Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C([NH:12][C:13](=[O:26])[C@@H:14]1[CH2:18][C@H:17](OC2C=CC=CC=2)[CH2:16][NH:15]1)(C)(C)C.[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[OH:37].C1(O)C=CC=CC=1>>[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[O:37][N:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C:13]([NH2:12])=[O:26]
Reactant: Oc1ccc2ccccc2c1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1
Solvent: O=C(O)C(F)(F)F
Solvent: Oc1ccccc1
Product: NC(=O)[C@@H]1CCCN1Oc1ccc2ccccc2c1

Procedure:
Following substantially the same procedure for synthesizing N-t-butyl-4(S)-phenoxy-L-prolineamide trifluoroacetic acid salt as outlined in Example 1, Steps 6 through 8, but substituting 2-naphthol for the phenol used therein, the 2-naphthyloxy proline amide was produced.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[CH:10])[CH2:4][CH2:3]1.Br[C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([CH3:21])[CH:20]=1)[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=1)[CH2:15]2.C(Cl)(Cl)Cl.CO>C(NC(C)C)(C)C.Cl[Pd](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.[Cu]I>[CH3:21][C:19]1[CH:20]=[C:12]([C:10]#[C:9][CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:13]=[C:14]2[C:18]=1[C:17](=[O:22])[N:16]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=1)[CH2:15]2
Reactant: Cc1cc(Br)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Reactant: C#CCN1CCN(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)NC(C)C
Product: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(Oc3ccccc3)cc1)C2
Temperature: 100 °C
Reaction time: 2 h
Yield: 43 %

Procedure:
A mixture of 1-methyl-4-prop-2-ynyl-piperazine (0.033 mL, 0.33 mmol), 5-bromo-7-methyl-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.102 g, 0.25 mmol), PdCl2(PPh3)2 (0.011 g, 0.015 mmol), and CuI (0.0028 g, 0.015 mmol) in diisopropyl amine (4 mL) was stirred at 100° C. for 2 h. Workup and silica gel column chromatography using 10:1 CHCl3-MeOH afforded 7-methyl-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-phenoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.05 g, 43%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH:22](OC)(OC)OC.C(OC)(OC)(OC)CCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>>[N:12]1([CH2:13][C:14]([CH3:20])([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[CH:22]1
Reactant: CCOC(=O)C(C)(C)CNc1c(N)cnc2ccccc12
Reactant: COC(OC)OC
Agent: CCCC(OC)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOC(=O)C(C)(C)Cn1cnc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
Ethyl 3-(3-aminoquinolin-4-ylamino)-2,2-dimethylpropanoate (see Example 26 Parts A through D, 5.3 g, 18 mmol) was treated according to a modification of the method described in Part B of Example 8 using trimethyl orthoformate in lieu of trimethyl orthobutyrate. Prior to the addition of trimethyl orthoformate (3.0 mL, 27 mmol) and pyridinium p-toluenesulfonate (0.050 g), the reaction was heated at reflux for 15 minutes. The reaction was heated at reflux overnight, allowed to cool to ambient temperature, washed with saturated aqueous sodium bicarbonate (2×35 mL), and extracted with water (45 mL) containing 10% hydrochloric acid (5 mL). The acidic extract was made basic with the addition of potassium carbonate and then extracted with dichloromethane (3×50 mL). The combined organic extracts were dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 4.3 g of ethyl 3-(1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate as an oil.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[C:13]#[N:14])=[CH:7][C:6]=1[CH3:19])C(C)=O.[N+:20]([O-])(O)=O.N([O-])=O.[Na+].C1C=CC=CC=1>C(O)(=O)C.[Cl-].[Na+].O>[C:13]([C:12]1[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=1[C:8]1[CH:7]=[C:6]2[C:5](=[CH:10][CH:9]=1)[NH:1][N:20]=[CH:19]2)#[N:14]
Reactant: CC(=O)Nc1ccc(-c2ccccc2C#N)cc1C
Reactant: O=[N+]([O-])O
Agent: O=N[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: N#Cc1ccccc1-c1ccc2[nH]ncc2c1
Temperature: 45 °C

Procedure:
2-(4-Acetamino-3-methylphenyl)benzonitrile (15.2 mmole, 3.8 g) was dissolved in 50 ml acetic acid and treated for 1 hour at room temperature with a stream of gaseous N2O5 generated by the addition of nitric acid to sodium nitrite. Benzene and brine were added to the reaction. The organic layer was separated, dried and warmed gently on a rotorvap (45° C.) for 1 hour. The solution was concentrated. Ether and saturated sodium bicarbonate were added. The organic phase was dried and concentrated. The residue was chromatographed over silica gel eluted with 50% ether in hexane to yield 240 mg of 5-(2-cyanophenyl)indazole. (MS)
Reaction SMILES: NC1C(O)=C2C([CH:6]3[CH:11]([C:12]2=[O:16])[CH2:10][CH2:9][CH2:8][CH2:7]3)=C(C)C=1.C([O:21][C:22](=[O:24])[CH3:23])(=O)C.C([OH:27])C>>[CH:7]1[CH:6]=[C:11]2[C:12]([C:22]([OH:21])([OH:24])[C:23](=[O:27])[C:10]2=[CH:9][CH:8]=1)=[O:16]
Reactant: CCO
Reactant: Cc1cc(N)c(O)c2c1C1CCCCC1C2=O
Reactant: CC(=O)OC(C)=O
Product: O=C1c2ccccc2C(=O)C1(O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 Gram of 7-amino-8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone was dissolved in 30 ml of ethanol and 0.5 ml of acetic anhydride was added. The solution was stirred at room temperature for 1 hour. After disappearance of the color formed by ninhydrin was confirmed on a thin-layer chromatography, the reaction mixture was concentrated. To the residue was added diisopropyl ether and the resulting precipitate was collected by filtration to obtain 0.8 g of 7-acetylamino-8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone (light brown crystal).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][OH:20])[CH2:3]1.C(N(CC)CC)C.[C:28](Cl)([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:3]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(N[C@H]1CC[C@@H](O)C[C@H]1CO)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CC[C@@H](O)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A sample of benzyl (1S,2R,4R)-4-hydroxy-2-(hydroxymethyl)cyclohexylcarbamate (8.78 g, 31.42 mMol) was dissolved in anhydrous CH2Cl2 prior to the addition of triethylamine (11 mL, 78.55 mMol) followed by DMAP (0.05 g) and then trityl chloride (10.52 g, 37.7 mMol) in one portion. The reaction mixture was stirred at rt overnight. The reaction was partitioned between CH2Cl2 and water. The organic layer was washed with brine and dried (MgSO4), filtered, concentrated and chromatographed. Benzyl (1S,2R,4R)-4-hydroxy-2-(trityloxymethyl)cyclohexylcarbamate was obtained as a white foamy solid (9.85 g, yield=60%).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]3=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].C(O)=O>CCO.O>[NH2:20][C:19]1[C:14]2[N:15]([C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([C:3]([OH:4])=[O:2])[CH2:10][CH2:9]3)=[N:12][C:13]=2[C:21]2[CH:22]=[CH:23][C:24]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:25][CH:26]=2)[CH:16]=[CH:17][N:18]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)nccn32)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: O
Solvent: CCO
Product: Nc1nccn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C

Procedure:
To a stirred mixture of trans-4-[8-amino-1-(4-phenoxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methyl ester (150.00 mg, 0.33 mmol) in EtOH (3.00 mL) was added solution of sodium hydroxide (67.8 mg, 1.69 mmol) in H2O (0.500 mL) at 0° C. Then the mixture was stirred at rt. overnight. The solvent was then removed under reduced pressure to give a residue which was dissolved in H2O (3 ml). The solution was acidified to pH 1 by formic acid. The product precipitated out and was collected by filtration and dried on high vacuum pump. 1H NMR (400 MHz, MeOD) δ 1.59-1.88 (m, 4H), 2.03-2.21 (m, 4H), 2.35-2.46 (m, 1H), 3.09-3.20 (m, 1H), 6.99 (d, J=5.1 Hz, 1H), 7.04-7.20 (m, 5H), 7.35-7.45 (m, 2H), 7.53-7.63 (m, 3H). MS (ES+): m/z 428.97 (MH+). HPLC: tR=2.25 min (OpenLynx, polar—5 min).
Reaction SMILES: C[Si](C)(C)[NH:3][C:4]1[C:5](=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14])[C:6]([O:8][CH3:9])=[O:7].CC#N.Cl[S:21]([C:24]1[N:34]=[C:27]2[N:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:26]2[N:25]=1)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:4]=1[NH:3][S:21]([C:24]1[N:34]=[C:27]2[N:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:26]2[N:25]=1)(=[O:22])=[O:23])=[O:7]
Reactant: COC(=O)c1cccc(C)c1N[Si](C)(C)C
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1cccc(C)c1NS(=O)(=O)c1nc2nc(C)cc(C)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution consisting of 145.9 mg (0.615 mmole) of methyl N-trimethylsilyl-3-methylanthranilate, 1 ml of CH3CN, and 80.4 mg (0.326 mmole) of 2-chlorosulfonyl-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine was stirred at room temperature and the reaction monitored by reverse phase HPLC. The reaction was about 30 percent complete after 4 hours. Pyridine, 29.1 μl (0.360 mmole), was added and the solution stirred for 10 min and again analyzed. Complete reaction had occurred. The solution was allowed to stand overnight. The CH3CN was removed under a nitrogen atmosphere and the residue treated with 2 ml of 1.0N HCl and 2 ml of CH2Cl2. The CH2Cl2 phase was transferred to a column containing 50 g of silica gel and chromatographed to obtain 112.5 mg of N-(2-methoxycarbonyl-6-methylphenyl)-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (0.300 mmole, 92.0 percent yield) as a white crystalline solid, m.p. 181°-182° C. The solid was dissolved in CHCl3 and the solvent again removed in vacuo affording the product as a light yellow powder, m.p. 192°-194° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[N:8][C:7]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O)C.[H-].[Na+].O[NH:28][C:29](=[NH:31])[CH3:30].C(OCC)(=O)C>C1COCC1>[C:15]([O:14][C:12](=[O:13])[NH:11][C:9]1[S:10][C:6]([C:4]2[O:3][N:31]=[C:29]([CH3:30])[N:28]=2)=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:8]=1)([CH3:17])([CH3:18])[CH3:16]
Reactant: CCOC(=O)c1sc(NC(=O)OC(C)(C)C)nc1-c1ccccc1
Reactant: CC(=N)NO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1noc(-c2sc(NC(=O)OC(C)(C)C)nc2-c2ccccc2)n1
Yield: 36 %

Procedure:
2-Tert-butoxycarbonylamino-4-phenyl-thiazole-5-carboxylic acid ethyl ester (1.9 g 5.6 mmol) was dissolved in dry THF (60 mL). Sodium hydride (60% in oil) and N-hydroxy-acetamidine (0.83 g, 11.2 mmol) dissolved in THF (30 mL) was added. The reaction mixture was heated to reflux over night. The reaction mixture was cooled and ethyl acetate (75 mL) glacial acetic acid (0.43 g) were added. The organic mixture was washed with brine (75 mL). The aqueous phase was extracted with ethylacetate The combined organic phases was washed with brine (50 mL) dried with MgSO4 and solvents were removed in vacuo to give a solid. Yield: 36%.
Reaction SMILES: [OH-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([O:17]CC)=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[N:4]1>O.C1COCC1.CO>[NH:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:5]=[N:4]1
Reactant: CCOC(=O)Cc1cccc(-c2cn[nH]c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(-c2cn[nH]c2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NaOH (57 g, 1.43 mol) was added to a solution of ethyl [3-(1H-pyrazol-4-yl)phenyl]acetate (110 g, 0.478 mol) in H2O/THF/MeOH (250 mL/250 mL/250 mL). The mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and the pH was adjusted to 3 to 4 via the addition of 3 M HCl, The solid was collected via filtration and dried to afford [3-(1H-pyrazol-4-yl)phenyl]acetic acid. MS ESI calcd. for C11H11N2O2 [M+H]+ 203. found 203. 1H-NMR (500 MHz, DMSO-d6) δ: 7.94 (s, 2H), 7.41-7.24 (m, 2H), 7.13 (t, J=7.6 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 3.13 (s, 2H).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([CH:26]3[CH2:28][CH2:27]3)[C:15]3[O:22][C:19]4([CH2:21][CH2:20]4)[CH2:18][C:17]([CH3:24])([CH3:23])[C:16]=3[CH:25]=2)=[CH:6][C:5]=1[F:29].CO.[OH-].[Na+].O>C(#N)C>[CH:26]1([C:14]2[C:15]3[O:22][C:19]4([CH2:20][CH2:21]4)[CH2:18][C:17]([CH3:23])([CH3:24])[C:16]=3[CH:25]=[C:12]([C:11]#[C:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:30])=[O:2])=[C:5]([F:29])[CH:6]=3)[CH:13]=2)[CH2:27][CH2:28]1
Reactant: COC(=O)c1ccc(C#Cc2cc(C3CC3)c3c(c2)C(C)(C)CC2(CC2)O3)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: CC1(C)CC2(CC2)Oc2c(C3CC3)cc(C#Cc3ccc(C(=O)O)c(F)c3)cc21

Procedure:
Following general procedure L and using 4-[(8-cyclopropyl-3,4-dihydro-4,4-dimethylspiro[2H-1-benzopyran-2,1′-cyclopropane]-6-yl)ethynyl]-2-fluoro-benzoic acid methyl ester (Compound 53, 0.019 g, 0.047 mmol), 5 mL of methanol and 1M sodium hydroxide solution (2 mL) followed by preparative reverse phase HPLC using 10% water in acetonitrile as the mobile phase, the title compound was obtained as a solid (0.01 g, 56%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][OH:25].C([Li])CCC>C1C=CC=CC=1>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][O:25][C:2]1[C:3]2[N:4]([N:12]=[CH:13][C:14]=2[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CN(C)CCCO
Reactant: CCOC(=O)c1cnn2c1c(Cl)nc1ccccc12
Agent: [Li]CCCC
Solvent: c1ccccc1
Product: CCOC(=O)c1cnn2c1c(OCCCN(C)C)nc1ccccc12

Procedure:
A solution of 2.76 g. of 4-chloropyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester in benzene is added dropwise, at 10° to a stirred soluttion of 1.03 g. of 3-dimethylamino-1-propanol and 0.64 g. of butyl lithium in 30 ml. of benzene. The reaction mixture is heated under reflux for 3 hours and is then filtered and concentrated under reduced pressure. The oily residue is dissolved in petroleum ether, treated with carbon and cooled for 12 hours in the refrigerator. The product, 4-[3-(dimethylamino)propoxy]pyrazolo[1,5-a]quinoxaline-3-carboxylic acid, ethyl ester, crystallizes in the form of white needles, m.p. 78°-81°.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[N:9][S:10][C:6]=2[C:5]=1[C:13](OC)=[O:14].CC(C)=O.Cl>O.O1CCCC1>[Cl:3][C:4]1[CH:12]=[CH:11][C:7]2[N:8]=[N:9][S:10][C:6]=2[C:5]=1[CH2:13][OH:14]
Reactant: COC(=O)c1c(Cl)ccc2nnsc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: OCc1c(Cl)ccc2nnsc12
Reaction time: 8 h

Procedure:
To a suspension of 4.5 g of sodium borohydride in 30 ml of water and 70 ml of tetrahydrofuran there are added dropwise with stirring and heating to 40°-50° C. in the course of haft an hour a solution of 1.9 g of 6-chloro-7-carbomethoxybenzo-1,2,3-thiadiazole in 30 ml of tetrahydrofuran (dissolved under hot conditions). Heating of the mixture is continued until the reaction is complete, and the mixture is then cooled to -20° to -30° C. using a CO2 cooling bath and treated dropwise with 15 ml of acetone, during which process gas is evolved vigorously. The reaction mixture is subsequently brought to pH 3 using 15% hydrochloric acid, with further vigorous cooling at -20° to -10° C. (evolution of gas), and stirring is continued overnight. Most of the tetrahydrofuran is then evaporated on a rotary evaporator, and the residue is extracted using ethyl acetate. The extracts are washed with water, dried over sodium sulfate and evaporated. The residue gives the title compound of m.p. 138°-140° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:13]=1[C:21]1[S:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1.O.O.[Sn](Cl)Cl.CCOC(C)=O>CCO>[S:22]1[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=[C:21]1[C:13]1[CH:14]=[CH:15][C:16]([NH2:18])=[CH:17][C:12]=1[O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: COCCOCCOCCOc1cc([N+](=O)[O-])ccc1-c1nc2ccccc2s1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: COCCOCCOCCOc1cc(N)ccc1-c1nc2ccccc2s1
Yield: 93 %

Procedure:
Prepared as described in the Nitro Reduction section using 2-[2-{2-(2-(2-methoxyethoxy)ethoxy)ethoxy}-4-nitrophenyl]-1,3-benzothiazole (0.15 g, 0.36 mmol) and tin (II) dichloride dihydrate (0.65 g, 2.87 mmol) in EtOH (12 to give the title compound (0.13 g, 92%) as a viscous, yellow oil after work-up and flash chromatography (EtOAc).
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].CC1C=CC(S(O)(=O)=O)=CC=1.[F:17][C:18]1([F:25])[CH2:22][NH:21][C@H:20]([C:23]#[N:24])[CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][CH2:2][C:3]([N:21]1[CH2:22][C:18]([F:25])([F:17])[CH2:19][C@H:20]1[C:23]#[N:24])=[O:4]
Reactant: O=C(Br)CBr
Reactant: N#C[C@@H]1CC(F)(F)CN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#C[C@@H]1CC(F)(F)CN1C(=O)CBr
Temperature: -10 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a CH2Cl2 solution (5 mL) containing bromoacetyl bromide (365 mg, 1.80 mmol) cooled to −10° C. was added dropwise (2S)-4,4-difluoro2-pyrrolidinecarbonitrile 4-methylbenzenesulfonate (described earlier) (500 mg, 1.64 mmol) and triethylamine (199 mg, 1.97 mmol) in CH2Cl2 (5 mL). After stirring for 2 hours at 10° C. the reaction was quenched with H2O and the organics extracted with CH2Cl2 and washed with 1.0 M HCl. After drying over MgSO4 the solvents were reduced in vacuo yielding 400 mg (1.57 mmol, 96% yield) of the title compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)[N:7]=[C:6]([C:17]1[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1)[N:5]=2.[CH3:29][N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1>CN1CCCC1=O>[CH:26]1([CH2:25][N:3]2[C:2]([N:33]3[CH2:34][CH2:35][CH:31]([N:30]([CH3:36])[CH3:29])[CH2:32]3)=[N:10][C:9]3[C:4]2=[N:5][C:6]([C:17]2[C:18]([CH3:24])=[N:19][C:20]([NH2:23])=[N:21][CH:22]=2)=[N:7][C:8]=3[N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:28][CH2:27]1
Reactant: CN(C)C1CCNC1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Solvent: CN1CCCC1=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3CCC(N(C)C)C3)n(CC3CC3)c2n1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 46 %

Procedure:
N-Methylpyrrolidone (1 ml) was added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and 3-(dimethylamino)pyrrolidine (285 mg, 2.49 mmol) and the resulting mixture was stirred at 120° C. for 3.5 hours. The reaction mixture was partitioned with chloroform and saturated brine and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was concentrated under reduced pressure, then methylene chloride-ether was added to the residue, and the precipitate was collected by filtration, washed with ether, and dried under reduced pressure to give the title compound (55 mg, 46%) as a pale orange solid.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[N:4]=1
Reactant: Cc1cccc(-c2c(-c3ccncc3)[nH]c(=O)n(C)c2=O)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cccc(-c2c(-c3ccncc3)nc(Cl)n(C)c2=O)c1

Procedure:
A mixture of 3-methyl-5-(3-methylphenyl)-6-(4-pyridyl)-2,4(1H,3H)-pyrimidindione (12.5 g, 0.043 mol) and phosphorus oxychloride (65 ml) was refluxed for 16 h. The excess of phosphorus oxychloride was evaporated followed by co-distillation with toluene. The remainder was carefully partitioned between dichloromethane and aqueous sodium hydrogencarbonate. The organic solution was washed with water, dried and evaporated to leave the title compound. MS (m/z): 312 (M)+; C17H14ClN3O requir. 311.8.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].B1(C=C)OB([CH:30]=[CH2:31])OB(C=C)O1.C1C=CN=CC=1.O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:30]([C:7]1[N:12]=[N:11][C:10]2[O:13][CH2:14][CH2:15][C:9]=2[CH:8]=1)=[CH2:31]
Reactant: O=S(=O)(Oc1cc2c(nn1)OCC2)C(F)(F)F
Reactant: C=CB1OB(C=C)OB(C=C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: c1ccncc1
Product: C=Cc1cc2c(nn1)OCC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 5,6-dihydrofuro[2,3-c]pyridazin-3-yl trifluoromethanesulfonate (500 mg, 1.85 mmol) in dimethoxyethane (20 ml) was degassed then treated with tetrakis(triphenylphosphine)palladium (0) (116 mg), potassium carbonate (257 mg), 2,4,6-trivinylcyclotriboroxane pyridine complex (for a preparation of this reagent see F. Kerins and D. F. O'Shea, J. Org. Chem. 2002, 67, 4968-4971) (416 mg) and water (3.6 ml). The mixture was stirred at 80° C. for 2 hours then partitioned between DCM and saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with 10% methanol in DCM then the combined organic extracts dried and evaporated. The residue was chromatographed eluting with ethyl acetate affording a white solid (111 mg, 36%).