Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:19][C:20]#[C:21][CH3:22])[C:8](=[N:16][C:17]#[N:18])OC1C=CC=CC=1)=[O:5])[CH3:2].[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:36][CH2:35][CH2:34][N:33]([C:8]([N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:19][C:20]#[C:21][CH3:22])=[N:16][C:17]#[N:18])[CH2:32]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC#CCN(CC(=O)OCC)C(=NC#N)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCN(CC(=O)OCC)C(=NC#N)N1CCCC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10.0 g 1-ethoxycarbonylmethyl-1-(but-2-ynyl)-3-cyano-2-phenyl-isourea are added to a mixture of 10.0 g 3-tert-butoxycarbonylaminopiperidine and 4.8 g potassium carbonate in 50 ml of dimethylformamide. The reaction mixture is stirred for 1 d at ambient temperature and then a further 1.6 g potassium carbonate and 3.0 g 3-tert-butoxycarbonylaminopiperidine are added. After another 3 d at ambient temperature water is added and the mixture is extracted with ethyl acetate. The organic extracts are dried over sodium sulphate, the solvent is removed, and the residue is purified on silica gel (cyclohexane/ethyl acetate 5:1->1:2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH2:16][C:9]1(CC1C=CC=CC=1)[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([N:8]1[CH:9]2[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1C2CCCC1(Cc1ccccc1)CNC2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCCC1CNC2
Yield: 49.7 %

Procedure:
A mixture of benzyl-3,9-diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (477 mg, 1.51 mmol, 1.0 eq) and palladium hydroxide on carbon (466 mg) in ethanol (10 mL) was stirred with hydrogenation under ballon pressure until no more hydrogen uptake. The reaction was then filtered through celite and concentrated under reduced pressure. The crude was purified using chromatography (MeOH/Ethyl Acetate) which gave 3,9-Diaza-bicyclo[3.3.1]nonane-9-carboxylic acid tert-butyl ester (170 mg) in 47% yield. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.49 (s, 11H) 1.57-1.70 (m, 1H) 1.70-1.79 (m, 2H) 1.79-2.01 (m, 2H) 2.43-2.58 (m, J=19.14, 12.69, 6.32, 6.32 Hz, 1H) 2.93-3.05 (m, 2H) 3.05-3.18 (m, 2H) 3.99 (br. s., 1H) 4.11 (br. s., 1H)
Reaction SMILES: Cl[CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5][NH:4][C:3]1=[O:11].S([O-])([O-])(=O)=[O:13].[NH4+].[NH4+]>O>[CH3:10][C:7]1([CH3:9])[CH2:6][CH2:5][NH:4][CH:2]([C:3]([OH:11])=[O:13])[CH2:8]1
Reactant: O=S(=O)([O-])[O-]
Reactant: CC1(C)CCNC(=O)C(Cl)C1
Agent: [NH4+]
Solvent: O
Product: CC1(C)CCNC(C(=O)O)C1
Temperature: 110 °C
Yield: 70.7 %

Procedure:
A suspension of 9.6 g (0.054 moles) of 3-chloro-5,5-dimethyl-2-oxoperhydroazepine and 18.98 g (0.054 moles) of Ba(OH)2.8H2O in 250 ml of water, was heated in a Parr apparatus at 110° C. for 2 hours. Then, 7.22 g (0.054 moles) of ammonium sulphate were added. The precipitate was filtered off, and the solution was evaporated in vacuo to dryness. The residue was treated with hot 2-propanol and filtered to afford a white solid which was dissolved in water and passed over an ion-exchange column (Dovex 50). The residual salts were removed with 200 ml of water and the aminoacid was eluted with 2N ammonium hydroxide to yield 6.0 g of 4,4-dimethyl pipecolic acid. M.P. >300° C. (dec.).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH:6][NH2:7])=[NH:5].C(O)C.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[OH-].[Na+]>O>[ClH:11].[NH2:2][NH:3][C:4]([NH:6][N:7]=[CH:16][C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)=[NH:5]
Reactant: N=C(NN)NN
Reactant: O=Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: N=C(NN)NN=Cc1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
The preparation of the subject compound may also be accomplished as follows: 25 g. of 1,3-diaminoguanidine hydrochloride is dissolved in 1800 ml. of boiling ethanol. To this boiling solution, 28 g. of 4-chlorobenzaldehyde in 300 ml. of ethanol is added over a period of 8 hours. The reaction mixture is then cooled at 0° C. overnight, clarified, and the filtrate concentrated to 500 ml. volume and cooled at 0° C. 29 g. of precipitate is obtained. This is slurried in 300 ml.of water, the pH adjusted to 8-8.5 with sodium hydroxide solution, the slurry heated to boiling and filtered. Cooling the filtrate gives 18 g. ofessentially pure product melting at 243°-244° C., as in the previous preparation.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N:10]2[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:12]([CH3:24])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH3:25][C:26]([CH3:29])([O-:28])[CH3:27].[K+].[Cl-].[NH4+]>C1COCC1>[C:26]([O:28][C:2]1[CH:3]=[C:4]([N:10]2[C@@H:15]([CH3:16])[CH2:14][N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:12]([CH3:24])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9])([CH3:29])([CH3:27])[CH3:25]
Reactant: CC(C)(C)[O-]
Reactant: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc(C#N)c(OC(C)(C)C)c2)[C@@H](C)CN1C(=O)OC(C)(C)C
Yield: 30.6 %

Procedure:
Into 20 ml of THF was dissolved 3.12 g of tert-butyl (2R,5S)-4-(3-fluoro-4-cyanophenyl)-2,5-dimethylpiperazine-1-carboxylate, and then 1.40 g of potassium tert-butoxide was added thereto, followed by heating under refluxing overnight. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with chloroform. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation to obtain 1.11 g of the title compound.
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH2:25]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:34]3[CH2:33][CH2:32][N:31]([S:28]([CH2:25][CH2:26][CH3:27])(=[O:29])=[O:30])[CH2:36][CH2:35]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCS(=O)(=O)N1CCNCC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: CCCS(=O)(=O)N1CCN(Cc2cnc(NC(=O)N(C3CCCCC3)C3CCCCC3)s2)CC1
Yield: 27.4 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (50 mg, 0.15 mmol), 1-propanesulfonyl-piperazine hydrochloride (52 mg, 0.23 mmol) and sodium triacetoxyborohydride (48 mg, 0.23 mmol) to afford 21 mg (27%) of the desired product after purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C@@H:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][OH:14].CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:11][C@@H:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][OH:14])=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: N[C@H](CO)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H](CO)c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.8 %

Procedure:
To a solution of 4-bromobenzoic acid (892 mg, 4.44 mmol) in THF (9.9 mL) was added (S)-2-amino-2-phenylethanol (609 mg, 4.44 mmol), DIEA (1.9 mL, 11.1 mmol), PyBroP (2.5 g, 5.32 mmol), and HOBT (815 mg, 5.32 mmol). The reaction mixture was stirred at room temperature for 20 h. The reaction mixture was extracted with EtOAc. The organic layer was washed with water and brine. After dried over anhydrous sodium sulfate, filtered and concentrated in vacuo, the crude product was purified by flash chromatography (gradient EtOAc in DCM) yielding (S)-4-bromo-N-(2-hydroxy-1-phenylethyl)benzamide (850 mg, 60%). LCMS (m/z): 338.1 (MH+), 0.61 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][N:19]=3)[CH:17]=2)=[C:11]([CH3:27])[N:10]=[N:9]1.[NH2:28][CH2:29][CH:30]1[CH2:32][CH2:31]1>>[CH:30]1([CH2:29][NH:28][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([N:16]3[CH:17]=[C:13]([C:12]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=[N:10][C:11]=4[CH3:27])[N:14]=[CH:15]3)=[N:19][CH:20]=2)[CH2:32][CH2:31]1
Reactant: NCC1CC1
Reactant: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Product: Cc1nnn(-c2ccccc2F)c1-c1cn(-c2ccc(C(=O)NCC3CC3)cn2)cn1
Yield: 47 %

Procedure:
As described for example 43c, 6-(4-(1-(2-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (74 mg, 0.203 mmol) was converted, using aminomethylcyclopropane instead of isopropylamine, to the title compound (40 mg, 47%) which was obtained as a white foam after purification by chromatography (reverse phase HPLC). MS: m/e=418.3 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]3[CH:28]=[C:29]([OH:33])[CH:30]=[CH:31][CH:32]=3)[CH:26]=2)[CH:10]=1.Cl[CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C(#N)C.C(Cl)Cl>[CH3:7][NH:8][C:9]1[N:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:12]=[C:11]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][CH2:38]4)[CH:28]=3)[CH:26]=2)[CH:10]=1
Reactant: CNc1cc(-c2cncc(-c3cccc(O)c3)c2)cc(-c2ccccn2)n1
Reactant: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CNc1cc(-c2cncc(-c3cccc(OCCN4CCCC4)c3)c2)cc(-c2ccccn2)n1

Procedure:
Potassium carbonate (3.0 eq, 0.686 mmol, 95 mg) is added to a suspension of 3-(6′-Methylamino-[2,2′;4′,3″]terpyridin-5″-yl)-phenol (Example 2.189, step 1) (1.0 eq, 0.229 mmol, 81 mg) in dry acetonitrile (2.0 ml) under an inert atmosphere of nitrogen. 1-(2-Chloro-ethyl)-pyrrolidine (3 eq, 0.686 mmol, 92 mg) is added and the reaction is heated using microwave radiation at 150° C. for 2 hours. The reaction mixture is dissolved in DCM and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 453.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[N:14]([CH3:16])[CH3:15])[C:5]([N:7]([O:9][CH3:10])[CH3:8])=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>O1CCCC1.O>[CH3:16][N:14]([CH3:15])[C:13]1[CH:12]=[CH:11][C:4]([C:5](=[O:6])[N:7]([O:9][CH3:10])[CH3:8])=[CH:3][C:2]=1[NH:1][C:24](=[O:25])[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CON(C)C(=O)c1ccc(N(C)C)c(N)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(N(C)C)c(NC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of EXAMPLE 458B in a mixture of tetrahydrofuran (20 mL) and water (20 mL) was added cesium carbonate (6.02 g, 18.58 mmol) and benzyl chloroformate (1.5 mL, 10.16 mmol). The reaction mixture was stirred at room temperature for 16 hours, and concentrated. The residue was partitioned between ethyl acetate (100 mL) and brine (75 mL). The organic layer was washed with brine, and concentrated. The residual oil was purified by flash chromatography eluting with 40% ethyl acetate in hexanes to provide the title product. MS (DCI/NH3) m/z 358 (M+H)+.
Reaction SMILES: CCCCC.C([Li])(C)(C)C.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=3)[N:21]=[C:20]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=3)[N:19]=2)=[CH:14][CH:13]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=2)=[CH:47][CH:46]=1>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:40]([C:37]1[CH:38]=[CH:39][C:34]([C:20]2[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:31])[CH3:32])=[CH:26][CH:25]=3)[N:23]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:45]4[CH:46]=[CH:47][C:48]([C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][N:52]=5)=[CH:49][CH:50]=4)=[CH:17][CH:16]=3)[N:19]=2)=[CH:35][CH:36]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: Brc1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(Br)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Agent: [Pd]
Agent: [Li]C(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nc(-c3ccc(-c4ccc(-c5ccccn5)cc4)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Under a stream of argon, 3.5 ml of a pentane solution containing 5.2 mmol of tert-butyl lithium was slowly added to 15 ml of tetrahydrofuran cooled to −78° C., and 10 ml of tetrahydrofuran in which 0.61 g of 2-(4-bromophenyl)pyridine was dissolved was further added dropwise to this solution. After stirring at −78° C. for 30 minutes, 1.64 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 1.00 g portion of 2-(4-bromophenyl)-4,6-bis(4-tert-butylphenyl)-1,3,5-triazine prepared in Reference Example 1 and 0.12 g of tetrakis(triphenylphosphine) palladium(0) were dissolved in 35 ml of tetrahydrofuran and added to this solution, followed by stirring under heating reflux for 13 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was purified by a silica gel column chromatography (eluting solution hexane:dichloromethane=3:2 to 4:3) and then again recrystallized from dichloromethane-methanol to obtain a white solid of the intended 2,4-bis(4-tert-butylphenyl)-6-[4′-(2-pyridyl)biphenyl-4-yl]-1,3,5-triazine (1.00 g, yield 87%). Its melting point and glass transition temperature are shown in Table 4.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[C:21]([C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[S:32])[CH:27]=[CH:28][CH:29]=1)([OH:23])=[O:22].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][C:31](=[S:32])[NH:30][C:26]3[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=3)[C:21]([OH:23])=[O:22])[CH:17]=1)=[CH:5]2
Reactant: O=C(O)c1cccc(N=C=S)c1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)Nc1cccc(C(=O)O)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with 3-carboxyphenyl isothiocyanate (0.185 g, 1.0 mmol) in tetrahydrofuran (10 mL) and was heated briefly to 50° C. and then allowed to stand overnight at room temperature. The tetrahydrofuran was boiled off on the rotary evaporator (no vacuum) to give a solid. Ethyl acetate (10 mL) was added, and the mixture was allowed to stand overnight at room temperature. The insoluble material was collected by filtration, washed with ethyl acetate, and air-dried to give the product (0.379 g), mp 221-223° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29]Br)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]>>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([CH2:26][CH2:27][CH2:28][CH2:29][O:1][C:2]2[C:3]([CH3:15])=[CH:4][C:5]3[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=3[CH:14]=2)=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23]
Reactant: Cc1cc2c(cc1O)C(C)(C)OC(=O)N2
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Product: Cc1cc2c(cc1OCCCCS(=O)c1ccc(Cl)c(Cl)c1)C(C)(C)OC(=O)N2

Procedure:
Prepared analogously to Example 4 from 6-hydroxy-4,4,7-trimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichlorophenylsulfinyl)-butylbromide.
Reaction SMILES: COC1C=CC(C([NH:20][C:21]2[N:29]=[CH:28][N:27]=[C:26]3[C:22]=2[N:23]=[CH:24][N:25]3[C@H:30]2[O:35][C@@H:34]([CH2:36][O:37]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC(OC)=CC=3)[C@H:32]([OH:33])[CH2:31]2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(O)(=O)C>[CH2:31]1[C@@H:30]([N:25]2[C:26]3[N:27]=[CH:28][N:29]=[C:21]([NH2:20])[C:22]=3[N:23]=[CH:24]2)[O:35][C@@H:34]([CH2:36][OH:37])[C@@H:32]1[OH:33]
Reactant: COc1ccc(C(Nc2ncnc3c2ncn3[C@@H]2C[C@@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccc(OC)cc3)O2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: Nc1ncnc2c1ncn2[C@@H]1C[C@@H](O)[C@H](CO)O1
Yield: 85.3 %

Procedure:
Compound 9 (0.44 g, 0.56 mmol) was treated with an aqueous solution of acetic acid 80% (17 mL) at room temperature for 5 h. The mixture was concentrated to dryness, the residue was dissolved in water (20 mL) and washed with diethyl ether (2×15 mL). The aqueous layer was concentrated and co-evaporated with toluene and methanol. The desired 2′-deoxy-β-L-adenosine (β-L-dA) (0.12 g, 83%) was obtained after purification by silica gel column chromatography (0-12% MeOH in dichloromethane) and filtration through a Millex HVA unit (0.45μg, Millipore): mp 193-194° C. (crystallized from water)(Lit. 184-185° C. for L-enantiomer [Ref.: Robins, M. J.; Khwaja, T. A.; Robins, R. K. J. Org. Chem. 1970, 35, 636-639] and 187-189° C. for D-enantiomer [Ref.: Ness, R. K. in Synthetic Procedures in Nucleic Acid Chemistry; Zorbach, W. W., Tipson, R. S., Eds.; J. Wiley and sons: New York, 1968; Vol 1, pp 183-187]; 1H NMR (DMSO-d6): δ 2.2-2.3 and 2.6-2.7 (2m, 2H, H-2′ and H-2″), 3.4-3.6 (2m, 2H, H-5′ and H-5″) 3.86 (pq, 1H, H4′), 4.3-4.4 (m, 1H, H-3′), 5.24 (t, 1H, OH-5′, JH,OH=5.8 Hz), 5.30 (d,1H, OH-3′, JH,OH=4.0 Hz), 6.32 (dd, 1H, H-1′, J1′,2′=6.2 Hz, J1′, 2″=7.8 Hz), 7.3 (br s, 2H, NH2-6), 8.11 and 8.32 (2s, 2H, H-2 and H-8); ms: matrix G/T, (FAB+) m/z 252 [M+H]+, 136 [BH2]+, (FAB−) m/z 250 [M−H]−, 134 [B]−; UV (95% ethanol): λmax 258 nm (ε 14300), λmin 226 nm (ε 2100); [α]D20=+25 (c 1.03, H2O), (Lit. [α]D20=+23 (c 1.0, H2O) for L-e3nantiomer [Ref.: Robins, M. J.; Khwaja, T. A.; Robins, R. K. J. Org. Chem. 1970, 35, 636-639] and [α]D20=−25 (c 0.47, H20) for D-enantiomer [Ref.: Ness, R. K. in Synthetic Procedures in Nucleic Acid Chemistry; Zorbach, W. W., Tipson, R. S., Eds.; J. Wiley and sons: New York, 1968; Vol 1, pp 183-187]). Anal. Calcd for C10H13N5O3+1.5 H2O (M=278.28): C, 43.16; H, 5.80; N, 25.17. Found: C, 43.63; H, 5.45; N, 25.33.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([Cl:11])[S:8][C:7]=1[Cl:12])=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[Cl:12][C:7]1[S:8][C:9]([Cl:11])=[CH:10][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cc(Cl)sc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)c1cc(Cl)sc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
3-Thiophenecarboxylic acid ethyl ester (1.56 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (5.36 g) was added. The mixture was stirred at room temperature for 4 hours, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred for 15 minutes and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2,5-dichloro-3-thiophenecarboxylic acid ethyl ester (2.3 g). 2,5-Dichloro-3-thiophenecarboxylic acid ethyl ester (2.25 g) was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (20 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2,5-dichloro-3-thiophenecarboxylic acid (1.89 g) as crystals.
Reaction SMILES: [C:1]1([CH:9]=O)[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(OC(=O)C)(=O)C>C1(C)C(C)=CC=CC=1>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH:11]=[CH:9][C:1]1[CH:2]=[CH:3][C:4]([CH:7]=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc2ccccc2n1
Reactant: O=Cc1ccc(C=O)cc1
Solvent: Cc1ccccc1C
Solvent: CC(=O)OC(C)=O
Product: O=Cc1ccc(C=Cc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Yield: 35 %

Procedure:
1,4-Benzenedialdehyde (30 g, 0.22 mol), 2-methylquinoline (21 g, 0.15 mol) and acetic anhydride (41.5 ml, 0.40 mol) were dissolved in 160 ml of xylene, followed by heating under reflux for 7 hours. After the reaction mixture was allowed to cool down to room temperature, 200 ml of petroleum ether were added and the resulting precipitate was collected by filtration. Further, the mother liquor was concentrated under reduced pressure and the residue was recrystallized from diethyl ether, whereby 13.6 g of the title compound were obtained (yield: 35%).
Reaction SMILES: [N:1]([CH2:4][CH:5]1[CH2:10][CH:9]2[N:11](C(OC(C)(C)C)=O)[CH:6]1[CH2:7][CH2:8]2)=[N+:2]=[N-:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]([CH2:4][CH:5]1[CH2:10][CH:9]2[NH:11][CH:6]1[CH2:7][CH2:8]2)=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1C2CCC1C(CN=[N+]=[N-])C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: [N-]=[N+]=NCC1CC2CCC1N2
Reaction time: 3 h

Procedure:
To the title compound of step B in DCM was added TFA. After 3 h at rt, the reaction mixture was concentrated to give the title compound (1.7 g) as the TFA salt.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([CH3:16])([CH3:15])[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[CH3:17]>C(O)(=O)C.O.[Zn]>[CH3:16][C:7]([C:5]1[S:6][CH:2]=[C:3]([CH3:17])[CH:4]=1)([CH3:15])[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9]
Reactant: Cc1cc(C(C)(C)C(=O)N2CCCC2)sc1Br
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1csc(C(C)(C)C(=O)N2CCCC2)c1

Procedure:
To a solution of the 1-[2-(5-bromo-4-methyl-2-thienyl)-2-methylpropanoyl]pyrrolidine in acetic acid (8 ml) and water (5 ml) was added zinc dust (1.0 g, 15 mmol). The mixture was heated under reflux for 24 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate and then washed sequentially with 1N hydrochloric acid, 1N sodium hydroxide and a saturated brine solution. The ethyl acetate solution was dried over magnesium sulfate and then evaporated. The residue was purified by flash chromatography on silica eluting with a 20–75% mixture of ethyl acetate in iso-hexane to afford 1-[2-methyl-2-(4-methyl-2-thienyl)propanoyl]pyrrolidine (0.151 g) as a colourless solid.