Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2Cl)(=[O:4])[CH3:3].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][O:26][C:27]1[C:28]([CH3:34])=[CH:29][C:30]([NH2:33])=[CH:31][CH:32]=1>>[C:2]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[N:12]=[CH:11][N:10]=[C:9]2[NH:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][CH2:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[C:28]([CH3:34])[CH:29]=1)(=[O:4])[CH3:3]
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Reactant: Cc1cc(N)ccc1OCc1ccccn1
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(OCc4ccccn4)c(C)c3)c2cc1OC(C)=O
Yield: 60 %

Procedure:
Using an analogous procedure to that described in Example 1, 6-acetoxy-4-chloro-7-methoxyquinazoline, hydrochloride salt, was reacted with 5-amino-2-tolyl 2-pyridylmethyl ether to give 6-acetoxy-7-methoxy-4-[3-methyl-4-(2-pyridylmethoxy)anilino]quinazoline in 60% yield;
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[C:11](Cl)=[N:12][CH:13]=[C:14]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:15]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:11]1[C:10]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:15][C:14]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:13][N:12]=1
Reactant: Clc1ncc(Cn2ccnc2)cc1Br
Reactant: OB(O)c1ccco1
Product: c1coc(-c2cc(Cn3ccnc3)cnc2-c2ccco2)c1

Procedure:
Synthesized using 2-furanylboronic acid (123 mg, 1.10 mmol) and 6 (150 mg, 0.55 mmol) according to Method C. Yellow solid. Yield: 108 mg, 0.37 mmol, 67%. 1H NMR (500 MHz, CDCl3): δH (ppm): 5.19 (s, 2H), 6.26 (dd, J=3.5, 0.6 Hz, 1H), 6.41 (dd, J=3.5, 0.9 Hz, 1H), 6.41-6.48 (m, 2H), 6.93 (t, J=1.3 Hz, 1H), 7.12 (bs, 1H), 7.49-7.50 (m, 2H), 7.60 (bs, 1H), 7.61 (d, J=2.2 Hz, 1H), 8.50 (d, J=2.2 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=47.9, 110.0, 111.6, 111.7, 111.7, 119.0, 124.8, 130.0, 130.4, 136.0, 137.3, 142.8, 143.3, 146.8, 147.4, 149.9, 151.7; MS (ESI): m/z=292.09 [M+H]+.
Reaction SMILES: [Cl-].[Li+].C([Mg]Cl)(C)C.[S:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]1)(=[O:16])[CH2:14][CH3:15]>C1COCC1>[OH:16][C:13]([C@H:17]1[CH2:22][CH2:21][C@H:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]1)([C:9]1[S:8][CH:12]=[CH:11][N:10]=1)[CH2:14][CH3:15]
Reactant: c1cscn1
Reactant: CCC(=O)[C@H]1CC[C@H](C(=O)OC)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(O)(c1nccs1)[C@H]1CC[C@H](C(=O)OC)CC1
Reaction time: 0.5 h

Procedure:
Isopropyl magnesium chloride lithium chloride (1.3 M in THF, 6.66 mL, 8.66 mmol) was added drop-wise to a solution of thiazole (0.675 mL, 9.44 mmol) in THF (5 mL) at 0° C. The reaction was stirred for 30 minutes and the ice bath was removed. Stirring was then continued for 10 minutes before the reaction was re-cooled in an acetone/dry ice bath, then a solution of methyl trans-4-propanoylcyclohexanecarboxylate (1.56 g, 7.87 mmol) in THF (15 mL) was transferred in via cannula. The reaction was stirred for 1 hour and the cooling bath was removed. Once warming was complete (˜1 hour) the reaction was diluted with saturated aqueous ammonium chloride (75 mL) and the resulting biphasic mixture was transferred to a separatory funnel. The organic phase was diluted with ethyl acetate (125 mL). The organic phase was separated, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes) to afford trans-methyl 4-[1-hydroxy-1-(1,3-thiazol-2-yl)propyl]cyclohexanecarboxylate. MS ESI calc'd. for C14H22NO3S [M+H]+ 284. found 284. 1H NMR (500 MHz, DMSO-d6) δ 7.70 (d, J=3.3 Hz, 1H), 7.49 (d, J=3.3 Hz, 1H), 3.53 (s, 3H), 2.07 (t, J=12.1 Hz, 1H), 1.95-1.63 (m, 4H), 1.44-1.06 (m, 6H), 1.01-0.81 (m, 2H), 0.65 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]1(=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH2:12]([NH:19][C:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: O=C1CCCc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C1=C(NCc2ccccc2)CCc2ccccc21

Procedure:
A mixture containing 171 mmol of-tetralone, 181 mmol of benzylamine and 100 mg of p-toluenesulfonic acid is brought to reflux with azeotropic distillation of the water/toluene mixture. After 2 hours of distillation, the medium is cooled and filtered. The expected product is obtained in the form of an oil after evaporation of the solvent.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O)([CH3:17])([CH3:16])[CH3:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>ClCCl.C(O)(=O)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:19]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1ccc(C=O)cc1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1C(C)(C)C
Temperature: 20 °C
Reaction time: 12 h

Procedure:
The synthesis is carried out in argon condition. 2 g (10.7 mmol) of N-Boc-piperazine and 2.06 g (10.7 mmol) of 3-tert-butyl-4-methoxybenzaldehyde are mixed in 30 ml of dry dichloromethane. After dissolution 2 drops of acetic acid is added, then 4.24 g (20 mmol) of NaBH(OAc)3 is added and the mixture is stirred for 12 h at 20° C. Then 20 ml of 5% NaHCO3 aqueous solution is added dropwise with care to the reaction mixture. The organic layer is separated, washed with 5% Na2CO3 solution, dried over sodium sulfate, filtered off and concentrated in vacuum at 50÷80° C. The residue (3.5 g of yellow oil) is used on the next step.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[CH2:22]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(NCCCC)CCC>>[CH2:22]([N:30]1[CH2:31][CH2:32][N:33]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:13]=[C:14]4[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]4[CH:21]=3)=[CH:8][CH:7]=2)[CH2:34][CH2:35]1)[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: c1ccc(CCN2CCNCC2)cc1
Reactant: Cc1cccn2cc(-c3ccc(OCCCCl)cc3)nc12
Solvent: CCCCNCCCC
Product: Cc1cccn2cc(-c3ccc(OCCCN4CCN(CCc5ccccc5)CC4)cc3)nc12

Procedure:
This compound was prepared according to the procedure described in Example 1 of U.S. Pat. No. 4,727,145. using 2-(4-chloropropoxyphenyl)-8-methylimidazo[1,2-a]pyridine and N-phenethylpiperazine instead of 2-(4-chloropropoxyphenyl)-imidazo[1,2-a]pyridine and dibutylamine respectively.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[OH-].[Na+].[CH3:15][C:16]([CH3:18])=[O:17].Cl>CCCCCCC.C(O)(C)C.O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:15][C:16](=[O:17])[CH:18]=[CH:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCCCCCC
Solvent: O
Product: O=C(C=Cc1ccc(C(F)(F)F)cc1)C=Cc1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A solution of 4-trifluoromethylbenzaldehyde (64.2 g; 0.369 mol) in heptane (70 ml) is stirred under a nitrogen atmosphere, then sodium hydroxide (15 g; 10% aq), water (30 g), and bis(2-hydroxyethyl)tallowamine N-oxide (6 g) are added. Next a solution of acetone (10.7 g; 0.184 mol) in heptane (30 ml) is added at 25° C. to 35° C. over a period of two hours. The resulting slurry is then stirred for two hours at 25° C. to 30° C. Concentrated hydrochloric acid (9.4 ml) and isopropyl alcohol (48 ml) are then added and the mixture heated at reflux for 1.5 hours, and is then cooled to 20° C. The solid is filtered, washed with heptane (40 ml) and water, and is dried to afford 54.5 g of 99.9% pure title product (yield: 79.1%), mp 153° C. to 155° C.
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)=[O:10])=[N+]=[N-].C(N(CC)CC)C.S>O1CCCC1>[NH2:1][C:4]1[CH2:5][C@@H:6]2[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[N:7]2[C:8]=1[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=1)=[O:10]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N=[N+]=[N-])C[C@H]12
Agent: S
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N)C[C@H]12
Reaction time: 0.25 h

Procedure:
A solution of p-nitrobenzyl (5R,6S)-2-azido-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (37 mg, 0.1 mmol) and triethylamine (14 μl, 0.1 mmol) in anhydrous tetrahydrofuran (2 ml) is cooled in an ice-bath while hydrogen sulfide is gently bubbled in over 15 minutes. After an additional 15 minutes at 0°, the solution is evaporated under vacuum and the residue is purified by preparative layer chromatography on silica gel to afford p-nitrobenzyl (5R,6S)-2-amino-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:11]2=[CH:12][CH:13]=[CH:14][C:15]3[C:16]([CH3:22])([CH3:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:7]5[C:8]=4[N:9]([C:10]=32)[C:4]2[C:5](=[CH:25][CH:26]=[CH:27][C:3]1=2)[C:6]5([CH3:24])[CH3:23].[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:29][C:19]1[CH:20]=[C:7]2[C:6]([CH3:24])([CH3:23])[C:5]3[CH:25]=[CH:26][CH:27]=[C:3]4[C:2]([CH3:28])([CH3:1])[C:11]5[C:10]6[N:9]([C:4]=34)[C:8]2=[C:17]([C:16]([CH3:21])([CH3:22])[C:15]=6[CH:14]=[CH:13][CH:12]=5)[CH:18]=1
Reactant: CC1(C)c2cccc3c2N2c4c1cccc4C(C)(C)c1cccc(c12)C3(C)C
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC1(C)c2cccc3c2N2c4c1cccc4C(C)(C)c1cc(Br)cc(c12)C3(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of 4,4,8,8,12,12-hexamethyl-8,12-dihydro-4H-benzo[1,9]quinolizino[3,4,5,6,7-defg]acridine (5 g, 13.68 mmol) in CHCl3 (133 mL) at 0° C. was added N-bromosuccinimide (2.44 g, 13.68 mmol) over a period of 20 min. While warming up to room temperature, the resulting solution was stirred in the absence of light overnight. The reaction was quenched with a saturated aqueous solution of Na2S2O3. The resulting mixture was extracted with CH2Cl2 (3×) and the combined organic fractions were dried with MgSO4. After filtration and evaporation of the solvent, the residue was subjected to column chromatography (silica, n-hexane/CH2Cl2 4:1). Final recrystallization from ethanol yielded 2-bromo-4,4,8,8,12,12-hexamethyl-8,12-dihydro-4H-benzo[1,9]quinolizino[3,4,5,6,7-defg]acridine as a white powder (5.6 g, 92%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:47]3[CH2:46][CH2:45][N:44]([CH2:43][CH2:42][O:41][CH2:40][CH2:39][OH:38])[CH2:49][CH2:48]3)=[O:36])[C@@:16]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: OCCOCCN1CCNCC1
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCOCCO)CC1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 1-[2-(2-hydroxyethoxy)-ethyl]-piperazine (Aldrich) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C36H46N6O4Cl2 [(M+H)+] 697.3031, observed 697.3026.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([CH3:13])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1.C(=O)([O-])[O-:19].[Na+].[Na+].C(O)C>O>[OH:19][CH2:2][C:3]1[C:12]([CH3:13])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:16][CH3:17])=[C:8]([O:14][CH3:15])[CH:9]=2)[N:4]=1
Reactant: COc1cc2nc(C)c(CBr)nc2cc1OC
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cc2nc(C)c(CO)nc2cc1OC

Procedure:
8.9 g (30 mmols) of 2-(bromomethyl)-6,7-dimethoxy-3-methyl-quinoxaline are suspended in a mixture of 158 g (1.5 mols) of sodium carbonate, 350 ml of water and 100 ml of ethanol. The suspension is boiled under reflux for four hours. 300 ml of water are then added and the resulting mixture is extracted with three times 120 ml of chloroform. The organic phase is dried over magnesium sulphate. The solvent is evaporated in vacuo. The solid residue is recrystallised from methanol. This gives 3.5 g (50%) of a white powder. Melting point: 176° to 177° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)\[CH:11](C(OC1C(C(C)C)CCC(C)C1)C([O-])=O)[C:12]([CH3:15])([CH3:14])[CH3:13].[OH-:36].[K+]>C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N:31]1[CH:35]=[N:34][CH:33]=[N:32]1)\[CH:11]([OH:36])[C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: [OH-]
Reactant: CC1CCC(C(C)C)C(OC(C(=O)[O-])C(/C(=C\c2ccc(Cl)cc2Cl)n2cncn2)C(C)(C)C)C1
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)C(O)/C(=C\c1ccc(Cl)cc1Cl)n1cncn1
Yield: 68.5 %

Procedure:
Similarly, 0.7 g of (+)-[(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-yl]-(-)-menthoxyacetate was treated with 20 cc of a 90% aqueous ethanol solution containing 0.1 g of potassium hydroxide and the resulting crude crystals were recrystallized from a carbon tetrachloride-n-hexane mixture to obtain 0.3 g of (+)-(E)-1-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-yl)-4,4-dimethyl-1-penten-3-ol: [α]D24 +26.0 (c=1.0, CHCl3); melting point 160°-161° C.
Reaction SMILES: [SH:1][CH:2]([CH2:8][SH:9])[CH2:3][S:4]([O-:7])(=[O:6])=[O:5].[Na+].Cl>>[SH:1][CH:2]([CH2:8][SH:9])[CH2:3][S:4]([OH:7])(=[O:6])=[O:5]
Reactant: O=S(=O)([O-])CC(S)CS
Agent: Cl
Agent: [Na+]
Product: O=S(=O)(O)CC(S)CS

Procedure:
prepared from sodium 2,3-dimercaptopropanesulfonate (Aldrich, 95%) by neutralization with HCl or treatment with an acid ion-exchange resin, e.g. DOWEX™ MSC-1.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1.C(Cl)Cl.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH3:20][S:21]([O:1][CH2:2][C:3]1([C:8]#[N:9])[CH2:6][C:5](=[CH2:7])[CH2:4]1)(=[O:23])=[O:22]
Reactant: C=C1CC(C#N)(CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C1CC(C#N)(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1-(hydroxymethyl)-3-methylenecyclobutanecarbonitrile (0.756 g, 0.00614 mol) in methylene chloride (20 mL, 0.3 mol) was added triethylamine (1.28 mL, 0.00921 mol) followed by methanesulfonyl chloride (0.594 mL, 0.00767 mol) at 0° C. The reaction was stirred at rt for 1 h, quenched with water, and extracted with dichloromethane. The combined organic layers were washed with water, brine, and then dried over magnesium sulfate and evaporated to dryness. The residue was used directly in next step.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH:15]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:16]>CO>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:20]3[CH2:21][CH2:22][N:17]([CH:15]=[O:16])[CH2:18][CH2:19]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: O=CN1CCNCC1
Solvent: CO
Product: O=CN1CCN(C[C@H](O)COc2cccc3[nH]ccc23)CC1
Yield: 86 %

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 1-formylpiperazine in 86% yield. mp 106-107°. FDMS m/e=303 (M+ of free base). α[D]589=−1.98 (c=1.0, methanol).
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=1[C:18]([F:21])([F:20])[F:19]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)=[CH:13][C:12]=1[C:18]([F:19])([F:20])[F:21]
Reactant: N#Cc1ccc(F)cn1
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Product: N#Cc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1

Procedure:
The title compound was prepared by a procedure similar to that described for D1 starting from 5-fluoro-2-pyridinecarbonitrile and 4-chloro-3-(trifluoromethyl)phenol. LC-MS (ESI): m/z 299 [M+H]+; 3.59 min (ret time).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].O[C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH3:8])[O:9][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1ccc(O)cc1Cl
Product: COC(=O)[C@H](C)Oc1ccc(C)c(Cl)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the 3-chloro-4-methylphenol instead of the m-cresol and the (R)-methyl 2-hydroxypropanoate instead of the (S)-methyl 2-hydroxypropanoate.
Reaction SMILES: CS([C:5]1[N:9]([CH3:10])[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=1)(=O)=O.[C:15]([NH:18][CH2:19][CH2:20][NH2:21])(=[O:17])[CH3:16].[OH-].[Na+]>O>[CH3:10][N:9]1[C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[N:6]=[C:5]1[NH:21][CH2:20][CH2:19][NH:18][C:15](=[O:17])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2ccccc21
Reactant: CC(=O)NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NCCNc1nc2ccccc2n1C
Yield: 30 %

Procedure:
A mixture of 2-methylsulfonyl-1-methyl-1H-benzimidazole (7.0 g, 0.033 mol) and N-acetylethylenediamine (17.0 g, 0.167 mol) was heated at 120°-125° C. for 8 hours. The mixture was cooled, diluted with H2O, made basic (pH8) with 2.5N NaOH, and filtered. The filtrate was extracted with EtOAc, and the combined extracts were washed with brine, dried, and concentrated to give a yellow solid 2.3 g (30%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[C:9]1=[O:20])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[F:31])[CH2:26]Br.C(=O)([O-])[O-].[K+].[K+]>>[C:1]([O:5][C:6](=[O:21])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:26][C:25]3[CH:28]=[CH:29][C:30]([F:31])=[C:23]([F:22])[CH:24]=3)=[CH:17][CH:18]=2)[C:9]1=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(O)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(OCc3ccc(F)c(F)c3)cc2)C1=O

Procedure:
In an analogous manner to that described in Example 2c), the alkylation of the (S)-[1-(4-hydroxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester [Example 16 a)] with 3,4-difluorobenzylbromide in presence of potassium carbonate yields the title compound as a white solid; MS: m/e=419 (M+H)+.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=[O:9])=CC=1.[N+:13]([CH2:16][C@@H:17]1[CH2:21][C@H:20](CC([O-])=O)[CH:19]=[CH:18]1)([O-:15])=[O:14]>CO>[N+:13]([CH2:16][C@H:17]1[CH2:21][C@@H:20]([OH:9])[CH:19]=[CH:18]1)([O-:15])=[O:14]
Reactant: O=C([O-])C[C@@H]1C=C[C@H](C[N+](=O)[O-])C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=[N+]([O-])C[C@@H]1C=C[C@H](O)C1
Reaction time: 8 h

Procedure:
To a 5 mL round-bottom flask is added at room temperature p-toluenesulphonic acid monohydrate (0.01 g, 0.053 mmol), methanol (8 mL) and (1R-cis)-4-nitromethyl-2-cyclopentene -acetate as prepared in Example 10 (0.20 g, 1.1 mmol) and the resulting solution is stirred overnight. The crude reaction mixture is loaded on a silica column (32 μm-63 μm) and purified by flash chromatography by eluting with 20% ethyl acetate/hexane. The fractions containing the product (Rf=0.3) are combined and are concentrated in vacuo to give (1R-cis)-4-nitromethyl-2-cyclopenten-1-ol as a clear oil which exhibited the following physical data: MS(CI) m/z=126 [C6H8NO2 +, Loss of H2O followed by rapid protonation]; and [α]D20 =+4.8° (c=0.16, CHCl3).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[N:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14]>C1COCC1>[Br:3][C:4]1[CH:5]=[C:6]2[CH:7]=[CH:8][N:9]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[C:10]2=[N:11][CH:12]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.9 %

Procedure:
Sodium hydride (0.63 g, 25.15 mol) was added in small portion to a stirred solution of 5-bromo-7-azaindole (3.3 g, 16.75 mmol) in THF (50 mL) at room temperature and the resulting suspension was stirred at room temperature for 15 min. Triisopropylsilyl chloride (5.3 mL, 25.15 mmol) was added and the mixture was heated at 80° C. for 3 h. The solvent was evaporated and the residue was dissolved in water (50 mL). The aqueous layer was extracted with EtOAc (3×50 mL), dried (Na2SO4) and concentrated under reduced pressure. The crude product was purified by Biotage HPFC system (10% EtOAc/Hexane) to afford the desired 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine as a white solid (5.2 g, 88%); Mass Spec 355 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[CH:22][N:21]=[C:20]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[C:19]=1[N+:35]([O-:37])=[O:36]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[C:19]([N+:35]([O-:37])=[O:36])=[C:20]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)[N:21]=[CH:22][N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(Cl)c2[N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester (3.03 mmol, 610 mg) and sodium hydride (10.6 mmol, 255 mg) were dissolved in dry THF (20 mL) and stirred for 30 minutes at room temperature. Then, (6-chloro-5-nitro-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (3.03 mmol, 1.0 g) was added. The reaction was stirred at room temperature for 30 minutes. Its progress was monitored by thin layer chromatography and LCMS. Sodium hydride was quenched with water and the desired compound was extracted in ethyl acetate. Organic solvents were evaporated in vacuo. Flash chromatography (Silica gel 60; 30/70 EtOAc/Hexanes) provided Compound A1 as a yellow solid (1.2 g, 68%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.10 (s, 1H), 8.33 (s, 1H), 7.90 (d, 2H), 7.79 (d, 2H), 5.51 (heptet, 1H), 3.58 (m, 2H), 3.46 (m, 2H), 2.97 (s, 3H), 1.84 (m, 4H), 1.36 (s, 9H). LCMS (ESI), m/z 494.4 (M+H+, 100%).