3-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one,
Reaction SMILES: C([O-])(=O)C.[CH:5]1([CH2:8][NH3+:9])[CH2:7][CH2:6]1.C([O:12][C:13](=O)[CH2:14][S:15][C:16]#[N:17])C>>[CH:5]1([CH2:8][NH:9][C:16]2[S:15][CH2:14][C:13](=[O:12])[N:17]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CSC#N
Reactant: [NH3+]CC1CC1
Agent: CC(=O)[O-]
Product: O=C1CSC(NCC2CC2)=N1
Temperature: 90 °C
Yield: 47 %

Procedure:
A mixture of cyclopropylmethylammonium acetate (0.45 g, 3.44 mmol) and thiocyanato-acetic acid ethyl ester (0.5 g, 3.44 mmol) was heated to 90° C. for 2 h. The reaction mixture was partitioned between 6N HCl and dichloromethane. The layers were separated. The aqueous layer was made basic by the addition of 6N ammonium hydroxide, and then extracted with dichloromethane. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The aqueous layer was also concentrated to dryness and the residue was triturated with DMF. The DMF solution was filtered and concentrated to dryness. The residues were combined and purified on a silica gel column with 100% ethyl acetate to afford 2-cyclopropylmethylamino-thiazol-4-one (275 mg, 47%).
Reaction SMILES: [NH2:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:23]([O:27][C:28]([NH:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(CC)CC)C.C[CH2:47][O:48]C(C)=O>>[CH2:16]([O:15][C:11]1[CH:10]=[C:9]([CH2:8][CH:2]([NH:1][C:47]([NH:36][CH2:35][C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:28]([O:27][C:23]([CH3:26])([CH3:24])[CH3:25])=[O:29])=[CH:38][CH:37]=2)=[O:48])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(N)Cc1cccc(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN)cc1
Reactant: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)NCc1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: -10 °C
Yield: 99 %

Procedure:
160 (530 mg, 1.76 mmol) was dissolved in AcOEt (30 mL) and trisphosgene (0.33 equivalent, 173 mg) was added while stirring at −10° C. The mixture was allowed to warm to room temperature, then refluxed for 1 h. 4-(tert-butoxycarbonylamino)benzylamine (391 mg, 1 equivalent) and triethylamine (2 equivalent) were added successively and the resulting solution was stirring at room temperature overnight. 100 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 5/5) to afford 161 as white solid (960 mg, 99%). 1H NMR (DMSO): δ 1.28 (t, 3H, J=6.5 Hz), 1.61 (s, 9H), 3.01 (dd, 1H, J=13.8, 8.3 Hz), 3.09 (dd, 1H, J=13.8, 5.0 Hz), 4.19 (q, 2H, J=6.5 Hz), 4.24 (d, 2H, J=5.1 Hz), 4.57 (s, 1H), 5.20 (s, 2H), 6.38 (d, 1H, J=7.8 Hz), 6.61 (t, 1H, J=5.1 Hz), 6.90 (d, 1H, J=7.1 Hz), 7.02 (d, 1H, J=8.7 Hz), 7.21 (d, 2H, J=8.1 Hz), 7.33 (t, 1H, J=7.8 Hz), 7.50 (m, 5H), 7.57 (d, 2H, J=8.1 Hz), 9.35 (s, 1H).
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].[C:22]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([CH2:45][NH2:46])=[CH:41][CH:40]=3)=[N:35][CH:36]=2)[CH2:27][CH2:26]1)(=[O:24])[CH3:23]>O1CCCC1>[C:22]([N:25]1[CH2:26][CH2:27][N:28]([C:31]2[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([CH2:45][NH:46][C:1]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:2])=[CH:43][CH:44]=3)=[N:35][CH:36]=2)[CH2:29][CH2:30]1)(=[O:24])[CH3:23]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(=O)N1CCN(c2ccc(CCc3ccc(CN)cc3)nc2)CC1
Reactant: CC(C)(C)OC(=O)NN
Solvent: C1CCOC1
Product: CC(=O)N1CCN(c2ccc(CCc3ccc(CNC(=O)NNC(=O)OC(C)(C)C)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
To a suspension of 1,1′-carbonyldiimidazole (125.2 mg, 0.792 mmol) in anhydrous tetrahydrofuran (1 ml) was added tert-butyl carbazate (102.1 mg, 0.792 mmol), and the mixture was stirred at room temperature for 1 hr. 1-(4-{2-[5-(4-Acetylpiperazin-1-yl)pyridin-2-yl]ethyl}phenyl)methanamine (130.7 mg, 0.386 mmol) was added, and the mixture was stirred at room temperature for 4 hrs. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and aqueous sodium carbonate solution were added. The mixture was stirred, stood still and partitioned. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate→methanol:dichloromethane=1:20). The fraction containing the target product was concentrated and the obtained solid was suspended in a mixture of ethyl acetate (5 ml) and diisopropyl ether (10 ml), filtered and dried under reduced pressure to give tert-butyl 2-[(4-{2-[5-(4-acetylpiperazin-1-yl)pyridin-2-yl]ethyl}benzyl)carbamoyl]hydrazinecarboxylate (145.9 mg, yield 76.1%) as a white solid.
Reaction SMILES: C1(O[C:8](=[O:40])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[S:29]([CH3:32])(=[O:31])=[O:30])[N:19]=[C:18]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]4[CH3:39])[N:17]=3)=[CH:12][CH:11]=2)C=CC=CC=1.[NH2:41][C@H:42]1[CH2:46][CH2:45][CH2:44][C@@H:43]1[OH:47]>>[F:28][C:26]1[CH:25]=[CH:24][C:23]([S:29]([CH3:32])(=[O:30])=[O:31])=[C:22]([C:20]2[N:19]=[C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][C@@H:34]3[CH3:39])[N:17]=[C:16]([C:13]3[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:41][C@H:42]4[CH2:46][CH2:45][CH2:44][C@@H:43]4[OH:47])=[O:40])=[CH:11][CH:12]=3)[CH:21]=2)[CH:27]=1
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1
Reactant: N[C@H]1CCC[C@@H]1O
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)N[C@H]3CCC[C@@H]3O)cc2)cc(-c2cc(F)ccc2S(C)(=O)=O)n1

Procedure:
Method as described for example 58 using intermediate 32 (100 mg, 0.18 mmol) and (1S,2S)-2-aminocyclopentanol (27 mg, 0.267 mmol). The reaction mixture was purified by prep HPLC at low pH to afford the title compound. (50 mg, 49%)
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7]([O:10][CH3:11])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[S:13]([N:23]1[CH2:27]C[C@@H:25](O)[CH2:24]1)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[S:13]([N:23]1[CH2:24][CH2:25][C@H:11]([O:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:12])=[CH:6][CH:5]=2)(=[O:9])=[O:8])[CH2:27]1)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: Cc1ccc(S(=O)(=O)N2CC[C@@H](O)C2)cc1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CCN(S(=O)(=O)c3ccc(C)cc3)C2)cc1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Methyl para-toluenesulphonate (54 g) was added in portions to solution of 1-tosyl-3-(R)-(-)-hydroxypyrrolidine (49 g--see Preparation 2) and triphenylphosphine (76 g) in anhydrous tetrahydrofuran (700 ml) at 0° C. The mixture was cooled to -20° C. and diethyl azodicarboxylate (58 g--"DEAD") was added, dropwise, over 30 minutes. During this time, the temperature of the mixture was not allowed to rise above -10° C. When the addition was complete the mixture was allowed to warm to room temperature and stirred for 16 hours. The mixture was concentrated in vacuo to give a solid which was purified by column chromatography on silica eluting with hexane containing dichloromethane (50%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from 1-propanol to give the title compound as a colourless solid, yield 56 g, m.p. 110° C., [α]25D -5.2° (c 1.0, CH2Cl2).
Reaction SMILES: C(Cl)/C=C(/CCC[C@@H](CCC[C@@H](CCCC(C)C)C)C)\C.[CH3:22][C:23]1[C:32]([CH3:33])=[C:31]2[C:26]([CH2:27][CH2:28][C:29]([CH2:35][CH2:36][CH2:37][CH:38]([CH2:40][CH2:41][CH2:42][CH:43]([CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])[CH3:44])[CH3:39])([CH3:34])[O:30]2)=[C:25]([CH3:51])[C:24]=1[OH:52].[C:53](OC(=O)C)(=[O:55])[CH3:54].N1C=CC(C)=CC=1>[Zn]>[CH3:33][C:32]1[C:23]([CH3:22])=[C:24]([O:52][C:53]([CH3:54])=[O:55])[C:25]([CH3:51])=[C:26]2[CH2:27][CH2:28][C@:29]([CH2:35][CH2:36][CH2:37][C@@H:38]([CH2:40][CH2:41][CH2:42][C@@H:43]([CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])[CH3:44])[CH3:39])([CH3:34])[O:30][C:31]=12
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCCC(C)CCCC(C)CCCC(C)C)O2
Agent: C/C(=C\CCl)CCC[C@H](C)CCC[C@H](C)CCCC(C)C
Agent: [Zn]
Solvent: Cc1ccncc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Yield: 84.7 %

Procedure:
2.283 g of TMHQ and 0.236 g of metallic zinc powder were suspended in 11.8 ml of ligroin in an atmosphere of nitrogen. A solution of 4.943 g of phytyl chloride [purity 95.7%] in 7.9 ml of ligroin was dripped into said suspension under agitation and refluxed for a period of 2 hours 15 minutes. The suspension was heated and subjected to reflux for another 3 hours to obtain a reaction mixture of dl-α-tocopherol. 11.5 ml of acetic anhydride and 0.218 g of γ-picoline were added to the reaction mixture, which was then refluxed for 5 hours, to obtain 7.118 g of dl-α-tocopheryl acetate which reflected a pale yellow coloring. The absorbance of this dl-α-tocopheryl acetate was determined to be E415 mμ40%EtOH =0.098. Estimation of the dl-α-tocopheryl acetate by high pressure liquid chromatography with the use of n-nonane as the standard substance indicated that its purity was 84.4% and the yield was 84.7%.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[N:16]2[C:17](=[O:23])[NH:18][C:19]3=[CH:20][CH:21]=[CH:22][C:14](=[C:15]23)[O:13][CH2:12]1)[CH3:10]>C(#N)C.C(O)(=O)C>[Br:1][C:22]1[C:14]2[O:13][CH2:12][C:11]([CH2:9][CH3:10])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[N:16]3[C:17](=[O:23])[NH:18][C:19]([C:15]=23)=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Solvent: CC(=O)O
Solvent: CC#N
Product: CCC1(c2ccccn2)COc2c(Br)ccc3[nH]c(=O)n1c23
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48.6 %

Procedure:
N-Bromosuccinimide (70 mg, 0.4 mmol) was added to a solution of 4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (80 mg, 0.4 mmol) in acetonitrile (5 mL) and acetic acid (10 mL) cooled to 0° C. The reaction was stirred for 30 min, was concentrated to remove residual acetic acid, and the resulting residue was dissolved in ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 7-bromo-4-ethyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one (0.07 g. 80%). LCMS calculated for C16H15BrN3O2 (M+H)+: m/z=360.1, 362.1. found: 359.8, 361.8.
Reaction SMILES: [CH:1]1([N:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]([CH3:18])[CH2:9]2)[C:5](=[O:7])[CH3:6])[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:1]1([N:4]([CH:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([C:25](=[O:26])[C:24]3[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)[CH:10]([CH3:18])[CH2:9]2)[C:5](=[O:7])[CH3:6])[CH2:2][CH2:3]1
Reactant: CC(=O)N(C1CC1)C1CC(C)Nc2ccccc21
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)N2c3ccccc3C(N(C(C)=O)C3CC3)CC2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To the solution of N-cyclopropyl-N-(2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)-acetamide (82 mg, 0.34 mmol) in DCM (5 mL) was added 4-methoxybenzoyl chloride (68 mg, 0.40 mmol), followed by DIPEA (104 mg, 0.80 mmol). The reaction mixture was stirred at r.t. overnight. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate. The reaction mixture was washed with sat. sodium bicarbonate and brine. The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography (hexanes-ethyl acetate) to afford only the cis isomer as a slightly yellow solid product (81 mg, 68%). The mixture of two enantiomers was purified by chiral HPLC using the OD column and the two enatiomers were obtained:
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]3[C:7]=2[C:8](Cl)=[N:9][C:10]([Cl:20])=[N:11]3)[CH2:4][CH2:3][CH2:2]1.[NH3:22]>>[NH2:22][C:8]1[C:7]2[C:12](=[CH:13][C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[C:6]=2[O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[N:11]=[C:10]([Cl:20])[N:9]=1
Reactant: N
Reactant: COc1cc2nc(Cl)nc(Cl)c2c(OC2CCC2)c1OC
Product: COc1cc2nc(Cl)nc(N)c2c(OC2CCC2)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
5-Cyclobutyloxy-2,4-dichloro-6,7-dimethoxyquinazoline (300 mg, 0.0009 mol) was suspended in a saturated ethanolic ammonia solution (10 ml) and the reaction stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, resuspended in a minimum volume of diethyl ether and the resulting solid filtered off. Drying under suction gave the subtitle compound as a white solid (189 mg, 68%). Rf 0.69 (diethyl ether). 1H-NMR (CDCl3): δ=1.56 (1H, m), 1.82 (1H, m), 2.26 (2H, m), 2.42 (2H, m), 3.85 (3H, s), 3.94 (3H, s), 4.92 (1H, m), 5.82 (1H, bs), 6.94 (1H, s), 7.72 (1H, bs).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:23])([CH3:22])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH:29]([CH3:30])[C:28](=O)[CH:27]=[C:26]([O:32]C)[CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][Mg]I>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:22])([CH3:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:12]=[CH:11][C:10]=1[CH:24]1[CH2:25][C:26](=[O:32])[CH:27]=[C:28]([CH3:34])[CH:29]1[CH3:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCC(C)(C)c1ccc(C2CC(OC)=CC(=O)C2C)c(OCc2ccccc2)c1
Reactant: C[Mg]I
Product: CCCCCCC(C)(C)c1ccc(C2CC(=O)C=C(C)C2C)c(OCc2ccccc2)c1

Procedure:
Following the procedure of Example 1, 5-[2-benzyloxy-4-(1,1-dimethylheptyl)phenyl]-3-methoxy-6-methyl-2-cyclohexen-1-one is reacted via the Grignard reaction with methyl magnesium iodide to give the title compound.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][CH:7]=1.[S:10]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]#[N:20])(=[O:17])=[O:16])=[CH:11]1>>[CH3:1][S:2][C:3]1[S:4][C:5](/[CH:8]=[C:18](/[S:15]([C:12]2[CH:13]=[CH:14][S:10][CH:11]=2)(=[O:17])=[O:16])\[C:19]#[N:20])=[CH:6][CH:7]=1
Reactant: N#CCS(=O)(=O)c1ccsc1
Reactant: CSc1ccc(C=O)s1
Product: CSc1ccc(/C=C(\C#N)S(=O)(=O)c2ccsc2)s1

Procedure:
Reaction of 2-methylmercaptothiophen-5-carboxaldehyde and thien-3-ylsulfonylacetonitrile as in Example 1 gave (E)-3-(2-methylmercaptothien-5-yl)-2-(thien-3-ylsulfonyl)acrylonitrile
Reaction SMILES: [N:1]1[N:9]2[C:4]([N:5]=[C:6]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:7]3=[C:8]2[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][CH2:25][Cl:26].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:26][CH2:25][CH2:24][CH2:23][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:8]2[N:9]3[C:4]([N:5]=[C:6]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:7]=24)=[CH:3][CH:2]=[N:1]3)=[CH:15][CH:14]=1
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 18.3 %

Procedure:
To a solution of 4-(6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]inden-10-yl)-phenol (60 mg, 0.2 mmol) in DMF (1 mL) was added 1-bromo-3-chloropropane (67 mg, 0.4 mol) and K2CO3 (45 mg, 0.3 mmol). The mixture was stirred at 80° C. for 5 hours, then cooled, diluted with EtOAc (3 mL) and washed with H2O. The organic layer was washed with brine, dried over MgSO4, and concentrated. The residue was purified via preparative LCMS to give 10-[4-(3-chloro-propoxy)-phenyl]-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene (13 mg, 32% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH3:10][C:11]1([CH3:23])[CH2:16][NH:15][CH2:14][CH2:13][N:12]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCN(C(C)C)C(C)C>CC#N>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([N:15]2[CH2:14][CH2:13][N:12]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]([CH3:23])([CH3:10])[CH2:16]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1nccc(I)c1Cl
Reactant: CC1(C)CNCCN1c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(c2ccnc(Cl)c2Cl)CCN1c1ccccc1
Temperature: 100 °C

Procedure:
A mixture of D10 (1.083 g, 3.955 mmol), 2,2-dimethyl-1-phenylpiperazine (0.903 g, 4.745 mmol) [C.A.S. 2946-75-0] and DIPEA (1.378 ml, 7.909 mmol) in CH3CN (15 ml) was heated in a sealed tube at 100° C. for 5 days. After cooling, the solvent was concentrated in vacuo. The residue was purified by column chromatography (silica gel; Heptane/EtOAc 100/10 to 80/20 as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate D55 (0.56 g, 42%).