Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.Cl[C:8]1[N:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=1>CO.O>[NH2:14][C:10]1[N:11]=[CH:12][N:13]=[C:8]([N:2]2[CH2:5][CH:4]([OH:6])[CH2:3]2)[CH:9]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: OC1CNC1
Agent: Cl
Solvent: CO
Solvent: O
Product: Nc1cc(N2CC(O)C2)ncn1
Yield: 84.6 %

Procedure:
A solution of 3-azetidinol hydrochloride (454 mg, 4.1 mmol) in MeOH and water was loaded onto an Isolute® SCX-2 cartridge that was washed with MeOH and the product eluted with 2M ammonia in MeOH. The relevant fractions were concentrated to dryness under reduced pressure. The resultant residue was then added to a solution of 6-chloro-pyrimidin-4-ylamine (151 mg, 1.16 mmol) in IMS (10 mL) under argon and heated under reflux for 18 hours. The reaction mixture was cooled and then loaded onto an Isolute® SCX-2 column. The column was then washed with MeOH and eluted with 2 M ammonia in MeOH. The relevant fractions were concentrated to dryness under reduced pressure and the resulting residue was purified by flash chromatography (NH2 cartridge, 0-5% MeOH in DCM) to give the desired compound as a white solid (163 mg, 85% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.90 (d, J=1.0 Hz, 1H), 6.18 (s, 2H), 5.65 (d, J=6.5 Hz, 1H), 5.21 (d, J=1.1 Hz, 1H), 4.54-4.53 (m, 1H), 4.07 (dd, J=8.7, 6.7 Hz, 2H), 3.59 (dd, J=8.8, 4.6 Hz, 2H).
Reaction SMILES: C(OC([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[CH3:9])=O)(C)(C)C.C(N(CC)CC)C.F[C:26]1[C:35]([O:36][CH3:37])=[C:34]2[C:29]([C:30](=[O:45])[C:31]([C:42]([OH:44])=[O:43])=[CH:32][N:33]2[C@@H:38]2[CH2:40][C@@H:39]2[F:41])=[CH:28][CH:27]=1>CS(C)=O>[F:41][C@H:39]1[CH2:40][C@H:38]1[N:33]1[C:34]2[C:29](=[CH:28][CH:27]=[C:26]([N:15]3[CH2:16][CH2:17][C@@H:13]([C:10]4([NH:8][CH3:9])[CH2:11][CH2:12]4)[CH2:14]3)[C:35]=2[O:36][CH3:37])[C:30](=[O:45])[C:31]([C:42]([OH:44])=[O:43])=[CH:32]1
Reactant: CN(C(=O)OC(C)(C)C)C1([C@@H]2CCNC2)CC1
Reactant: COc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CNC1([C@@H]2CCN(c3ccc4c(=O)c(C(=O)O)cn([C@@H]5C[C@@H]5F)c4c3OC)C2)CC1
Temperature: 100 °C
Yield: 49.7 %

Procedure:
After adding 3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]pyrrolidine (102 mg, 379 μmol) and triethylamine (0.50 ml) to dried dimethyl sulfoxide (1 ml, 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (112 mg, 379 μmol) was added thereto and stirred while heating in an oil bath of 100° C. for 15 hours under a nitrogen atmosphere. After concentrating the reaction solution under a reduced pressure, the residue was dissolved in chloroform (100 ml). After washing the organic layer with a 10% aqueous citric acid solution (100 ml), the organic layer was dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, and after adding dropwise concentrated hydrochloric acid (2 ml) to the residue while cooling with ice, it was stirred at room temperature for 30 minutes. After adding 1 mol/l hydrochloric acid (2 ml) to the reaction solution and washing the yellow acidic aqueous solution with chloroform (50 ml×4), the pH was adjusted to 12.0 with an aqueous sodium hydroxide solution. After adjusting the pH of the basic aqueous solution to 7.4 with 1 mol/l hydrochloric acid, extraction with chloroform (100 ml×3) was performed. After drying over anhydrous sodium sulfate, the solvent was evapolated under a reduced pressure. The residue thus obtained was then purified by a preparative chromatography (developed into the lower layer of a 7:3:1 mixture of chloroform:methanol:water), purified further by recrystallization from ethanol, and then dried under a reduced pressure. 78.3 mg (50%) of the title compound was thereby obtained in the form of yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[C:15](=[O:16])[CH2:14][CH:13]2[CH2:12][NH:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.Br[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:18]([N:11]1[CH2:10][C:9]2([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:13]([CH2:14][C:15]2=[O:16])[CH2:12]1)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCc1ccccc1
Reactant: COc1cccc(C23CNCC2CC3=O)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cccc(C23CN(CCc4ccccc4)CC2CC3=O)c1

Procedure:
In the manner of Example 9, 5-(m-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-6-one, dimethyl acetal can be reacted with 1-bromo-2-phenylethane and sodium carbonate in toluene to give 3-phenethyl-5-(m-methoxyphenyl)-3-azabicyclo[3.2.0]heptan-6-one, dimethyl acetal.
Reaction SMILES: [CH2:1]([N:8]=[C:9]([C:11]1[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][N:12]=1)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>COCCO.[Ru]>[CH2:1]([N:8]1[C:17](=[O:19])[CH:16]2[CH:11]([NH:12][CH2:13][CH2:14][CH2:15]2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=C(O)c1cccnc1C(O)=NCc1ccccc1
Agent: [Ru]
Solvent: COCCO
Product: O=C1C2CCCNC2C(=O)N1Cc1ccccc1
Yield: 90.1 %

Procedure:
47.6 g (0.2 mol) of pyridine-2,3-dicarboxylic acid N-benzylimide (British Patent 1,086,637; Chem. Abstr. 68, 95695w) are hydrogenated in 400 ml of glycol monomethyl ether over 15 g of ruthenium-on-active charcoal (5% strength) at 90° C. under 100 bar until the calculated amount of hydrogen has been taken up. The catalyst is then filtered off and the filtrate is concentrated on a rotary evaporator. 44 g of an oily crude product are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH3:10])=[C:8]([CH2:11][C:12]3[NH:13][CH:14]=[CH:15][N:16]=3)[S:7][C:6]=2[CH:17]=1.O.[CH3:19][N:20](C)C=O>>[NH:16]1[CH:15]=[CH:14][N:13]=[C:12]1[CH2:11][C:8]1[S:7][C:6]2[CH:17]=[C:2]([C:19]#[N:20])[CH:3]=[CH:4][C:5]=2[C:9]=1[CH3:10]
Reactant: Cc1c(Cc2ncc[nH]2)sc2cc(Br)ccc12
Reactant: CN(C)C=O
Solvent: O
Product: Cc1c(Cc2ncc[nH]2)sc2cc(C#N)ccc12

Procedure:
A mixture of 6-bromo-2-(1-imidazolylmethyl)-3-methylbenzo[b]-thiophene (1.01 g) and cuprous cyanide (1.80 g) in N,N-dimethylformamide (20 ml) was heated under reflux for 22 hours and then cooled and poured into water. The solid was filtered off, washed with water and then suspended in a mixture of concentrated aqueous ammonia solution (100 ml) and ethyl acetate (150 ml) and the mixture was stirred until no solid remained. The organic layer was separated, washed with water, dried (Na2SO4) and evaporated. The residue was crystallised from ethyl acetate/petrol (b.p. 60°-80°) to give 2-(1-imidazolylmethyl)-3-methylbenzo[b]thiophene-6-carbonitrile (0.58 g), m.p. 154°-155°.
Reaction SMILES: [C:1]([NH:3][C:4](=[N:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])[C:19]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:20]=2[N:21]=1)OC1C=CC=CC=1)#[N:2].[NH3:42]>C(O)(C)C>[C:1]([NH:3][C:4]([NH:12][CH2:13][CH2:14][NH:15][C:16]1[N:17]=[C:18]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][C:35]=2[F:41])[C:19]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[F:33])[C:20]=2[N:21]=1)=[NH:42])#[N:2]
Reactant: N#CNC(=NCCNc1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1)Oc1ccccc1
Reactant: N
Solvent: CC(C)O
Product: N#CNC(=N)NCCNc1nc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3ccccc3F)c2n1
Reaction time: 144 h
Yield: 60 %

Procedure:
To a solution of phenyl N-cyano-N′-(2-{[4-(2,4-difluorophenyl)-8-(2-fluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl]amino}-ethyl)imidocarbamate in isopropanol (2 mL) was added a 2M solution of ammonia in isopropanol (2 mL). The mixture was irradiated with microwave at about 60° C. for about 20 min. LC/MS showed a mixture containing approximately 25% product and 75% starting material. The mixture was kept in a sealed tube for 6 days. LC/MS showed 100% product. The solvent was evaporated and the residue was purified to give the title compound (20 mg, 60%). LC-MS m/z 479 (M+H)+, 2.84 min (ret time).
Reaction SMILES: [CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([NH:20][CH2:21][CH2:22][NH:23][CH2:24][CH3:25])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N(OC(ON2C(=O)CCC2=O)=O)[C:49](=[O:50])C1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:8]([CH2:34][CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[CH2:21][CH2:22][N:23]([CH2:24][CH3:25])[C:49]3=[O:50])[CH:18]=2)[NH:13][C:12]=1[C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[CH:27]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCNCCNc1ccc2[nH]c(-c3cc(C)cc(C)c3)c(CCN(CCCCc3ccc([N+](=O)[O-])cc3)Cc3ccccc3)c2c1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN1CCN(c2ccc3[nH]c(-c4cc(C)cc(C)c4)c(CCN(CCCCc4ccc([N+](=O)[O-])cc4)Cc4ccccc4)c3c2)C1=O
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To a solution of N-[3-(2-{benzyl-[4-(4-nitrophenyl)butyl]amino}ethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-N′-ethyl-ethane-1,2-diamine (20 mg in 3 mL dry methylene chloride) at 0° C. was added 9.6 mg N,N′-disuccinimidyl carbonate followed by triethylamine (0.110 mL of a 10% solution in methylene chloride) and the mixture stirred at low temperature. After 30 minutes, the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic portion was washed with saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to provide the crude title compound (21 mg).
Reaction SMILES: [CH:1]1([C:5]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]#[N:24])=[CH:13][CH:12]=3)[C:8]3[CH:25]=[C:26]([C:30]4[N:34]([CH3:35])[C:33]5[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=5[N:31]=4)[CH:27]=[C:28]([CH3:29])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C)C=O>[CH:1]1([C:5]2[N:9]([CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:23]4[NH:42][N:41]=[N:40][N:24]=4)=[CH:13][CH:12]=3)[C:8]3[CH:25]=[C:26]([C:30]4[N:34]([CH3:35])[C:33]5[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=5[N:31]=4)[CH:27]=[C:28]([CH3:29])[C:7]=3[N:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CCC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc3ccccc3n2C)cc2c1nc(C1CCC1)n2Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-cyclobutyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1.CN(C=O)C>O>[C:15]([Si:12]([CH3:14])([CH3:13])[O:9][CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:11][CH:10]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
A mixture of 4-nitrobenzylalcohol (10.0 g), tert-butyl-dimethylsilyl chloride (11.8 g), imidazole (11.2 g) and DMF (50 ml) was stirred at room temperature for 1.5 hours. To the mixture was added water (500 ml), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethyl acetate/hexane=1/7) to give tert-butyldimethyl-4-nitrobenzyloxysilane (17.5 g) as pale yellow oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[C:10]([CH3:19])([CH3:18])[CH2:9]1)=O)(C)(C)C.[ClH:20]>ClCCl.C(OCC)C>[ClH:20].[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C:10]1([CH3:19])[CH3:18])(=[O:15])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCN(S(C)(=O)=O)C(C)(C)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)CNCCN1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a solution of 4-methanesulfonyl-3,3-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (914 mg) in dichloromethane (20 mL) at 0° C. was added dropwise HCl (6.65 mL of a 2 M solution in diethyl ether). The reaction mixture was stirred at room temperature for 2 h. The precipitate formed was then collected by filtration and dried to afford 1-methanesulfonyl-2,2-dimethyl-piperazine hydrochloride salt as a white solid (540 mg, 75%).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([OH:51])=O)[CH2:15]2)=[CH:10][CH:9]=1.[CH3:55][NH2:56]>>[CH3:1][O:2][CH2:3][C@H:4]([CH3:54])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@@H:16]([CH2:47][C:48]([CH3:53])([CH3:52])[C:49]([NH:56][CH3:55])=[O:51])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: CN
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CC(C)(C)C(=O)O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Product: CNC(=O)C(C)(C)C[C@H]1C[C@H](c2ccc(COC[C@@H](C)COC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1

Procedure:
According to general procedure D, 1.0 mmol of 3-[(2R,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-2,2-dimethyl-propionic acid are reacted with methylamine (8M in EtOH) to afford the title compound which is identified based on its Rf-value.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][C:6]=1[CH3:11])[CH3:2].C1(C)C=C(C)C=C(C)C=1S(ON)(=O)=O.CO[CH:29](OC)[N:30](C)C>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:3][C:4]([C:5]1[C:6]2[N:7]([N:30]=[CH:29][CH:11]=2)[CH:8]=[CH:9][CH:10]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1cccnc1C
Reactant: COC(OC)N(C)C
Agent: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccn2nccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
To a clear solution of 2-methyl-nicotinic acid ethyl ester (50.6 g, 306 mmol) in anhydrous methylene chloride (200 mL) was added O-mesitylenesulfonylhydroxylamine (73 g, 337 mmol; prepared according to a literature procedure described in Krause; J. G., Synthesis 1972, 140); in portions at 0° C. The solution obtained was stirred at 0° C. for 15 min, and then at rt for 1 h. Concentration under reduced pressure gave a yellow solid. After the solid was dissolved in anhydrous DMF (300 mL), N,N-dimethylformamide dimethyl acetal (122 mL, 918 mmol) was added at 0° C. The mixture was stirred at 0° C. for 15 min, and then at 90° C. for 3 h. The reaction mixture was concentrated under reduced pressure, mixed with H2O (200 mL), and extracted with Et2O (3×180 mL). The combined organic solutions were washed sequentially with brine (50 mL), 1N aqueous HCl (50 mL), and brine (50 mL), and dried over Na2SO4. Filtration through a SiO2 column, which was then eluted with 30% EtOAc in heptane, gave compound 777A (43.3 g, 74%) as a yellow solid. HPLC: 80% at 3.20 min (retention time) plus 20% corresponding methyl ester at 2.83 min (retention time) (YMC S5 ODS-A column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 mincontaining 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm). MS (ES): m/z 191 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[CH:2]1.[C:12]1([C:18]2[S:26][C:25]3[C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=4)=[N:23][CH:22]=[N:21][C:20]=3[CH:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][NH:34][C:31]2[CH:30]=[CH:29][C:28]([NH:27][C:24]3[C:25]4[S:26][C:18]([C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[CH:19][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:33][CH:32]=2)=[CH:2]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Nc1ccc(Nc2ncnc3cc(-c4ccccc4)sc23)cc1
Product: c1ccc(-c2cc3ncnc(Nc4ccc(NCc5c[nH]c6ccccc56)cc4)c3s2)cc1

Procedure:
The title compound was prepared from 1H-indole-3-carbaldehyde(12 mg, 0.079 mmol) and N-(6-Phenyl-thieno[3,2-d]pyrimidin-4-yl)-benzene-1,4-diamine (150 mg, 0.471 mmol) by a procedure analogous to example 73. RP18-HPLC RT: 6.932 minutes; API MS: 448.20 (M+1) MP: 259-261° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].C[O-].[Na+].Cl[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1.Cl>CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9])[CH2:14][C:15]1[N:16]=[CH:17][NH:18][CH:19]=1
Reactant: Cc1cccc(C)c1O
Reactant: ClCc1c[nH]cn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(Cc2c[nH]cn2)cc(C)c1O
Yield: 54 %

Procedure:
To a solution of 12.2 g of 2,6-dimethylphenol in methanol are added 20 ml of 30% sodium methoxide solution, and the resultant mixture is warmed to 50° C. The mixture is maintained at that temperature while 5.8 g of 4-chloromethylimidazole in methanol are added, with stirring. After the addition is complete, the reaction mixture is stirred at 50°-60° C. for about 4 hours, then is cooled and poured into cold water. That mixture is acidified with hydrochloric acid and washed with ethyl acetate. The pH of the aqueous solution is then adjusted to 7-8, and the product is obtained by extraction with ethyl acetate. The desired 4-(3',5'-dimethyl-4'-hydroxybenzyl)imidazole is obtained in 54% yield. The free base is converted to the corresponding hydrochloride salt by treatment with HCl in a mixture of ethyl acetate and isopropanol. That salt melts at 210°-214° C.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4].C(N(CC)CC)C.Cl[C:16]([O:18][CH3:19])=[O:17].NCC(O)=O>C1COCC1>[CH3:19][O:18][C:16]([NH:1][C@@H:2]([CH2:6][OH:7])[CH:3]([CH3:5])[CH3:4])=[O:17]
Reactant: CC(C)[C@@H](N)CO
Reactant: COC(=O)Cl
Agent: NCC(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)N[C@@H](CO)C(C)C
Temperature: -20 °C

Procedure:
39.7 g (0.385 mol) of D-valinol (Aldrich) are dissolved under nitrogen in 500 ml of dry THF. 58.7 ml (0.424 mol) of triethylamine are added, the mixture is cooled to -20° C. and 32.8 ml (0.424 mol) of methyl chloroformate (Aldrich) are added dropwise to the mixture with stirring. The mixture is subsequently stirred at this temperature for 30 minutes and then brought to room temperature. 60 g (0.078 mol) of glycine are added and the mixture is stirred once more for 15 minutes. The precipitate is filtered off with suction, the filtrate is concentrated and the residue is taken up in diethyl ether. The organic phase is washed with 1N HCl, saturated NaHCO3 solution and saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated, and the residue is dried in a high vacuum.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]3[N:18]=[C:19]([NH:22][CH2:23][CH3:24])[N:20]=[CH:21][C:10]=3[C:9]2=[O:25])[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:31]1[O:32][CH:33]=[CH:34][N:35]=1)CCC.[F-].[NH4+]>C1(C)C=CC=CC=1.Cl[Pd-2](Cl)(P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([NH:22][C:19]1[N:20]=[CH:21][C:10]2[C:9](=[O:25])[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:31]4[O:32][CH:33]=[CH:34][N:35]=4)[CH:3]=3)[CH2:17][C@H:16]3[N:12]([CH2:13][CH2:14][CH2:15]3)[C:11]=2[N:18]=1)[CH3:24]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(Br)c1)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: Cl[Pd-2](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3ncco3)c1)C2=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 39.5 %

Procedure:
Compound 13 (0.060 mg, 0.149 mmol) obtained in Example 13 was dissolved in toluene (3 mL), and the mixture was stirred at 100° C. for 6 hours after adding 2-(tri-n-butylstannyl)oxazole (0.062 mL, 0.298 mmol) and dichlorobis(triphenylphosphino)palladium(II) (Pd(PPh3)2Cl2; 11.0 mg, 0.0149 mmol). Thereafter, a saturated aqueous ammonium fluoride solution was added to the reaction mixture, and the mixture was vigorously stirred for 30 minutes, and filtered through sellite. After extracting the filtrate with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained upon concentration under reduced pressure was purified by preparative TLC to give the title compound (Compound 15) (23.0 mg, 39%).
Reaction SMILES: [N+:1]([C:4]1[C:5](Cl)=[N:6][C:7]([Cl:11])=[C:8]([Cl:10])[CH:9]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=1>>[Cl:10][C:8]1[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][OH:22])=[CH:16][CH:15]=2)=[N:6][C:7]=1[Cl:11]
Reactant: Nc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Cl
Product: O=[N+]([O-])c1cc(Cl)c(Cl)nc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 34 from 3-nitro-2,5,6-trichloropyridine (Horn, U.; Mutterer, F.; Weis, C. D. Helv. Chim. Acta., 1976, 59,190.) and 4-aminophenylethyl alcohol.
Reaction SMILES: CC(C)=[O:3].OS(O)(=O)=O.O=[Cr](=O)=O.S(=O)(=O)(O)O.[CH:19]1([C@H:25]2[CH2:29][NH:28][C@H:27]([CH2:30][OH:31])[CH2:26]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(O)(=O)C>[CH:19]1([C@H:25]2[CH2:29][NH:28][C@H:27]([C:30]([OH:3])=[O:31])[CH2:26]2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: OC[C@@H]1C[C@@H](C2CCCCC2)CN1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)[C@@H]1C[C@@H](C2CCCCC2)CN1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of Jones reagent (2 ml) was added sulfuric acid (0.5 ml) and acetic acid (2.5 ml). (2S-trans)-4-Cyclohexyl-2-pyrrolidinemethanol (0.5 g) in 5 ml of acetic acid was added to the above solution and after the addition, it was stirred at room temperature for 15 minutes. The reaction mixture was filtered through a Celite pad and washed with 10 ml of acetic acid. Isopropyl alcohol (2 ml) was added to the filtrate, stirred well, and a clear solution decanted and concentrated to a thick oil. The oil was dissolved in 5 ml of water and the pH was brought to 6.0 by the addition of concentrated ammonium hydroxide. The resultant precipitate was filtered, washed with 5 ml of water and excess ether, and vacuum dried to yield 0.42 g of (trans)-4-cyclohexyl-L-proline as a pink solid, which was crystallized from methanol to obtain colorless crystals.