Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12]O.S(Cl)([Cl:16])=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH3:11])=[CH:4][C:3]=1[CH2:12][Cl:16]
Reactant: COc1cc(Br)c(CO)cc1OC
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cc(Br)c(CCl)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Bromo-4,5-dimethoxy-phenyl)-methanol (2.47 g) is dissolved in methylene chloride (30 ml) and thereto is added thionyl chloride (875 μl), and the mixture is stirred at room temperature for 30 minutes. The reaction solution is concentrated under reduced pressure, and thereto is added hexane and the resulting crystal is filtered to give 1-bromo-2-chloromethyl-4,5-dimethoxy-benzene (2.25 g). MS (m/z): 229/231
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:12]2[N:16]3[CH2:17][CH2:18][NH:19][CH2:20][C:15]3=[N:14][N:13]=2)[NH2:11])=[CH:6][CH:5]=1.[N+](C1C=CC(C([O:30][C@H:31]2[C:35]3[N:36]=[CH:37][N:38]=[C:39]([Cl:40])[C:34]=3[C@H:33]([CH3:41])[CH2:32]2)=O)=CC=1)([O-])=O.CCN(C(C)C)C(C)C.CN1C(=O)CCC1.[OH-].[Na+]>CO>[ClH:3].[ClH:40].[NH2:11][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=1)[C:12]1[N:16]2[CH2:17][CH2:18][N:19]([C:39]3[C:34]4[C@H:33]([CH3:41])[CH2:32][C@@H:31]([OH:30])[C:35]=4[N:36]=[CH:37][N:38]=3)[CH2:20][C:15]2=[N:14][N:13]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Reactant: NC(c1ccc(Cl)cc1)c1nnc2n1CCNC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CO
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCn4c(nnc4C(N)c4ccc(Cl)cc4)C3)c21
Yield: 42.4 %

Procedure:
A solution of (4-chlorophenyl)(5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazin-3-yl)methanamine bishydrochloride (50 mg, 0.149 mmol), (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (49.8 mg, 0.149 mmol) and DIEA (0.130 mL, 0.745 mmol) in NMP (0.30 mL, 0.149 mmol) was heated at 100° C. for 1 day. The crude reaction mixture was diluted with methanol and filtered. The filtrate was purified (C18, 5-95% MeCN/H2O+1% TFA). The fractions containing product were isolated by basifying with 25% NaOH and extracting into CH2Cl2/isopropanol (3:1). The organic layers were concentrated, and the residue was diluted with methanol. The solution was saturated with HCl (g). The solution was evaporated to give (5R,7R)-4-(3-(Amino(4-chlorophenyl)methyl)-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol bishydrochloride (15.3 mg, 25%). LCMS (APCI+) rt=2.28 min. 1H NMR (400 MHz, d6-DMSO+3 drops D2O) δ 8.83 (d, J=7.8 Hz, 1H), 7.55 (s, 4H), 6.02 (d, J=8.6 Hz, 1H), 5.30 (m, 1H), 4.54 (m, 1H), 4.36 (m, 1H), 4.24 (m, 1H), 4.09 (m, 1H), 3.48 (m, 1H), 2.21 (m, 1H), 2.08 (m, 1H), 1.26 (m, 1H), 1.19 (m, 3H).
Reaction SMILES: OC[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[O:10]2)=[CH:5][CH:4]=1.Cl.C[C:16](C)=[O:17].CCCCCC>CC(C)=O.CCCCCC>[OH:17][CH2:16][C:8]1[C:9](=[O:13])[O:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][CH:12]=2
Reactant: CC(C)=O
Reactant: O=c1ccc2ccc(CO)cc2o1
Agent: Cl
Solvent: CCCCCC
Product: O=c1oc2ccccc2cc1CO
Temperature: 110 °C

Procedure:
In a 25-mm-diameter test tube with a side tubulation for applying vacuum was placed 7-hydroxymethylcoumarin (300 mg, 1.70 mmol) and 2-deoxy-3,5-di-O-p-toluoyl-α-D-ribofuranosyl chloride (600 mg, 1.54 mmol). The test tube was tightly stoppered, and about 1 mm vacuum was applied to the tube through the tubulation. The evacuated tube was then heated in an oil bath at 110° C. for 5 min. During the first 2 min of heating there was vigorous evolution of HCl gas. The reaction mixture was then cooled to room temperature, and the residue was taken up in 3 to 4 ml of a 1:1 mixture of acetone and hexane. The solution was then submitted to chromatography on a 50 mm ×150 mm silica gel column using acetone/hexane 1:1 as the eluant. The fractions containing product were identified by TLC and were pooled and concentrated to a glass. The glass was taken up in 10 ml of ethyl acetate. The ethyl acetate solution in a 50 ml Erlenmeyer flask was placed in a jar containing 20 ml of pentane. The jar was then sealed and the crystallization was allowed to proceed. Yield was 330 mg of white crystals (41% of theory); the melting point was 92°-106° C. Rf =0.48 in acetone/hexane 1:1. NMR showed this material to be approximately a 1:1 mixture of α and β -anomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](Cl)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:25]3[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1cc(Nc2cncc(Cl)n2)cc(OC)c1OC
Product: COc1cc(Nc2cncc(-c3ccc(Cl)cc3)n2)cc(OC)c1OC
Yield: 71 %

Procedure:
Using Method B with 212 mg (0.72 mmol) 2a and 135 mg (0.86 mmol) 4-chloro-phenylboronic acid, 190 mg pure title compound (59.7%) were obtained after purification by preparative HPLC (eluent:AcOEt). Reaction time: 18 hours. 1H-NMR (DMSO), δ (ppm), J (Hz): 3.63 (s, 3H, CH3O(4′)), 3.82 (s, 6H, CH3O(3′+5′)), 6.88 (d, 2H, Harom(2′+6′), J=8.52), 7.24 (s, 2H, Harom(2+6)), 7.97 (d, 1H, Harom (3′+5′)), 8.05 (s, 1H, HP5), 8.40 (s, 1H, HP3), 9.46 (s, 1H, OH), 9.82 (s, 1H, NHamine); MS, (C19H18ClN3O4), m/z: 354.3 [M++1, 100].
Reaction SMILES: [C:1]1([S:7][CH2:8][Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([Sn:14](Cl)([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH3:13].[Cl-].[NH4+]>CCCCCC.C1COCC1.C1COCC1>[C:1]1([S:7][CH2:8][Sn:14]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][CH2:11][CH2:12][CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Li]CSc1ccccc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)CSc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Using the apparatus and procedure of Example I, 100 ml. of an approximately one-molar solution of (phenylthio) methyllithium in hexane-THF solvent was added dropwise with stirring to 0.1 mole of tributyltin chloride dissolved in THF. The temperature was maintained by means of an ice bath in the range of from 0° C to 20 C. Following the complete addition over a one-half hour period, the reaction mixture was stirred for 1.5 hours at room temperature and hydrolyzed by pouring into aqueous one-molar ammonium chloride. Extraction from the hydrolyzate with ether solvent and purification by vacuum distillation yielded the desired product, (phenylthiomethyl) tributyltin, b.p. 152°-157° C (0.09 mm). Infrared and proton nuclear magnetic resonance spectral analyses confirmed the assigned structure.
Reaction SMILES: [SH:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([OH:11])[N:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CCCCCC>C(O)C.[OH-].[Na+].O>[CH2:12]([S:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([OH:11])[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Oc1nc(S)nc2nc[nH]c12
Reactant: BrCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCCCCC
Product: Oc1nc(SCc2ccccc2)nc2nc[nH]c12
Yield: 42.9 %

Procedure:
2.00 g (11.9 mmol) of 2-mercapto-6-hydroxypurine was dissolved in a solvent mixture of 10 ml of ethanol, 10.9 ml of 2N sodium hydroxide and 15 ml of water. Under ice cooling with stirring, 2.06 ml (17.9 mmol) of benzylbromide was added to the solution, following stirring at room temperature for 30 minutes. Again under ice cooling, the mixture was neutralized with 2N hydrochloric acid and 30 ml of n-hexane was added to the mixture. A precipitated was collected by filtration, washed with ethyl acetate and dried to afford 1.32 g (yield, 45%) of 2-benzylthio-6-hydroxypurine as a crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Li])CCC.CN(CCN(C)C)C.[CH2:22]1[O:32][C:25]2([CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26]2)[O:24][CH2:23]1>CCOCC.C1COCC1>[F:8][C:5]1[N:6]=[CH:7][C:2]([C:28]2([OH:31])[CH2:29][CH2:30][C:25]3([O:32][CH2:22][CH2:23][O:24]3)[CH2:26][CH2:27]2)=[CH:3][CH:4]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccc(F)nc2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.8 %

Procedure:
A solution of 5-bromo-2-fluoropyridine (2 g, 0.011 mol) in 50 mL of dry ether under nitrogen was cooled to −78° C. n-butyllithium (7.5 mL, 0.011 mol, 1.6 M solution in hexane) and TMEDA (2.5 g, 0.022 mol) were added dropwise. The orange solution was stirred for an additional 1 h at −78° C. and then treated dropwise over 10 min with a solution of 1,4-cyclohexanedione monoethylene ketal (1.8 g, 0.011 mol) in 20 mL of dry THF. The reaction mixture was stirred for 1 h, allowed to warm to 20° C. and poured into ice water (400 mL). The organic layer was separated, and the aqueous layer was extracted twice with EtOAc (20 mL×2). The combined organic extracts were dried over MgSO4 and evaporated to give 2 g of white solid. Chromatography on silica gel afforded 1.7 g (67% yield) of white crystals: MS: 254 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[N:11]2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1.[CH2:31]([O:35][C:36](Cl)=[O:37])[CH:32]([CH3:34])[CH3:33].[OH-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH2:31]([O:35][C:36](=[O:37])[NH:30][C:27]1[CH:28]=[CH:29][C:24]([C:3]2[N:4]=[C:5]3[N:11]([CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[CH:6]3[O:16][CH:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[C:2]=2[CH3:1])=[CH:25][CH:26]=1)[CH:32]([CH3:34])[CH3:33]
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1c(-c2ccc(N)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1c(-c2ccc(NC(=O)OCC(C)C)cc2)nc2n1CCc1ccccc1C2OC1CCN(C)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenylamine (example 173) (50 mg, 0.124 mmole) in CH2Cl2 (0.5 mL) is added 4-dimethylaminopyridine (17 mg, 0.136 mmole). The reaction mixture is cooled to 0° C. and isobutylchloroformate (18 μL, 0.136 mmole) is added dropwise. The reaction mixture is stirred at room temperature 2 h, diluted with water and made alkaline with 1N NaOH. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative TLC over silica gel eluting with (acetone:NEt3) to afford {4-[1-methyl-4-(1-methyl-piperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulen-2-yl]-phenyl}-carbamic acid isobutyl ester melting at 196° C.
Reaction SMILES: Cl.[Na].[OH:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6](Cl)[N:5]=1.[CH3:13][OH:14]>>[OH:3][C:4]1[N:9]=[C:8]([CH3:10])[C:7]([Cl:11])=[C:6]([O:14][CH3:13])[N:5]=1
Reactant: CO
Reactant: Cc1nc(O)nc(Cl)c1Cl
Agent: Cl
Agent: [Na]
Product: COc1nc(O)nc(C)c1Cl
Yield: 59 %

Procedure:
Hydrogen chloride gas was passed into a suspension of 80.4 g (0.4 mole) of the sodium salt of 2-hydroxy-4-methyl-5,6-dichloropyrimidine in 600 ml of methanol until the mixture reacted strongly acid. The mixture was then stirred for a further hour and thereafter the solvent was distilled off in vacuo. The residue was triturated with 50 ml of water and filtered off. 41.3 g (59% of theory) of 2-hydroxy-4-methyl-5-chloro-6-methoxy-pyrimidine were obtained in the form of a beige powder of melting point 235° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4].[H-].[Na+].[CH3:25]I>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:25])[C:11]2([CH3:22])[CH3:21])[CH:7]=[N:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cncn1C1c2ccccc2C(=O)NC1(C)C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncn1C1c2ccccc2C(=O)N(C)C1(C)C
Temperature: -10 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(3,3-dimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester (55 mg, 0.184 mmol) in DMF (3.7 mL) at −10° C. is added sodium hydride (60% dispersion in oil 10 mg, 0.25 mmol). The reaction is stirred for 5 min at −10° C. and then placed at room temperature for 10 min. The resulting red solution is re-cooled to −10° C. and methyl iodide (0.025 mL, 0.40 mmol) is added dropwise. The reaction is placed at room temperature. After 10 min the yellow reaction mixture is quenched by the addition of saturated aqueous NH4Cl (ca. 1 mL). The resulting mixture is diluted with ethyl acetate and saturated aqueous NaHCO3. The layers are separated and the aqueous layer is extracted twice with ethyl acetate (ca. 10 mL). The organic layers are combined, dried with Na2SO4, filtered and concentrated in vacuo to afford 3-(2,3,3-trimethyl-1-oxo-1,2,3,4-tetrahydro-isoquinolin-4-yl)-3H-imidazole-4-carboxylic acid methyl ester as a yellow foam requiring no further purification prior to the next transformation; HRMS (ES) m/z 300.1354 [(M+H)+; calculated for C16H18N3O3: 340.1348]; 1H NMR (400 MHz, MeOD) δ ppm 1.30 (s, 3H), 1.41 (s, 3 H), 3.10 (s, 3 H), 4.04 (br. s., 3 H), 6.85 (br. s., 1 H), 7.50 (br. s., 1 H), 7.61-7.73 (m, 2 H), 8.09-8.27 (m, 3 H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH:33]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[N:12]=2)[CH:10]=1)=O)C.[CH3:50][NH2:51]>>[CH3:50][NH:51][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:19]=[C:18]3[C:14]([N:15]=[CH:16][N:17]3[C@@H:20]3[CH2:24][C@H:23]([NH:25][C:26](=[O:29])[CH2:27][CH3:28])[C@@H:22]([OH:30])[C@H:21]3[OH:31])=[C:13]([NH:32][CH:33]([C:42]3[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=3)[C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[N:12]=2)[CH:10]=1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1cnn(-c2nc(NC(c3ccc(OC)cc3)c3ccc(OC)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CC)[C@@H](O)[C@H]4O)c3n2)c1
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NC(c4ccc(OC)cc4)c4ccc(OC)cc4)nc(-n4cc(C(=O)NC)cn4)nc32)[C@H](O)[C@@H]1O
Temperature: 65 °C

Procedure:
A mixture of 1-[6-{[Bis-(4-methoxy-phenyl)-methyl]-amino}-9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-9H-purin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 168, step 3) (0.2 g, 0.298 mmol) and 40% aqueous methyl amine solution (5 ml) is heated to 65° C. for 12 h. The reaction mixture concentrated in vacuo and purification of the crude residue by chromatography on silica eluting with 3% methanol in chloroform yields the title compound. LC-MS (0.1% formic acid, acetonitrile): 656 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][CH2:9][C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[O:12][C:11]=2[CH3:22])[N:3]=1.ClC1C=CC(C2OC(C)=C(CO)C=2)=CC=1.[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C([O-])([O-])=O.[K+].[K+]>>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[O:12][C:11]([CH3:22])=[C:10]([CH2:9][O:8][C:4]3[CH:5]=[N:6][CH:7]=[C:2]([N:38]4[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]4)[N:3]=3)[CH:14]=2)=[CH:16][CH:17]=1
Reactant: Cc1oc(-c2ccc(Cl)cc2)cc1COc1cncc(Cl)n1
Reactant: C1CNCCN1
Agent: Cc1oc(-c2ccc(Cl)cc2)cc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1oc(-c2ccc(Cl)cc2)cc1COc1cncc(N2CCNCC2)n1

Procedure:
The title compound was prepared according to the procedure of example 50, step 2, starting from 2-chloro-6-[5-(4-chlorophenyl)-2-methylfuran-3-ylmethoxy]pyrazine [3.14 g, 9.39 mmol; obtained according to the procedure of example 50, step 1, starting from 5-(4-chlorophenyl)-3-hydroxymethyl-2-methylfuran], piperazine (2.47 g, 28.6 mmol) and K2CO3 (1.36 g, 9.86 mmol) with the exception that the final filtration through alumina was omitted. The yield of the of the title compound was 2.11 g (58%) which was obtained as a beige colored solid. Purity 100% (HPLC). MS m/z 384 (M)+. HRMS m/z calcd for C20H21ClN4O2 (M)+ 384.1353, found 384.1357.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N+:6]([C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[NH2:16])([O-:8])=[O:7]>N1C=CC=CC=1>[NH2:16][C:10]1[CH:11]=[CH:12][C:13]([NH:15][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:14][C:9]=1[N+:6]([O-:8])=[O:7]
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 0.17 h

Procedure:
Methanesulfonyl chloride (11.5 g, 0.1 mmol) was added gradually over 3 min to a solution of 2-nitrobenzene-1,4-diamine (15.3 g) in pyridine (70 ml). The temperature of the mixture rose to ca. 70° C. The solution was set aside for 10 min, and then refluxed for 15 min. The pyridine was evaporated under reduced pressure, and the residue was recrystallized from ethanol (with charcoal) to give the product as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2].[CH2:25](OC(=O)COC1C2CCCCC=2C(S)=CC=1)C.ClC1C=C(C=CC=1Cl)C=O>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:25])[C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[O:21])=[CH:16][C:15]=2[Cl:22])=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: CCOC(=O)COc1ccc(S)c2c1CCCC2
Reactant: CCOC(=O)COc1ccc(Sc2ccc(C=O)cc2Cl)cc1C
Agent: O=Cc1ccc(Cl)c(Cl)c1
Product: CCOC(=O)COc1cc(C)c(Sc2ccc(C=O)cc2Cl)cc1C

Procedure:
The title compound was prepared according to the method described for preparing compound 10.4, using compound 22.3 and 3,4-dichlorobenzaldehyde as the starting materials. 1H NMR (400 MHz) (CDCl3) δ 9.85 (1H, s); 7.82 (1H, d, J=1.7 Hz); 7.49 (1H, dd, J=1.7, 8.2 Hz); 7.36 (1H, s); 6.70 (1H, s); 6.58 (1H, d, J=8.2 Hz); 4.71 (2H, s); 4.31 (2H, q, J=7.1 Hz); 2.31 (3H, s); 2.27 (3H, s); 1.33 (3H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([NH:20][C:21]3[N:25]=[C:24]([C:26]4([C:29]([O-])=[O:30])[CH2:28][CH2:27]4)[O:23][N:22]=3)[CH:16]=[CH:17][C:18]=2[CH3:19])[C:3]1=[O:32].[BH4-].[Na+].[Cl-].[NH4+]>CO>[OH:30][CH2:29][C:26]1([C:24]2[O:23][N:22]=[C:21]([NH:20][C:15]3[CH:16]=[CH:17][C:18]([CH3:19])=[C:13]([C:4]4[C:3](=[O:32])[N:2]([CH3:1])[C:11]5[C:6]([CH:5]=4)=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=5)[CH:14]=3)[N:25]=2)[CH2:28][CH2:27]1
Reactant: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C4(C(=O)[O-])CC4)n3)ccc1C)c(=O)n2C
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc2c(cn1)cc(-c1cc(Nc3noc(C4(CO)CC4)n3)ccc1C)c(=O)n2C

Procedure:
To a solution of 1-(3-(3-(1,7-dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylphenylamino)-1,2,4-oxadiazol-5-yl)cyclopropanecarboxylate 23 (100 mg, 0.22 mmol) in MeOH (10 mL), three batches of NaBH4 (66.5 mg, 1.76 mmol) were added during a period of 30 min. After the reaction was determined to be completed by LC/MS, ammonium chloride solution was added to quench the reaction. The resulting mixture was extracted with DCM (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated to yield a reside which was purified by preparative HPLC to yield 3-(5-(5-(1-(hydroxymethyl)cyclopropyl)-1,2,4-oxadiazol-3-ylamino)-2-methylphenyl)-1,7-di methyl-1,6-naphthyridin-2(1H)-one (A69). 1H NMR (400 MHz, d6-DMSO) δ 9.07 (s, 1H), 8.03 (s, 1H), 7.91 (s, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.33 (dd, J=2.4, 8.4 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.87 (s, 2H), 3.83 (s, 3H), 2.86 (s, 3H), 2.16 (s, 3H), 1.35 (m, 2H), 1.21 (m, 2H). MS m/z 418.2 (M+1).
Reaction SMILES: OC1C(C(=O)C)=CSC=1C1C=CC2CCCCC=2C=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29]3[S:33][CH:32]=[C:31]([C:34](=[O:36])[CH3:35])[C:30]=3[O:37]C)=[CH:28][C:23]=2[CH2:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:29]3[S:33][CH:32]=[C:31]([C:34](=[O:36])[CH3:35])[C:30]=3[OH:37])=[CH:28][C:23]=2[CH2:22][CH2:21]1
Reactant: COc1c(C(C)=O)csc1-c1ccc2c(c1)CCO2
Agent: CC(=O)c1csc(-c2ccc3c(c2)CCCC3)c1O
Product: CC(=O)c1csc(-c2ccc3c(c2)CCO3)c1O
Yield: 53 %

Procedure:
Synthesis was carried out in the same manner as in Synthesis Method 2 (6) in Reference Synthetic Example 3 by using 1.58 g (0.0058 mol) of 1-[5-(2,3-dihydro-benzofuran-5-yl)-4-methoxythiophen-3-yl]ethanone to obtain the desired product (0.8 g yield: 53%).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([CH2:17]O)[C:13]([CH3:16])=[N:14][CH:15]=2)[CH:6]=[CH:7][C:8]=1[CH3:9].S(Cl)([Cl:21])=O>>[ClH:21].[Cl:1][CH2:17][C:12]1[C:13]([CH3:16])=[N:14][CH:15]=[C:10]([C:5]2[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([CH3:2])[CH:4]=2)[CH:11]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(-c2cnc(C)c(CO)c2)cc1C
Agent: Cl
Product: Cc1ccc(-c2cnc(C)c(CCl)c2)cc1C

Procedure:
The title compound, MS: m/e=245.1 (M+) was obtained as a yellow solid (98% yield) by the reaction of [5-(3,4-dimethyl-phenyl)-2-methyl-pyridin-3-yl]-methanol hydrochloride (1:1) with thionyl chloride at 20° C. for 1 h then 2 h at reflux.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.Cl[P:11]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>O1CCCC1.[Zn].C1(C)C=CC=CC=1>[C:18]1([PH:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: Cc1ccccc1
Product: c1ccc(Pc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 84 %

Procedure:
20×10-3 cm3 of 1,2-dibromoethane was added dropwise in a nitrogen gas atmosphere to a suspension of 461 mg (7.05 mg-atoms) of zinc (powder) in 10 cm3 of tetrahydrofuran, the mixture was heated to reflux for about 2 minutes and cooled to room temperature, 30×10-3 cm3 of chlorotrimethylsilane was added and the mixture was stirred for about 2 minutes to prepare an activated zinc. Subsequently, 1.04 g (4.71 mmol) of chlorodiphenylphosphine was added dropwise and the mixture was stirred at room temperature. To the reaction mixture was added dropwise 10 cm3 (10 mmol) of 1 mol·dm-3 hydrochloric acid and then 10 cm3 of toluene. The mixture was stirred, the aqueous layer and the toluene layer were separated off, the toluene layer was determined by gas chromatography, giving diphenylphosphine in 84% yield.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]=[C:12]([CH:14]3[CH2:17][C:16](=O)[CH2:15]3)[S:13][C:9]=2[CH:8]=1.C([BH3-])#N.[Na+]>CO>[Br:6][C:7]1[CH:20]=[CH:19][C:10]2[N:11]=[C:12]([C@H:14]3[CH2:15][C@@H:16]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:17]3)[S:13][C:9]=2[CH:8]=1
Reactant: O=C1CC(c2nc3ccc(Br)cc3s2)C1
Reactant: C1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Brc1ccc2nc([C@H]3C[C@@H](N4CCCC4)C3)sc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyrrolidine (295 μl, 3.54 mmol) was added to a solution of the product of Example 1C (100 mg, 0.354 mmole) in 2 ml methanol and the mixture was stirred at room temperature for 1 hour. Sodium cyanoborohydride (56 mg, 0.891 mmole) was added and the resulting mixture was stirred at room temperature overnight. The reaction was quenched with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the crude product which was purified by column chromatography (0.5% ammonium hydroxide and 5% methanol in dichloromethane) to give 65 mg (55%) of the title compound. 1H NMR (400 MHz, CDCl3) for the cis isomer δ ppm 7.97 (d, J=1.84 Hz, 1H) 7.80 (d, J=8.90 Hz, 1H) 7.54 (dd, J=8.75, 1.99 Hz, 1H) 3.56-3.66 (m, 1H) 3.05-3.19 (m, 1H) 2.55-2.75 (m, 6H) 2.41-2.53 (m, 2H) 1.75-1.92 (m, 4H). MS: (M+H)+=337/339.