Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:25]/[O:26][C:27]2([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:29][CH2:28]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][OH:24])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:25]/[O:26][C:27]2([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:28][CH2:29]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][O:24][S:47]([CH3:46])(=[O:49])=[O:48])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CO)cs1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2COS(C)(=O)=O)cs1
Reaction time: 2 h

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2S,3S)-2-(hydroxymethyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (1 g, 1.57 mmol) at 0° C. in THF (15.7 ml) was added TEA (0.66 ml, 4.7 mmol) and MsCl (25 μl, 0.32 mmol). After 2 h, the reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo, affording the title compound (assumed quantitative). LCMS: R=0.99 min, m/z=714.1 (M+1), Method 2m_acidic.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[C-:13]#[N:14].[Na+]>C(O)C>[N:9]1[C:10]2[C:5](=[CH:4][C:3]([CH2:2][C:13]#[N:14])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: BrCc1ccc2ncccc2c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCO
Product: N#CCc1ccc2ncccc2c1
Temperature: 50 °C
Yield: 18.3 %

Procedure:
To a solution of crude 6-bromomethylquinoline (1.8 g) in 95% ethanol (30 mL) was added NaCN (2.0 g, 40.8 mmol) at room temperature. The mixture was heated at 50° C. for 3 hours and then concentrated under vacuum. Water (50 mL) and ethyl acetate (50 mL) were added. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with brine, dried over Na2SO4 and concentrated under vacuum. The combined crude product was purified by column (Petroleum Ether/EtOAc 5:1) to give 2-(quinolin-6-yl)acetonitrile (0.25 g, 8% over two steps). 1H NMR (300 MHz, CDCl3) δ 8.95 (dd, J=1.5, 4.2 Hz, 1 H), 8.12-8.19 (m, 2 H), 7.85 (s, 1 H), 7.62 (dd, J=2.1, 8.7 Hz, 1 H), 7.46 (q, J=4.2 Hz, 1 H), 3.96 (s, 2 H). MS (ESI) m/e (M+H)+ 169.0.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:17]3[N:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=[N:20][C:16]=3[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:25])=[CH:4][CH:3]=1.[NH2:26][CH:27]([CH3:30])[CH2:28][OH:29]>O>[OH:29][CH2:28][CH:27]([NH:26][C:2]1[N:7]=[CH:6][C:5]([N:8]2[C:17]3[N:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]4=[N:20][C:16]=3[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:25])=[CH:4][CH:3]=1)[CH3:30]
Reactant: CC(N)CO
Reactant: O=c1c2ccccc2c2nc3ccccn3c2n1-c1ccc(Br)nc1
Solvent: O
Product: CC(CO)Nc1ccc(-n2c(=O)c3ccccc3c3nc4ccccn4c32)cn1
Temperature: 180 °C
Reaction time: 0.83 h
Yield: 67 %

Procedure:
A mixture of compound 21 (1.0 equiv., 0.583 mmol, 0.228 g) and 2-amino-1-propanol (1.5 ml) was stirred for 50 min under microwave irradiation (microwave settings: temperature=180° C., maximum pressure=17 bar, maximum power=200 W). The reaction mixture was mixed with water (10 ml) and stirred at room temperature for 5 min. The resulting precipitate was filtered off and subsequently washed with water and tetrahydrofuran to afford 6-[6-[(2-hydroxy-1-methyl-ethyl)amino]-pyridin-3-yl]-pyrido[2′,1′:2,3]imidazo[4,5-c]isoquinolin-5(6H)-one (I11) (0.150 g, yield=67%, purity (LC)=96%).
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42](=O)[CH2:43][C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]=[CH:46][CH:45]=1.C(N(CC)CC)C>ClCCCl>[N:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]#[C:43][C:44]1[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]=[CH:46][CH:45]=1
Reactant: O=C(Cc1ccnc2ccccc12)c1ccccn1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: C(#Cc1ccnc2ccccc12)c1ccccn1
Yield: 43.4 %

Procedure:
A mixture of triphenyphosphine oxide (5.56 g, 10 mmol) in 1,2-dichloroethane (30 mL) is cooled in an ice bath. Trifluoromethanesulfonic anhydride (1.57 mL, 10 mmol) is added dropwise over 15 min. To this mixture is added a solution of 1-(2-pyridyl)-2-(4-quinolyl)ethan-1-one (2.5 g, 10 mmol) in 1,2-dichloroethane (10 mL) and triethylamine (2.84 mL, 20 mmol). The ice bath is removed and the mixture heated at reflux for 16 h. The mixture is diluted with dichloromethane (100 mL) and washed with water (3×100 mL), dried (magnesium sulfate), filtered, concentrated in vacuo, and chromatographed on SiO2 (0 to 100% hexane in ethyl acetate) to yield 1 g of title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]([N:5]([CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([OH:19])=[CH:14][CH:15]=2)[CH2:10]1)[CH2:6][CH2:7][CH3:8])=[O:4].[CH3:22][C:23](C)([O-])C.[K+].C(I)C>CS(C)=O>[CH2:22]([O:19][C:13]1[CH:12]=[C:11]2[C:16]([CH2:17][CH2:18][CH:9]([N:5]([CH2:6][CH2:7][CH3:8])[C:3](=[O:4])[C:2]([F:20])([F:21])[F:1])[CH2:10]2)=[CH:15][CH:14]=1)[CH3:23]
Reactant: CC(C)(C)[O-]
Reactant: CCCN(C(=O)C(F)(F)F)C1CCc2ccc(O)cc2C1
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCI
Product: CCCN(C(=O)C(F)(F)F)C1CCc2ccc(OCC)cc2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
To a solution of 2,2,2-trifluoro-N-(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-N-propyl-acetamide (1.0 g, 3.32 mmol) in DMSO (30 mL) under an inert atmosphere was added a slurry of potassium t-butoxide (392 mg, 3.49 mmol, 1.05 eq.) in DMSO (10 mL). The reaction was stirred at room temperature for 30 min. and then ethyl iodide (0.32 mL, 3.98 mmol, 1.2 eq.) was added dropwise. The reaction mixture was stirred for 2 h, quenched with water, and extracted with EtOAc (2×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated onto silica gel (10 g). This was placed on top of a flash column and eluted with 20% acetone in hexanes to afford N-(7-ethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-2,2,2-trifluoro-N-propyl-acetamide as an oil (660 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1.Cl.Cl[CH2:24][C:25]1[N:26]=[C:27]([CH3:30])[S:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C(=O)C>O>[CH3:30][C:27]1[S:28][CH:29]=[C:25]([CH2:24][N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[C:2]2[NH:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]2)[N:26]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2csc(C)n2)CC1
Temperature: 70 °C
Reaction time: 8 h
Yield: 37.5 %

Procedure:
A mixture of 2.9 parts of ethyl 4-[(1H-benzimidazol-2-yl)amino]-1-piperidinecarboxylate, 1.8 parts of 4-(chloromethyl)-2-methylthiazole monohydrochloride, 2.12 pans of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 70° C. The reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated and the residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 1.5 parts (37.5%) of ethyl 4-[[1-[(2-methyl-4-thiazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate; mp. 160° C. (comp. 12).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:3]1.N1C=CN=C1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)C>[Si:21]([O:1][CH:2]1[CH2:3][CH2:4][CH:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:6][CH2:7]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)C1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C1CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2.00 g (11.38 mmol) of the crude product from Example 8A (90% pure) are dissolved in 50 ml of dry DMF, and 1.47 g (21.62 mmol) of imidazole and 2.40 g (15.93 mmol) of tert-butyldimethyl-silyl chloride are added. The reaction mixture is stirred at RT for 20 h. 40 ml each of diethyl ether and of saturated aqueous sodium bicarbonate solution are then added to the mixture. After phase separation, the organic phase is dried over magnesium sulfate and the solvent is removed on a rotary evaporator. The crude product is used in the next reaction without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:6][CH2:5][C:4](=[O:19])[NH:3]1.[H-].[Na+].Cl[CH:23]([OH:25])[CH3:24]>CN(C=O)C.O>[OH:25][CH2:23][CH2:24][N:3]1[C:4](=[O:19])[CH2:5][CH2:6][CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[C:2]1=[O:1]
Reactant: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1
Reactant: CC(O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3ccccc3C2=O)C(=O)N1CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(2,6-Dioxopiperidin-3-yl)isoindoline-1,3-dione (2.5 g) was dissolved in DMF (dry, 60 mL). 95% NaH (0.24 g) was added. The mixture was stirred for 30 minutes at room temperature. Then, chioroethanol (0.68 mL) was added, and the mixture was stirred over night at room temperature. The reaction mixture was diluted with 300 mL of water and extracted with ethyl acetate (3×60 mL). Organic phases were combined and washed twice with water, and once with brine, then dried over anhydrous magnesium sulfate. Rotary evaporation of solvent yielded crude product, which was purified by silica gel column chromatography (acetic ether: petroleum ether=1:1) to yield 1.1 g of pure title product. 1H NMR (CDCl3, ppm) δ 7.88-7.90 (m, 2H), 7.77-7.79 (m, 2H), 5.06 (dd, 1H, J=5.6, 12.4Hz), 4.02-4.12 (m, 2H), 3.76-3.80 (m, 2H), 2.94-3.02 (m, 1H), 2.72-2.90 (m, 2H), 2.29-2.31 (m, 1H), 2.14-2.23 (m, 1H).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[CH:21][CH:20]=1
Reactant: Fc1ccc(CCl)cc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Fc1ccc(CN2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h
Yield: 94 %

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (29.9 g) was dissolved in chloroform (150 ml), triethylamine (32 ml) and p-fluorobenzyl chloride (27.5 ml) were successively added under ice-cooling, and the mixture was stirred overnight. The reaction solution was successively washed with a 20% aqueous solution of sodium hydroxide (150 ml×2) and water (150 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (chloroform:methanol=10:1) to give the title compound (49.4g) as a yellow oily substance. Yield=94%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24]OS(C)(=O)=O)[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:30]1([C:36]2([OH:42])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:23][CH2:24][N:39]2[CH2:40][CH2:41][C:36]([OH:42])([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:37][CH2:38]2)[CH2:10][C:11]([N:13]([CH3:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: COc1ccc(N(C)C(=O)CC(CCOS(C)(=O)=O)c2ccc(Cl)c(Cl)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C)C(=O)CC(CCN2CCC(O)(c3ccccc3)CC2)c2ccc(Cl)c(Cl)c2)cc1
Temperature: 60 °C
Yield: 12.4 %

Procedure:
3,4-Dichloro-beta-(2-methanesulfonyloxyethyl)-N-methyl-N-(4-methoxyphenyl)benzene propanamide (4.2 g) in DMF (20 mL) was treated with 4-phenyl-4-hydroxypiperidine (1.53 g) and K2CO3 (1.19 g). The mixture was heated at 60° C. for 18 hours. The cooled reaction mixture was diluted the EtOAc (200 mL) and washed with H2O (3×150 mL). The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to give an oil. Silica gel chromatography eluting with 90:10 (CH2Cl2 :MeOH) gave the title compound (0.58 g). Mass spectrum (CI): 541.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1)(=O)=O.[F-:19].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:19][CH2:6][C@@H:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]1
Reactant: [F-]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](COS(C)(=O)=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)OC(=O)N1CC[C@@H](CF)C1

Procedure:
Tetrabutylammonium fluoride (1M solution in THF, 530 mL) was added to (R)-tert-butyl 3-(((methylsulfonyl)oxy)methyl)pyrrolidine-1-carboxylate (30 g from previous step) and the resulting mixture was refluxed overnight. After cooling, the solvent was removed and the residue was partitioned between 10% aqueous citric acid and dichloromethane. The organic layer was washed with water, dried over sodium sulfate, filtered and the solvent was removed on a rotary evaporator. The residue was purified by flash chromatography on a silica gel column (0 to 50% ethyl acetate/hexanes) to afford 14.3 g of (R)-tert-butyl 3-(fluoromethyl)pyrrolidine-1-carboxylate as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 4.49-4.41 (m, 1H), 4.37-4.29 (m, 1H), 3.40-3.28 (m, 2H), 3.24-3.18 (m, 1H), 3.02-2.98 (m, 1H), 2.58-2.52 (m, 1H), 1.95-1.88 (m, 1H), 1.67-1.54 (m, 1H), 1.38 (s, 9H).
Reaction SMILES: [Cl:1][C:2]([Cl:28])([Cl:27])[CH2:3][O:4][C:5](=[O:26])[CH:6]([S:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=1.[C:29]1([C:35]2[O:36][C:37]([C:43]([F:46])([F:45])[F:44])=[C:38]([C:40](O)=[O:41])[N:39]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(C2OC(C(F)(F)F)=C(COC(=O)C3C=CC(CC(SCCC4C=CC(F)=CC=4)C(OCC(Cl)(Cl)Cl)=O)=CC=3)N=2)C=CC=CC=1>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][S:16][CH:6]([C:5]([O:4][CH2:3][C:2]([Cl:27])([Cl:1])[Cl:28])=[O:26])[CH2:7][C:8]2[CH:9]=[CH:10][C:11]([CH2:14][O:15][C:40]([C:38]3[N:39]=[C:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:36][C:37]=3[C:43]([F:45])([F:46])[F:44])=[O:41])=[CH:12][CH:13]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: O=C(OCC(Cl)(Cl)Cl)C(Cc1ccc(CO)cc1)SCCc1ccc(F)cc1
Agent: O=C(OCc1nc(-c2ccccc2)oc1C(F)(F)F)c1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1
Product: O=C(OCc1ccc(CC(SCCc2ccc(F)cc2)C(=O)OCC(Cl)(Cl)Cl)cc1)c1nc(-c2ccccc2)oc1C(F)(F)F

Procedure:
The title compound was prepared from 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2 trichloro-ethyl ester (675 mg, 1.45 mmol) and 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (410 mg, 1.59 mmol) in the same manner as described for 4-[2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-2-(2,2,2-trichloro-ethoxy-carbonyl)-ethyl]-benzoic acid 2-phenyl-5-trifluoromethyl-oxazol-4-ylmethylester. The crude product was obtained as an oil which was carried on to the next step without further purification (892 mg, 79.4%). 1H NMR (500 MHz, CDCl3): δ 8.15 (d, 2H), 7.57 (d, 1H), 7.52 (t, 2H), 7.41 (d, 2H), 7.12 (t, 2H), 6.97 (t, 2H), 5.42 (s, 2H), 4.72 (q, 2H), 3.59 (dd, 1H), 3.25 (dd, 1H), 2.78-3.05 (m, 5H). Mass Spectrum: M+H+ 705.89.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][OH:15])[CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:13]([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH:11]2[CH:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C(CO)CC2CC21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(COS(C)(=O)=O)CC2CC21
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an ice-cold solution of 3-Hydroxymethyl-2-azabicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (2.52 grams, 11.83 mmol) in dry dichloromethane (10 mL) was added triethylamine (2.5 mL, 17.75 mmol) followed by methanesulfonyl chloride (1.0 mL, 13.01 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with dichloromethane. Organic layer was washed with saturated sodium bicarbonate solution followed brine, dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure and the crude product was purified by flash column chromatography using 230-400 mesh silica gel to obtain title compound, 3.09 grams as gummy liquid. Yield: 90%.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:13](=[O:14])/[C:12](=[CH:15]/[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)/[C:11](=[CH:28]\[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:10]1=[O:35])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:6]([CH2:8][N:9]1[C:13](=[O:14])/[C:12](=[CH:15]/[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH3:25])=[C:18]([O:26][CH3:27])[CH:17]=2)/[C:11](=[CH:28]\[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)/[C:10]1=[O:35])([OH:7])=[O:5]
Reactant: COc1cc(/C=C2/C(=O)N(CC(=O)OC(C)(C)C)C(=O)/C2=C/c2ccccc2)cc(OC)c1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(/C=C2/C(=O)N(CC(=O)O)C(=O)/C2=C/c2ccccc2)cc(OC)c1OC
Reaction time: 4 h
Yield: 80.9 %

Procedure:
To a solution of (3E,4E)-1-t-butoxycarbonylmethyl -3-benzylidene-4-(3,4,5-trimethoxybenzylidene)-2,5-pyrrolidinedione (3.5 g) obtained in Example 42 in dichloromethane (40 ml) is added trifluoroacetic acid (10 ml) at room temperature, and the mixture is allowed to stand for 4 hours. The mixture is evaporated under reduced pressure to remove the solvent, and to the residue is added trichloromethane. The mixture is washed, dried, and evaporated to remove the solvent. The resulting residue is crystallized from diethyl ether to give (3 E,4E)- 1 -carboxymethyl-3-benzylidene-4-(3,4,5-trimethoxybenzylidene) -2,5-pyrrolidinedione (2.5 g) as yellow prisms.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:19][NH:20][CH3:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:20]([CH3:21])[CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: CNC
Reactant: Clc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1CCC2c1ccc(Cl)cc1
Yield: 47.6 %

Procedure:
A solution of 2,4-dichloro-7-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg, 0.668 mmol) and excess dimethylamine (3.34 mL, 6.68 mmol) in MeOH (4 mL) was stirred at rt for 30 min. The solvent was removed in vacuum and the crude product was purified by column chromatography on silica gel to afford 2-chloro-7-(4-chlorophenyl)-N,N-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (98 mg, 0.318 mmol, 47.6% yield). LC-MS (M+H)+=308.1.
Reaction SMILES: C(Cl)(=O)C(C)(C)C.C(N(CC)CC)C.[C:15]([N:22]([CH3:31])[C@H:23]([C:28]([OH:30])=O)[CH2:24][CH:25]([CH3:27])[CH3:26])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[NH2:32][C@H:33]([C:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36])[CH3:34]>C(Cl)(Cl)Cl>[C:15]([N:22]([CH3:31])[C@H:23]([C:28]([NH:32][C@H:33]([C:35]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36])[CH3:34])=[O:30])[CH2:24][CH:25]([CH3:26])[CH3:27])([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16]
Reactant: C[C@H](N)C(=O)Cc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@@H](C(=O)N[C@@H](C)C(=O)Cc1ccccc1)N(C)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
23.3 ml (18.9 g=157 mMol) pivaloyl chloride and 48 ml (28.9 g=286 mMol) triethylamine are added to a solution of 35 g (143 mMol) BOC-MeLeu-OH in 500 ml chloroform and the mixture stirred for 2 hrs. at room temperature under a nitrogen atmosphere. 30.7 g (171 mMol) H-Ala-Bzl dissolved in 300 ml chloroform are then added and the reaction mixture stirred for a further 2 hrs. at room temperature, again under a nitrogen atmosphere. The product is purified in accordance with the technique of example 1a) to yield the title compound: rotation, [α]D25 =-59.4° (c=1.0 in chloroform).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3C4C(=CC=3S[C:5]=2[CH:4]=[CH:3][CH:2]=1)C=CC(=O)C=4.S1C(B(O)O)=CC2C=CC=CC1=2.I[C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34]>>[CH3:8][C:9]1[CH:5]=[CH:4][C:3]2[C:33](=[O:34])[C:32]3[C:31]([C:2]=2[CH:1]=1)=[CH:39][CH:38]=[CH:37][CH:36]=3
Reactant: O=C(O)c1ccccc1I
Reactant: O=C1C=CC2=Cc3sc4ccccc4c3C2=C1
Agent: OB(O)c1cc2ccccc2s1
Product: Cc1ccc2c(c1)-c1ccccc1C2=O

Procedure:
Benzo[b]indeno[1,2-d]thiophen-9-one: from 2-benzo[b]thiopheneboronic acid and 2-iodobenzoic acid following method A.
Reaction SMILES: [CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([CH3:13])=[CH:6][C:3]=1[CH2:4]Cl.C(O)(=[O:16])C.C1N2CN3CN(C2)CN1C3.Cl>O>[CH3:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([CH3:13])=[CH:6][C:3]=1[CH:4]=[O:16]
Reactant: CC(=O)O
Reactant: Cc1cc(CCl)c(C)c([N+](=O)[O-])c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: Cc1cc(C=O)c(C)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
The mixture constituted by 2,5-dimethyl-3-nitrobenzyl-chloride (A) prepared according to M. J. Winchester and F. D. Popp, J. Het. Chem. 12, p. 547 (1975) (610 g), acetic acid (1280 ml, water (1280 ml) and hexamethylene tetramine (855 g) was heated with reflux under stirring for 2 hours. 1037 ml of concentrated hydrochloric acid were then added in 10 minutes and the mixture was again heated with reflux for 20 minutes. This mixture, cooled to 0° C., gave a solid which was filtered off, dried and recrystallised from cyclohexane (4 liters) to give 290.5 g (53%) of yellow needles corresponding to the aldehyde of formula B, melting point: =90°-93° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.[F:51][C@H]1CCNC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][C@H:24]([F:51])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: F[C@H]1CCNC1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Product: CC(C)(C)c1nc(N2CC[C@H](F)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (S)-3-fluoropyrrolidine hydrochloride and isolated as light-yellow solid (16.5 mg, 90%). MS(m/e): 389.4 (MH+).